|
1
|
Georgakopoulou VE. Optimizing patient outcomes in interstitial lung disease through pre- and post-transplant management strategies. World J Transplant 2025; 15:101866. [DOI: 10.5500/wjt.v15.i3.101866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 02/10/2025] [Accepted: 02/27/2025] [Indexed: 04/18/2025] Open
Abstract
Interstitial lung diseases (ILD) encompass a diverse group of over 200 chronic pulmonary disorders characterized by varying degrees of inflammation and fibrosis, which can lead to severe respiratory impairment. Lung transplantation offers a crucial therapeutic option for patients with advanced ILD, extending survival and improving quality of life. This review explores optimal management strategies in both the pre- and post-transplant phases to enhance patient outcomes. Comprehensive pre-transplant evaluation, including pulmonary function testing, imaging, and comorbidity assessment, is critical for determining transplant eligibility and timing. Post-transplant care must focus on preventing complications such as primary graft dysfunction and chronic lung allograft dysfunction, managed through tailored immunosuppression and proactive monitoring. Recent advancements in diagnostic techniques and therapeutic approaches, including emerging technologies like ex vivo lung perfusion and precision medicine, promise to further improve outcomes. The ultimate goal is to establish an evidence-based, multidisciplinary framework for optimizing ILD management and lung transplantation.
Collapse
Affiliation(s)
- Vasiliki E Georgakopoulou
- Department of Pathophysiology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens 11527, Greece
| |
Collapse
|
|
2
|
Liu H, Sun Y, Cai S, Zhao C, Xu X, Xu A, Zhou H, Yang C, Gu X, Ai X. Formononetin-Loaded PLGA Large Porous Microparticles via Intratracheal Instillation for Bleomycin-Induced Pulmonary Fibrosis Treatment. AAPS PharmSciTech 2025; 26:112. [PMID: 40246731 DOI: 10.1208/s12249-025-03089-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 03/11/2025] [Indexed: 04/19/2025] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown cause, with few effective therapies available and high mortality rates. Our preceding research indicated that formononetin (FMN) could improve the symptoms of the bleomycin-induced pulmonary fibrosis and be a promising drug against IPF. In this study, an inhalable formononetin-loaded poly(lactic-co-glycolic) acid (PLGA) large porous microspheres (FMN-PLGA-MSs) was prepared by the method of emulsion solvent evaporation. SEM showed that FMN-PLGA-MSs were loose particles existing many pores on the surfaces, and the measured mean geometric diameter was more than 10 µm. The encapsulation efficiency (EE) and drug loading efficiency (DL) were 87.72 ± 6.34% and 4.18 ± 0.30%. FMN in FMN-PLGA-MSs could be rapidly released within 2 h and sustainably released for 21 d. Cell tests and q-RT-PCR tests showed that FMN could inhibit the activation of fibroblasts and the deposition of extracellular matrix (ECM) by acting on the TGF-β1/Smad3 signaling pathway. FMN-PLGA-MSs showed higher antifibrotic effects than free FMN oral administration in the pulmonary fibrosis models of mice, remarkably improving pulmonary function, decreasing hydroxyproline levels, and attenuating lung injuries. By formulating formononetin into microsphere preparations, its solubility can be significantly enhanced, enabling effective pulmonary drug delivery. This approach not only improves lung targeting but also reduces systemic toxicity. Additionally, it facilitates superior lung deposition and extends the retention time of the formononetin within the lungs. Taken together, FMN-PLGA-MSs may be a promising inhaled medication for the treatment of IPF.
Collapse
Affiliation(s)
- Hongting Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
- Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Yao Sun
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
- Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Shihao Cai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
| | - Conglu Zhao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
- Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Xiang Xu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
- Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Aiguo Xu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Honggang Zhou
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China.
| | - Xiaoting Gu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China.
| | - Xiaoyu Ai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China.
| |
Collapse
|
|
3
|
Lv Y, Zhang G, Kong D, Jiang W. Filgotinib Improves Experimental Pulmonary Fibrosis by Modulating JAK1/STAT3/SOCS3/IL-17A Signalling. Basic Clin Pharmacol Toxicol 2025; 136:e70012. [PMID: 39995397 DOI: 10.1111/bcpt.70012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 02/12/2025] [Accepted: 02/14/2025] [Indexed: 02/26/2025]
Abstract
BACKGROUND Regulatory agencies in Europe and Japan have approved filgotinib, a selective JAK1 inhibitor, for use in treating rheumatoid arthritis, but its effect and mechanism of action in treating pulmonary fibrosis remain unclear. METHODS We performed an in vivo investigation in rats on filgotinib's effect on pulmonary fibrosis resulting from the intratracheal infusion of bleomycin (BLM). Then, we focused on the mechanisms by which filgotinib inhibits experimentally induced pulmonary fibrosis in vitro by determining its effect on TGF-β1-induced proliferation of mouse lung fibroblasts. RESULTS Continuous gavage of filgotinib at 20 mg/kg for 14 days elicited protective effects in the BLM-induced rat experimental pulmonary fibrosis model, as reflected in changes in Hounsfield units as an indicator of overall pulmonary function and in the lung coefficient and lung microscopic pathology scores as indicators of gross pulmonary pathology. Protein expression levels of IL-17A, phosphorylated tyrosine kinase (p-JAK1), p-STAT3 and cytokine signal transduction inhibitor 3 (SOCS3) were also changed. In in vitro studies, filgotinib at 1 μM reduced TGF-β1-induced fibroblast proliferation and produced lower levels of IL-17A, p-JAK1 and p-STAT3, but higher SOCS3. CONCLUSIONS Filgotinib appeared to alleviate experimental pulmonary fibrosis by reducing fibroblast proliferation via inhibition of the JAK1/STAT3/SOCS3/IL-17A pathway.
Collapse
Affiliation(s)
- Yunying Lv
- School of Pharmacy, Binzhou Medical University, Yantai, China
| | | | - Dexin Kong
- School of Pharmacy, Binzhou Medical University, Yantai, China
| | - Wanglin Jiang
- School of Pharmacy, Binzhou Medical University, Yantai, China
| |
Collapse
|
|
4
|
Liu J, Song X, Fu X, Niu S, Chang H, Shi S, Yang M, Wang P, Bai W. Exploring the Mechanism of Action and Potential Targets of Saorilao-4 Decoction in the Treatment of Pulmonary Fibrosis in Rats by Metabolomics. Food Sci Nutr 2025; 13:e4633. [PMID: 39898125 PMCID: PMC11783149 DOI: 10.1002/fsn3.4633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 10/13/2024] [Accepted: 11/14/2024] [Indexed: 02/04/2025] Open
Abstract
Pulmonary fibrosis (PF) is a chronic progressive disease marked by alveolar epithelial cell damage. Saorilao-4 decoction (SRL), a traditional Mongolian prescription, has demonstrated therapeutic effects on PF, though its mechanism of action remains elusive. This study used a bleomycin-induced fibrosis rat model to evaluate SRL's effects by measuring inflammatory factors, assessing fibrosis-related indices, and performing histopathological lung examinations. Serum metabolite levels in the experimental groups were measured using high-performance liquid chromatography coupled with mass spectrometry. Data analysis involved principal component and partial least-squares discriminant analyses, followed by functional enrichment analysis of differential metabolites. SRL significantly ameliorated alveolar interstitial injury, fibrosis, and metabolic disorders induced by bleomycin. Additionally, we identified 71 metabolic components related to PF progression, including sphingolipids and fatty acids. Administration of SRL affected 59 metabolic components involved in purine, cysteine and methionine, and arginine and proline metabolisms. Specifically, SRL regulated the levels of hexadecanoic acid, S-adenosylmethionine, 3-oxopalmitoyl coenzyme A, and dodecanoic acid metabolites, thereby improving the metabolic course of PF. In conclusion, this study offers insights into the potential mechanisms of SRL in treating PF from a metabolomics perspective. It provides valuable information for its clinical application.
Collapse
Affiliation(s)
- Jiali Liu
- Department of PharmacyBaotou Medical CollegeBaotouChina
| | - Xinni Song
- Department of PharmacyBaotou Medical CollegeBaotouChina
| | - Xinyue Fu
- Department of PharmacyBaotou Medical CollegeBaotouChina
| | - Shufang Niu
- Department of PharmacyBaotou Medical CollegeBaotouChina
| | - Hong Chang
- Department of PharmacyBaotou Medical CollegeBaotouChina
| | - Songli Shi
- Department of PharmacyBaotou Medical CollegeBaotouChina
| | - Meiqing Yang
- Department of PharmacyBaotou Medical CollegeBaotouChina
| | - Peng Wang
- Department of PharmacyBaotou Medical CollegeBaotouChina
- The Second Affiliated Hospital of Baotou Medical CollegeBaotouChina
| | - Wanfu Bai
- Department of PharmacyBaotou Medical CollegeBaotouChina
- Institute of Bioactive Substance and Function of Mongolian Medicine and Chinese Materia MedicaBaotou Medical CollegeBaotouChina
| |
Collapse
|
|
5
|
Jayes FL, Corder RD, Vachieri RB, Khan SA, Taylor DK. Multiple hour antifibrotic drug release enabled by a thermosensitive quadpolymer. Int J Pharm 2025; 669:125097. [PMID: 39694158 DOI: 10.1016/j.ijpharm.2024.125097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/13/2024] [Accepted: 12/15/2024] [Indexed: 12/20/2024]
Abstract
Injectable drug delivery for uterine fibroid therapy is an ambitious, possibly fertility-preserving concept, that could meet the challenges associated with the structure of these tumors and their location in the uterus. This study was conducted to advance a thermosensitive injectable quadpolymer for effective sustained release of anti-fibrotic drug formulations and to evaluate the feasibility of its use for delivery of the anti-fibrotic drug pirfenidone as a therapy to reduce fibroid cell proliferation. A series of quadpolymers were prepared by free radical polymerization of N-isopropylacrylamide (NIPAM) with different amounts of polylactic acid functionalized hydroxyethyl methacrylate (HEMA-PLA), acrylic acid (AAc), and methacrylate functionalized hyperbranched polyglycerol (HPG-MA) to optimize the sol-gel phase transition temperature and mechanical stiffness. Poly(NIPAM-co-HEMA-PLA-co-AAc-co-HPG-MA) with feed ratio (83-7-1-9), at 17% w/v, readily formed an aqueous solution that could be manipulated by syringe at room temperature. The quadpolymer also rapidly formed a stable gel at physiological body temperature, and partially biodegraded over time as confirmed by several spectroscopic characterization techniques. To evaluate the potential range of utility, quadpolymer 83-7-1-9 was loaded in-vitro with caffeine (a prototype hydrophilic drug) or the hydrophobic drug pirfenidone. Pirfenidone-loaded quadpolymer 83-7-1-9 formulations released 50% of drug loaded in double the time as compared to other reported liposome and nanoparticle injectable pirfenidone formulations. Furthermore, treatment of cultured fibroid cells with pirfenidone-loaded quadpolymer 83-7-1-9 formulations confirmed that activity of pirfenidone was preserved and proliferation of fibroid cells was inhibited. These results support that quadpolymer 83-7-1-9 is a promising candidate to be further developed for localized delivery of drugs for uterine fibroid therapy.
Collapse
Affiliation(s)
- Friederike L Jayes
- Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710; Department of Pathology, Duke University Medical Center, Durham, NC 27710
| | - Ria D Corder
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695
| | - Robert B Vachieri
- Department of Chemistry and Biochemistry, North Carolina Central University, Durham, NC 27707.
| | - Saad A Khan
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695
| | - Darlene K Taylor
- Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710; Department of Chemistry and Biochemistry, North Carolina Central University, Durham, NC 27707.
| |
Collapse
|
|
6
|
Wang Z, Guo Y, Li K, Huo Y, Wang S, Dong S, Ma M. Targeting the PI3K/mTOR pathway in idiopathic pulmonary fibrosis: Advances and therapeutic potential. Bioorg Med Chem 2024; 115:117908. [PMID: 39471771 DOI: 10.1016/j.bmc.2024.117908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 11/01/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease characterized by irreversible tissue scarring, leading to severe respiratory dysfunction. Despite current treatments with the drugs Pirfenidone and Nintedanib, effective management of IPF remains inadequate due to limited therapeutic benefits and significant side effects. This review focuses on the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway, a critical regulator of cellular processes linked to fibrosis, such as fibroblast proliferation, inflammation, and epithelial-mesenchymal transition (EMT). We discuss recent advances in understanding the role of the PI3K/mTOR pathway in IPF pathogenesis and highlight emerging therapies targeting this pathway. The review compiles evidence from both preclinical and clinical studies, suggesting that PI3K/mTOR inhibitors may offer new hope for IPF treatment by modulating fibrosis and improving patient outcomes. Moreover, it outlines the potential for these inhibitors to be developed into effective, personalized treatment options, underscoring the importance of further research to explore their efficacy and safety profiles comprehensively.
Collapse
Affiliation(s)
- Zhengyang Wang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
| | - Yanzhi Guo
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
| | - Kaiyin Li
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
| | - Yan Huo
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
| | - Shuyan Wang
- Department of Anesthesiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
| | - Suzhen Dong
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
| | - Mingliang Ma
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China; Wenzhou Key Laboratory of Biophysics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China.
| |
Collapse
|
|
7
|
Shin S, Jo H, Agura T, Jeong S, Ahn H, Pang S, Lee J, Park JH, Kim Y, Kang JS. Anti-Inflammatory Effects of Aptamin C in Pulmonary Fibrosis Induced by Bleomycin. Pharmaceuticals (Basel) 2024; 17:1577. [PMID: 39770419 PMCID: PMC11676684 DOI: 10.3390/ph17121577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/17/2024] [Accepted: 11/20/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: Vitamin C is a well-known antioxidant with antiviral, anticancer, and anti-inflammatory properties. However, its therapeutic applications are limited by rapid oxidation due to heat and light sensitivity. Aptamin C, which employs aptamers to bind vitamin C, has demonstrated enhanced stability and efficacy. This study investigates the potential of Aptamin C to inhibit the progression of pulmonary fibrosis, a prominent inflammatory lung disease with no effective treatment. Methods: Mice bearing bleomycin-induced pulmonary fibrosis were administered vitamin C or Aptamin C, and their weight changes and survival rates were monitored. Inflammatory cell infiltration was assessed in the bronchoalveolar lavage fluid (BALF), and the degree of alveolar fibrosis was measured by H&E and Masson's trichrome staining. To elucidate the mechanism of action of Aptamin C, Western blot analysis was performed in HaCaT and lung tissues from bleomycin-induced pulmonary fibrosis mice. Results: The Aptamin C-treated group showed a notably higher survival rate at 50%, whereas all subjects in the vitamin C-treated group died. Histological examination of lung tissue showed that inflammation was significantly suppressed in the Aptamin C-supplemented group compared to the vitamin C-supplemented group, with a 10% greater reduction in cell infiltrations, along with noticeably less tissue damage. Additionally, it was observed that Aptamin C increased SVCT-1 expression in the HaCaT cells and the lung tissues. Conclusions: Taken together, Aptamin C not only increases the stability of vitamin C but also induces an increase in SVCT-1 expression, facilitating greater vitamin C absorption into cells and tissues, thereby inhibiting the progression of symptoms and associated inflammatory responses in pulmonary fibrosis.
Collapse
Affiliation(s)
- Seulgi Shin
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; (S.S.); (H.J.); (T.A.); (S.J.); (H.A.); (S.P.); (Y.K.)
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 08826, Republic of Korea
- Department of Research and Development, N Therapeutics Co., Ltd., Seoul 08813, Republic of Korea
| | - Hyejung Jo
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; (S.S.); (H.J.); (T.A.); (S.J.); (H.A.); (S.P.); (Y.K.)
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 08826, Republic of Korea
| | - Tomoyo Agura
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; (S.S.); (H.J.); (T.A.); (S.J.); (H.A.); (S.P.); (Y.K.)
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 08826, Republic of Korea
| | - Seoyoun Jeong
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; (S.S.); (H.J.); (T.A.); (S.J.); (H.A.); (S.P.); (Y.K.)
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 08826, Republic of Korea
| | - Hyovin Ahn
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; (S.S.); (H.J.); (T.A.); (S.J.); (H.A.); (S.P.); (Y.K.)
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 08826, Republic of Korea
| | - Soyoung Pang
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; (S.S.); (H.J.); (T.A.); (S.J.); (H.A.); (S.P.); (Y.K.)
| | - June Lee
- Nexmos, Inc., Yongin-si 168267, Republic of Korea; (J.L.); (J.-H.P.)
| | - Jeong-Ho Park
- Nexmos, Inc., Yongin-si 168267, Republic of Korea; (J.L.); (J.-H.P.)
| | - Yejin Kim
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; (S.S.); (H.J.); (T.A.); (S.J.); (H.A.); (S.P.); (Y.K.)
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 08826, Republic of Korea
| | - Jae Seung Kang
- Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; (S.S.); (H.J.); (T.A.); (S.J.); (H.A.); (S.P.); (Y.K.)
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 08826, Republic of Korea
- Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
| |
Collapse
|
|
8
|
Zhang JW. Early pirfenidone treatment enhances lung function in idiopathic pulmonary fibrosis patients. World J Clin Cases 2024; 12:6247-6249. [PMID: 39371563 PMCID: PMC11362896 DOI: 10.12998/wjcc.v12.i28.6247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 07/25/2024] [Accepted: 07/30/2024] [Indexed: 08/13/2024] Open
Abstract
This editorial comments on the study by Lei et al investigating the efficacy of early treatment with pirfenidone on the lung function of patients with idiopathic pulmonary fibrosis (IPF) published. This study evaluates the efficacy of early treatment with pirfenidone on lung function in patients with IPF. The early and advanced stages of IPF are defined, highlighting the drug's benefits. While prior research indicates pirfenidone's effectiveness in advanced IPF, this study focuses on its advantages in early stages. The study emphasizes the importance of computed tomography imaging alongside biochemical data and lung function tests for a comprehensive analysis of symptom relief. Results show that early intervention with pirfenidone significantly reduces disease progression and preserves lung function, underscoring its potential as a critical treatment strategy in early IPF.
Collapse
Affiliation(s)
- Jin-Wei Zhang
- Medical School, University of Exeter, Exeter EX4 4PS, United Kingdom
| |
Collapse
|
|
9
|
Chang SH, Jung S, Chae JJ, Kim JY, Kim SU, Choi JY, Han HJ, Kim HT, Kim HJ, Kim HJ, Park WY, Sparks JA, Lee EY, Lee JS. Therapeutic single-cell landscape: methotrexate exacerbates interstitial lung disease by compromising the stemness of alveolar epithelial cells under systemic inflammation. EBioMedicine 2024; 108:105339. [PMID: 39303666 PMCID: PMC11437874 DOI: 10.1016/j.ebiom.2024.105339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 08/21/2024] [Accepted: 08/30/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND Interstitial lung disease (ILD) poses a serious threat in patients with rheumatoid arthritis (RA). However, the impact of cornerstone drugs, including methotrexate (MTX) and TNF inhibitor, on RA-associated ILD (RA-ILD) remains controversial. METHODS Using an SKG mouse model and single-cell transcriptomics, we investigated the effects of MTX and TNF blockade on ILD. FINDINGS Our study revealed that MTX exacerbates pulmonary inflammation by promoting immune cell infiltration, Th17 activation, and fibrosis. In contrast, TNF inhibitor ameliorates these features and inhibits ILD progression. Analysis of data from a human RA-ILD cohort revealed that patients with ILD progression had persistently higher systemic inflammation than those without progression, particularly among the subgroup undergoing MTX treatment. INTERPRETATION These findings highlight the need for personalized therapeutic approaches in RA-ILD, given the divergent outcomes of MTX and TNF inhibitor. FUNDING This work was funded by GENINUS Inc., and the National Research Foundation of Korea, and Seoul National University Hospital.
Collapse
Affiliation(s)
- Sung Hae Chang
- Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, 31151, South Korea
| | - Seyoung Jung
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Jeong Jun Chae
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, South Korea
| | - Jeong Yeon Kim
- Inocras, Inc., San Diego, CA, 92121, USA; Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Seon Uk Kim
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Ji Yong Choi
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Hye-Jeong Han
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Hyun Taek Kim
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Hak-Jae Kim
- Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Hyun Je Kim
- Department of Biomedical Science, Seoul National University, Seoul, 03080, Republic of Korea
| | - Woong Yang Park
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Jeffrey A Sparks
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Eun Young Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
| | - Jeong Seok Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea; Inocras, Inc., San Diego, CA, 92121, USA.
| |
Collapse
|
|
10
|
Xie Y, Shi S, Lv W, Wang X, Yue L, Deng C, Wang D, Han J, Ye T, Lin Y. Tetrahedral Framework Nucleic Acids Delivery of Pirfenidone for Anti-Inflammatory and Antioxidative Effects to Treat Idiopathic Pulmonary Fibrosis. ACS NANO 2024; 18:26704-26721. [PMID: 39276332 DOI: 10.1021/acsnano.4c06598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/17/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease, and developing an effective treatment remains a challenge. The limited therapeutic options are primarily delivered by the oral route, among which pirfenidone (PFD) improves pulmonary dysfunction and patient quality of life. However, its high dose and severe side effects (dyspepsia and systemic photosensitivity) limit its clinical value. Intratracheal aerosolization is an excellent alternative method for treating lung diseases because it increases the concentration of the drug needed to reach the focal site. Tetrahedral framework nucleic acid (tFNA) is a drug delivery system with exceptional delivery capabilities. Therefore, we synthesized a PFD-tFNA (Pt) complex using tFNA as the delivery vehicle and achieved quantitative nebulized drug delivery to the lungs via micronebulizer for lung fibrosis treatment. In vivo, Pt exhibited excellent immunomodulatory capacity and antioxidant effects. Furthermore, Pt reduced mortality, gradually restored body weight and improved lung tissue structure. Similarly, Pt also exhibited superior fibrosis inhibition in an in vitro fibrosis model, as shown by the suppression of excessive fibroblast activation and epithelial-mesenchymal transition (EMT) in epithelial cells exposed to TGF-β1. Conclusively, Pt, a complex with tFNA as a transport system, could enrich the therapeutic regimen for IPF via intratracheal aerosolization inhalation.
Collapse
Affiliation(s)
- Yuting Xie
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Sirong Shi
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Sichuan Provincial Engineering Research Center of Oral Biomaterials, Chengdu 610041, China
| | - Weitong Lv
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xinyu Wang
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lin Yue
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Conghui Deng
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Doudou Wang
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Han
- Department of Respiratory and Critical Care Medicine, Guizhou Provincial People's Hospital, Guiyang 550000, China
- National Health Commission Key Laboratory for Diagnosis and Treatment of Pulmonary Immune Diseases, Guiyang 550000, China
| | - Tinghong Ye
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Sichuan Provincial Engineering Research Center of Oral Biomaterials, Chengdu 610041, China
| |
Collapse
|
|
11
|
Babariya H, Gaidhane SA, Acharya S, Kumar S. Pirfenidone as a Cornerstone in the Management of Fibrotic Interstitial Lung Diseases and Its Emerging Applications: A Comprehensive Review. Cureus 2024; 16:e70497. [PMID: 39479105 PMCID: PMC11524648 DOI: 10.7759/cureus.70497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 09/30/2024] [Indexed: 11/02/2024] Open
Abstract
Pirfenidone is a groundbreaking antifibrotic agent that has become a cornerstone in managing fibrotic interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF). This review comprehensively analyzes pirfenidone's mechanisms of action, clinical efficacy, safety profile, and emerging applications beyond IPF. Pirfenidone exerts its therapeutic effects by inhibiting key pathways involved in fibrosis, including transforming growth factor-beta (TGF-β) and other pro-fibrotic cytokines. It also reduces oxidative stress and inflammation. Clinical trials have consistently demonstrated pirfenidone's ability to slow the decline in lung function, reduce disease progression, and improve survival rates in IPF patients. Furthermore, emerging evidence supports its potential use in other fibrotic ILDs and non-pulmonary fibrotic conditions, such as liver and kidney fibrosis. Despite its proven benefits, pirfenidone's safety and tolerability profiles require careful monitoring, with gastrointestinal and photosensitivity reactions being the most common adverse effects. Future research is poised to explore combination therapies, personalized treatment approaches, and novel applications of pirfenidone in a broader range of fibrotic disorders. As the field of antifibrotic therapy advances, pirfenidone remains a pivotal agent with the potential to significantly impact the management of fibrotic diseases across multiple organ systems. This review aims to provide clinicians and researchers with a detailed understanding of pirfenidone's current role and prospects in treating fibrosis.
Collapse
Affiliation(s)
- Harsh Babariya
- Internal Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Shilpa A Gaidhane
- Internal Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sourya Acharya
- Internal Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sunil Kumar
- Internal Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| |
Collapse
|
|
12
|
Lipinski M, Luks V, Rosenberg H. Just the facts: approach to the patient with Interstitial Lung Disease (ILD) in the emergency department. CAN J EMERG MED 2024; 26:452-454. [PMID: 38720142 DOI: 10.1007/s43678-024-00695-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 03/28/2024] [Indexed: 07/10/2024]
Affiliation(s)
- Matthew Lipinski
- Department of Emergency Medicine, The Ottawa Hospital, Ottawa, ON, Canada.
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
| | - Vanessa Luks
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- OHRI, Ottawa, ON, Canada
- Division of Respirology, The Ottawa Hospital, Ottawa, ON, Canada
| | - Hans Rosenberg
- Department of Emergency Medicine, The Ottawa Hospital, Ottawa, ON, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| |
Collapse
|
|
13
|
Pu HY, Cao Y, Jiang XL, Yang LH, Wang MK, Wang F, Wang L. Steroidal saponins and homoisoflavonoids from the fibrous roots of ophiopogon japonicus and their anti-pulmonary fibrosis activities. Nat Prod Res 2024:1-11. [PMID: 38498767 DOI: 10.1080/14786419.2024.2331044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 03/04/2024] [Indexed: 03/20/2024]
Abstract
The chemical investigation of the fibrous roots of Ophiopogon japonicus afforded two new steroidal saponins, named ophiojaponin F (1) and ophiojaponin G (2), together with twelve known steroidal saponins (3-14) and ten known homoisoflavonoids (15-24). The structures of the isolated compounds were established unambiguously via spectroscopic analyses (NMR and HR-ESI-MS). Ophiojaponin F (1) is a 23-hydroxylated spirostanol saponin, and this type of steroidal saponin rarely been reported in liriopogons. All isolates were evaluated for their anti-pulmonary fibrosis activities on TGF-β1-actived NIH3T3 cells for the first time. Among them, compounds 3, 4, 11-13, 15-19, 21 and 24 showed potential anti-pulmonary fibrosis effects with IC50 values ranging from 3.61 ± 0.86 μM to 21.33 ± 1.82 μM, and the main component ophiopogonin D (4) displayed the best activity with an IC50 value of 3.61 ± 0.86 μM. Thus, ophiopogonin D may be a potent candidate for the treatment of pulmonary fibrosis.
Collapse
Affiliation(s)
- Hang-Yi Pu
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yu Cao
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xi-Lang Jiang
- Key Laboratory of Chemical Metrology and Applications on Nutrition and Health for State Market Regulation, Chengdu, China
| | - Lin-Han Yang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ming-Kui Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
| | - Fei Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
| | - Lun Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
- Key Laboratory of Chemical Metrology and Applications on Nutrition and Health for State Market Regulation, Chengdu, China
| |
Collapse
|
|
14
|
Jain N, Shashi Bhushan BL, Natarajan M, Mehta R, Saini DK, Chatterjee K. Advanced 3D In Vitro Lung Fibrosis Models: Contemporary Status, Clinical Uptake, and Prospective Outlooks. ACS Biomater Sci Eng 2024; 10:1235-1261. [PMID: 38335198 DOI: 10.1021/acsbiomaterials.3c01499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2024]
Abstract
Fibrosis has been characterized as a global health problem and ranks as one of the primary causes of organ dysfunction. Currently, there is no cure for pulmonary fibrosis, and limited therapeutic options are available due to an inadequate understanding of the disease pathogenesis. The absence of advanced in vitro models replicating dynamic temporal changes observed in the tissue with the progression of the disease is a significant impediment in the development of novel antifibrotic treatments, which has motivated research on tissue-mimetic three-dimensional (3D) models. In this review, we summarize emerging trends in preparing advanced lung models to recapitulate biochemical and biomechanical processes associated with lung fibrogenesis. We begin by describing the importance of in vivo studies and highlighting the often poor correlation between preclinical research and clinical outcomes and the limitations of conventional cell culture in accurately simulating the 3D tissue microenvironment. Rapid advancement in biomaterials, biofabrication, biomicrofluidics, and related bioengineering techniques are enabling the preparation of in vitro models to reproduce the epithelium structure and operate as reliable drug screening strategies for precise prediction. Improving and understanding these model systems is necessary to find the cross-talks between growing cells and the stage at which myofibroblasts differentiate. These advanced models allow us to utilize the knowledge and identify, characterize, and hand pick medicines beneficial to the human community. The challenges of the current approaches, along with the opportunities for further research with potential for translation in this field, are presented toward developing novel treatments for pulmonary fibrosis.
Collapse
Affiliation(s)
- Nipun Jain
- Department of Materials Engineering, Indian Institute of Science, C.V Raman Avenue, Bangalore 560012 India
| | - B L Shashi Bhushan
- Department of Pulmonary Medicine, Victoria Hospital, Bangalore Medical College and Research Institute, Bangalore 560002 India
| | - M Natarajan
- Department of Pathology, Victoria Hospital, Bangalore Medical College and Research Institute, Bangalore 560002 India
| | - Ravi Mehta
- Department of Pulmonology and Critical Care, Apollo Hospitals, Jayanagar, Bangalore 560011 India
| | - Deepak Kumar Saini
- Department of Developmental Biology and Genetics, Indian Institute of Science, C.V Raman Avenue, Bangalore 560012 India
| | - Kaushik Chatterjee
- Department of Materials Engineering, Indian Institute of Science, C.V Raman Avenue, Bangalore 560012 India
| |
Collapse
|
|
15
|
Huang TH, Wei SH, Kuo HI, Hou HY, Kuo CW, Tseng YL, Lin SH, Wu CL. Baseline Blood Levels of Mucin-1 Are Associated with Crucial On-Treatment Adverse Outcomes in Patients with Idiopathic Pulmonary Fibrosis Receiving Antifibrotic Pirfenidone. Biomedicines 2024; 12:402. [PMID: 38398004 PMCID: PMC10886731 DOI: 10.3390/biomedicines12020402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 02/04/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Mucin-1 is a multi-functional glycoprotein expressed by type II alveolocytes and may be detectable in the circulation following pulmonary fibrosis. The prognostic utility of baseline pre-treatment blood levels of mucin-1 in patients with idiopathic pulmonary fibrosis (IPF) receiving antifibrotics has not yet been fully established. We retrospectively studied a cohort of patients (from two hospitals) with IPF who were receiving pirfenidone for >12 weeks. Baseline blood mucin-1 levels were measured via sandwich enzyme-linked immunosorbent assays. We investigated the performance of mucin-1 levels in longitudinally predicting the risks of acute exacerbation of IPF (AE-IPF) and severe adverse outcomes (SAO), including lung transplantation and death. Seventy patients were included; 20 developed AE-IPF; and 31 had SAO during the follow-up period. Patients with baseline mucin-1 levels ≥2.5 ng/mL had enhanced risks of AE-IPF (adjusted hazard ratio [aHR], 14.07; 95% confidence interval [CI], 4.26-46.49) and SAO within 2 years (aHR, 7.87; 95% CI, 2.86-21.70) and anytime during the follow-up (aHR, 4.68; 95% CI, 2.11-10.39). The risks increased across subgroups with increasing mucin-1 levels. Patients in the "mucin-1 ≥ 2.5" group also exhibited an accelerated decline in DLCO. This study supports baseline blood mucin-1 levels as a biomarker for IPF that predicts adverse outcomes during pirfenidone treatment.
Collapse
Affiliation(s)
- Tang-Hsiu Huang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 35 Siaodong Rd., Tainan 704, Taiwan; (T.-H.H.); (C.-W.K.); (S.-H.L.)
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Rd., Tainan 704, Taiwan; (S.-H.W.); (H.-Y.H.)
| | - Sheng-Huan Wei
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Rd., Tainan 704, Taiwan; (S.-H.W.); (H.-Y.H.)
| | - Hung-I Kuo
- Chest Hospital, Ministry of Health and Welfare, 864 Zhongshan Rd., Rende Dist., Tainan 717, Taiwan;
| | - Hsin-Yu Hou
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Rd., Tainan 704, Taiwan; (S.-H.W.); (H.-Y.H.)
| | - Chin-Wei Kuo
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 35 Siaodong Rd., Tainan 704, Taiwan; (T.-H.H.); (C.-W.K.); (S.-H.L.)
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Rd., Tainan 704, Taiwan; (S.-H.W.); (H.-Y.H.)
| | - Yau-Lin Tseng
- Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Rd., Tainan 704, Taiwan;
| | - Sheng-Hsiang Lin
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 35 Siaodong Rd., Tainan 704, Taiwan; (T.-H.H.); (C.-W.K.); (S.-H.L.)
- Department of Public Health, College of Medicine, National Cheng Kung University, 138 Sheng Li Rd., Tainan 704, Taiwan
- Biostatistics Consulting Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Rd., Tainan 704, Taiwan
| | - Chao-Liang Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, 1 Dasyue Road, East District, Tainan 701, Taiwan
- Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539 Chung Hsiao Rd., Chiayi 600, Taiwan
| |
Collapse
|
|
16
|
Li H, Wang YG, Chen TF, Gao YH, Song L, Yang YF, Gao Y, Huo W, Zhang GP. Panax notoginseng saponin alleviates pulmonary fibrosis in rats by modulating the renin-angiotensin system. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:116979. [PMID: 37532070 DOI: 10.1016/j.jep.2023.116979] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/27/2023] [Accepted: 07/28/2023] [Indexed: 08/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pulmonary fibrosis (PF) is a chronic, progressive, and often fatal interstitial lung disease. Traditional Chinese medicine formulations and their active ingredients have shown potential in the treatment of PF. Panax notoginseng saponin (PNS) is extracted from the widely used traditional Chinese medicinal herb Panax notoginseng (Burkill) F. H. Chen, exhibiting therapeutic effects in pulmonary diseases treatment. AIM OF THE STUDY This study aimed to investigate the effects and elucidate possible potential mechanisms of PNS on bleomycin (BLM)-induced PF in rats. MATERIALS AND METHODS PF was induced in rats by intratracheal administration of bleomycin (BLM, 5 mg/kg). After disease model induction, the rats were treated with PNS (50, 100, or 200 mg/kg per day) or pirfenidone (PFD, 50 mg/kg per day) for 28 days. Lung function, histopathological changes, collagen deposition, and E- and N-cadherin levels in lung tissue were evaluated. The mechanism of action of PNS was investigated using tandem mass tag-based quantitative proteomics analysis. Immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and Western blot analysis were performed to verify the proteomic results. RESULTS PNS treatment improved lung function, ameliorated the BLM-induced increase in the lung coefficient, attenuated the degree of alveolar inflammation and fibrosis, and reduced the elevated collagen level in PF rats. PNS treatment also down-regulated the expression of N-cadherin while up-regulating the expression of E-cadherin. Proteomic and bioinformatic analyses revealed that the renin-angiotensin system (RAS) was closely related to the therapeutic effect of PNS. Immunohistochemistry, Western blot, and ELISA results indicated that PNS exerted its anti-fibrotic effect via regulation of the balance between the angiotensin-converting enzyme (ACE)-angiotensin (Ang)II-AngII receptor type 1 (AT1R) and ACE2-Ang(1-7)-MasR axes. CONCLUSIONS PNS ameliorates BLM-induced PF in rats by modulating the RAS homeostasis, and is a new potential therapeutic agent for PF.
Collapse
Affiliation(s)
- Han Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100007, China.
| | - Yu-Guang Wang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
| | - Teng-Fei Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100007, China.
| | - Yun-Hang Gao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100007, China.
| | - Ling Song
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100007, China.
| | - Yi-Fei Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100007, China.
| | - Yue Gao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
| | - Wang Huo
- Department of Traditional Chinese Medicine, The Sixth Medical Center of PLA General Hospital, Beijing, 100048, China.
| | - Guang-Ping Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100007, China.
| |
Collapse
|
|
17
|
Diwan R, Bhatt HN, Beaven E, Nurunnabi M. Emerging delivery approaches for targeted pulmonary fibrosis treatment. Adv Drug Deliv Rev 2024; 204:115147. [PMID: 38065244 PMCID: PMC10787600 DOI: 10.1016/j.addr.2023.115147] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 11/02/2023] [Accepted: 11/29/2023] [Indexed: 01/01/2024]
Abstract
Pulmonary fibrosis (PF) is a progressive, and life-threatening interstitial lung disease which causes scarring in the lung parenchyma and thereby affects architecture and functioning of lung. It is an irreversible damage to lung functioning which is related to epithelial cell injury, immense accumulation of immune cells and inflammatory cytokines, and irregular recruitment of extracellular matrix. The inflammatory cytokines trigger the differentiation of fibroblasts into activated fibroblasts, also known as myofibroblasts, which further increase the production and deposition of collagen at the injury sites in the lung. Despite the significant morbidity and mortality associated with PF, there is no available treatment that efficiently and effectively treats the disease by reversing their underlying pathologies. In recent years, many therapeutic regimens, for instance, rho kinase inhibitors, Smad signaling pathway inhibitors, p38, BCL-xL/ BCL-2 and JNK pathway inhibitors, have been found to be potent and effective in treating PF, in preclinical stages. However, due to non-selectivity and non-specificity, the therapeutic molecules also result in toxicity mediated severe side effects. Hence, this review demonstrates recent advances on PF pathology, mechanism and targets related to PF, development of various drug delivery systems based on small molecules, RNAs, oligonucleotides, peptides, antibodies, exosomes, and stem cells for the treatment of PF and the progress of various therapeutic treatments in clinical trials to advance PF treatment.
Collapse
Affiliation(s)
- Rimpy Diwan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States
| | - Himanshu N Bhatt
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States
| | - Elfa Beaven
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States
| | - Md Nurunnabi
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States; The Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX 79968, United States.
| |
Collapse
|
|
18
|
The Efficacy and Safety of Herbal Medicine with Pirfenidone in the Treatment of Idiopathic Pulmonary Fibrosis: A Systematic Review. Processes (Basel) 2022. [DOI: 10.3390/pr10122477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Although there were randomized control trials (RCTs) that showed the considerable efficacy of herbal medicine (HM) in idiopathic pulmonary fibrosis (IPF) and systematic reviews on the value of some herbs in the treatment of IPF, there have been no systematic reviews comparing the combined use of complex HM against pirfenidone monotherapy in IPF. This review evaluated the efficacy of parallel administration of HM and pirfenidone in IPF treatment. We conducted a systematic review of RCTs that compared pirfenidone monotherapy against pirfenidone combined administration with HM in IPF. We searched the EMBASE, CENTRAL, PubMed, and CNKI databases for relevant RCTs published before July 2021. Six RCTs were eligible for inclusion. Compared with the control group, a greater recovery or a smaller reduction in forced vital capacity (FVC) and, in general, a valid improvement in the St. George’s Respiratory Questionnaire was observed in the treatment group. However, it should be noted that the risk of bias of the included RCTs was high or unclear in most categories. In IPF treatment, HM administered with pirfenidone effectively protected pulmonary function and improved the quality of life. However, given the number and quality of the included studies, the evidence was not strong enough to draw definitive conclusions. Well-designed future RCTs are warranted to evaluate the impact of HM on IPF.
Collapse
|
|
19
|
Antar SA, Saleh MA, Al-Karmalawy AA. Investigating the possible mechanisms of pirfenidone to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2. Life Sci 2022; 309:121048. [PMID: 36209833 PMCID: PMC9536875 DOI: 10.1016/j.lfs.2022.121048] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/23/2022] [Accepted: 10/02/2022] [Indexed: 01/10/2023]
Abstract
Pirfenidone (PFD) is a non-peptide synthetic chemical that inhibits the production of transforming growth factor-beta 1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), platelet-derived growth factor (PDGF), Interleukin 1 beta (IL-1β), and collagen 1 (COL1A1), all of which have been linked to the prevention or removal of excessive scar tissue deposition in many organs. PFD has been demonstrated to decrease apoptosis, downregulate angiotensin-converting enzyme (ACE) receptor expression, reduce inflammation through many routes, and alleviate oxidative stress in pneumocytes and other cells while protecting them from COVID-19 invasion and cytokine storm. Based on the mechanism of action of PFD and the known pathophysiology of COVID-19, it was recommended to treat COVID-19 patients. The use of PFD as a treatment for a range of disorders is currently being studied, with an emphasis on outcomes related to reduced inflammation and fibrogenesis. As a result, rather than exploring the molecule's chemical characteristics, this review focuses on innovative PFD efficacy data. Briefly, herein we tried to investigate, discuss, and illustrate the possible mechanisms of actions for PFD to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2 candidate.
Collapse
Affiliation(s)
- Samar A Antar
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt.
| | - Mohamed A Saleh
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, the United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Ahmed A Al-Karmalawy
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt.
| |
Collapse
|
|
20
|
Gu J, Wu Q, Zhang Q, You Q, Wang L. A decade of approved first-in-class small molecule orphan drugs: Achievements, challenges and perspectives. Eur J Med Chem 2022; 243:114742. [PMID: 36155354 DOI: 10.1016/j.ejmech.2022.114742] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/01/2022] [Accepted: 09/01/2022] [Indexed: 12/01/2022]
Abstract
In the past decade (2011-2020), there was a growing interest in the discovery and development of orphan drugs for the treatment of rare diseases. However, rare diseases only account for a population of 0.65‰-1‰ which usually occur with previously unknown biological mechanisms and lack of specific therapeutics, thus to increase the demands for the first-in-class (FIC) drugs with new biological targets or mechanisms. Considering the achievements in the past 10 years, a total of 410 drugs were approved by U.S. Food and Drug Administration (FDA), which contained 151 FIC drugs and 184 orphan drugs, contributing to make up significant numbers of the approvals. Notably, more than 50% of FIC drugs are developed as orphan drugs and some of them have already been milestones in drug development. In this review, we aim to discuss the FIC small molecules for the development of orphan drugs case by case and highlight the R&D strategy with novel targets and scientific breakthroughs.
Collapse
Affiliation(s)
- Jinying Gu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qiuyu Wu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qiuyue Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qidong You
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Lei Wang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| |
Collapse
|
|
21
|
Vazquez-Armendariz AI, Barroso MM, El Agha E, Herold S. 3D In Vitro Models: Novel Insights into Idiopathic Pulmonary Fibrosis Pathophysiology and Drug Screening. Cells 2022; 11:1526. [PMID: 35563831 PMCID: PMC9099957 DOI: 10.3390/cells11091526] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 04/29/2022] [Accepted: 04/30/2022] [Indexed: 12/31/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and often lethal interstitial lung disease of unknown aetiology. IPF is characterised by myofibroblast activation, tissue stiffening, and alveolar epithelium injury. As current IPF treatments fail to halt disease progression or induce regeneration, there is a pressing need for the development of novel therapeutic targets. In this regard, tri-dimensional (3D) models have rapidly emerged as powerful platforms for disease modelling, drug screening and discovery. In this review, we will touch on how 3D in vitro models such as hydrogels, precision-cut lung slices, and, more recently, lung organoids and lung-on-chip devices have been generated and/or modified to reveal distinct cellular and molecular signalling pathways activated during fibrotic processes. Markedly, we will address how these platforms could provide a better understanding of fibrosis pathophysiology and uncover effective treatment strategies for IPF patients.
Collapse
Affiliation(s)
- Ana Ivonne Vazquez-Armendariz
- Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), Cardio-Pulmonary Institute (CPI), Institute for Lung Health (ILH), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392 Giessen, Hessen, Germany; (M.M.B.); (E.E.A.); (S.H.)
| | | | | | | |
Collapse
|
|
22
|
Gupta V, Hammond CL, Roztocil E, Gonzalez MO, Feldon SE, Woeller CF. Thinking inside the box: Current insights into targeting orbital tissue remodeling and inflammation in thyroid eye disease. Surv Ophthalmol 2022; 67:858-874. [PMID: 34487739 PMCID: PMC8891393 DOI: 10.1016/j.survophthal.2021.08.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 08/24/2021] [Accepted: 08/30/2021] [Indexed: 12/21/2022]
Abstract
Thyroid eye disease (TED) is an autoimmune disorder that manifests in the orbit. In TED, the connective tissue behind the eye becomes inflamed and remodels with increased fat accumulation and/or increased muscle and scar tissue. As orbital tissue expands, patients develop edema, exophthalmos, diplopia, and optic neuropathy. In severe cases vision loss may occur secondary to corneal scarring from exposure or optic nerve compression. Currently there is no cure for TED, and treatments are limited. A major breakthrough in TED therapy occurred with the FDA approval of teprotumumab, a monoclonal insulin-like growth factor 1 receptor (IGF1R) blocking antibody. Yet, teprotumumab therapy has limitations, including cost, infusion method of drug delivery, variable response, and relapse. We describe approaches to target orbital fibroblasts and the complex pathophysiology that underlies tissue remodeling and inflammation driving TED. Further advances in the elucidation of the mechanisms of TED may lead to prophylaxis based upon early biomarkers as well as lead to more convenient, less expensive therapies.
Collapse
Affiliation(s)
- Vardaan Gupta
- Flaum Eye Institute, University of Rochester, 210 Crittenden Boulevard, Rochester, New York 14642, USA
| | - Christine L Hammond
- Flaum Eye Institute, University of Rochester, 210 Crittenden Boulevard, Rochester, New York 14642, USA
| | - Elisa Roztocil
- Flaum Eye Institute, University of Rochester, 210 Crittenden Boulevard, Rochester, New York 14642, USA
| | - Mithra O Gonzalez
- Flaum Eye Institute, University of Rochester, 210 Crittenden Boulevard, Rochester, New York 14642, USA
| | - Steven E Feldon
- Flaum Eye Institute, University of Rochester, 210 Crittenden Boulevard, Rochester, New York 14642, USA
| | - Collynn F Woeller
- Flaum Eye Institute, University of Rochester, 210 Crittenden Boulevard, Rochester, New York 14642, USA.
| |
Collapse
|
|
23
|
Atkova EL, Fedorov AA, Astrakhantsev AF, Rein DA, Krakhovetskiy NN. [Experimental investigation of the efficacy of pirfenidone in prevention of ostium cicatricial closure after dacryocystorhinostomy]. Vestn Oftalmol 2021; 137:31-39. [PMID: 34726855 DOI: 10.17116/oftalma202113705131] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
One of the main reasons of failure of dacryocystorhinostomy (DCR) is cicatricial closure of the ostium. Finding a way to prevent this outcome remains one of the leading aims of research in dacryology. The effectiveness of the most widespread methods is often considered contradictory by various researchers. Pirfenidone is a small-molecule agent that demonstrated good antifibrotic effect and low toxicity in previous in vitro research. There haven't been any in vivo studies of its intraoperative use in DCR. Purpose - to determine the in vivo efficacy of pirfenidone in prevention of ostium cicatricial closure following dacryocystorhinostomy in an animal experiment. MATERIAL AND METHODS The study was conducted on 18 Chinchilla rabbits. They were divided into 3 groups and each animal underwent modified dacryocystorhinostomy. On the final stage of surgery rabbits of group 1 were injected 1 ml of 0.15 mg/ml pirfenidone solution, rabbits of group 2 - 0.3 mg/ml pirfenidone solution. No injections were performed in group 3. Animals were terminated on days 7 (6 rabbits), 14 (6 rabbits) and 28 (6 rabbits) following surgery. Lacrimal stoma patency was evaluated in vivo by irrigation, and morphologically postmortem. Tissue samples obtained from the stoma area were examined histologically for signs of fibrosis. RESULTS Failure of dacryocystorhinostomy was observed in 4 out of 18 cases: all rabbits of group 3 terminated on days 14 and 28. The most pronounced morphological signs of fibrosis were also noted in group 3. No topical or systemic adverse effects of the medication were observed in groups 1 and 2. CONCLUSION Pirfenidone demonstrated high antifibrotic efficacy and low toxicity in experimental dacrycystorhinostomy in rabbits. These results provide grounds for further research into the use of pirfenidone in dacrycystorhinostomy.
Collapse
Affiliation(s)
- E L Atkova
- Research Institute of Eye Diseases, Moscow, Russia
| | - A A Fedorov
- Research Institute of Eye Diseases, Moscow, Russia
| | | | - D A Rein
- Research Institute of Eye Diseases, Moscow, Russia
| | | |
Collapse
|
|
24
|
Awonuga AO, Chatzicharalampous C, Thakur M, Rambhatla A, Qadri F, Awonuga M, Saed G, Diamond MP. Genetic and Epidemiological Similarities, and Differences Between Postoperative Intraperitoneal Adhesion Development and Other Benign Fibro-proliferative Disorders. Reprod Sci 2021; 29:3055-3077. [PMID: 34515982 DOI: 10.1007/s43032-021-00726-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/22/2021] [Indexed: 12/11/2022]
Abstract
Intraperitoneal adhesions complicate over half of abdominal-pelvic surgeries with immediate, short, and long-term sequelae of major healthcare concern. The pathogenesis of adhesion development is similar to the pathogenesis of wound healing in all tissues, which if unchecked result in production of fibrotic conditions. Given the similarities, we explore the published literature to highlight the similarities in the pathogenesis of intra-abdominal adhesion development (IPAD) and other fibrotic diseases such as keloids, endometriosis, uterine fibroids, bronchopulmonary dysplasia, and pulmonary, intraperitoneal, and retroperitoneal fibrosis. Following a literature search using PubMed database for all relevant English language articles up to November 2020, we reviewed relevant articles addressing the genetic and epidemiological similarities and differences in the pathogenesis and pathobiology of fibrotic diseases. We found genetic and epidemiological similarities and differences between the pathobiology of postoperative IPAD and other diseases that involve altered fibroblast-derived cells. We also found several genes and single nucleotide polymorphisms that are up- or downregulated and whose products directly or indirectly increase the propensity for postoperative adhesion development and other fibrotic diseases. An understanding of the similarities in pathophysiology of adhesion development and other fibrotic diseases contributes to a greater understanding of IPAD and these disease processes. At a very fundamental level, blocking changes in the expression or function of genes necessary for the transformation of normal to altered fibroblasts may curtail adhesion formation and other fibrotic disease since this is a prerequisite for their development. Similarly, applying measures to induce apoptosis of altered fibroblast may do the same; however, apoptosis should be at a desired level to simultaneously ameliorate development of fibrotic diseases while allowing for normal healing. Scientists may use such information to develop pharmacologic interventions for those most at risk for developing these fibrotic conditions.
Collapse
Affiliation(s)
- Awoniyi O Awonuga
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
| | - Charalampos Chatzicharalampous
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Mili Thakur
- Reproductive Genomics Program, The Fertility Center, Grand Rapids, MI, USA.,Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
| | - Anupama Rambhatla
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Farnoosh Qadri
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Modupe Awonuga
- Division of Neonatology, Department of Pediatrics and Human Development, Michigan State University, 1355 Bogue Street, East Lansing, MI, USA
| | - Ghassan Saed
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Michael P Diamond
- Department of Obstetrics and Gynecology, Augusta University, 1120 15th Street, CJ-1036, Augusta, GA, 30912, USA
| |
Collapse
|
|
25
|
Ghumman M, Dhamecha D, Gonsalves A, Fortier L, Sorkhdini P, Zhou Y, Menon JU. Emerging drug delivery strategies for idiopathic pulmonary fibrosis treatment. Eur J Pharm Biopharm 2021; 164:1-12. [PMID: 33882301 PMCID: PMC8154728 DOI: 10.1016/j.ejpb.2021.03.017] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 03/03/2021] [Accepted: 03/29/2021] [Indexed: 12/18/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a debilitating and fatal condition that causes severe scarring of the lungs. While the pathogenesis of IPF continues to be extensively studied and several factors have been considered, an exact cause has yet to be established. With inadequate treatment options and no cure available, overall disease prognosis is still poor. Existing oral therapies, pirfenidone and nintedanib, may attempt to improve the patients' quality of life by mitigating symptoms and slowing disease progression, however chronic doses and systemic deliveries of these drugs can lead to severe side effects. The lack of effective treatment options calls for further investigation of restorative as well as additional palliative therapies for IPF. Nanoparticle-based sustained drug delivery strategies can be utilized to ensure targeted delivery for site-specific treatment as well as long-acting therapy, improving overall patient compliance. This review provides an update on promising strategies for the delivery of anti-fibrotic agents, along with an overview of key therapeutic targets as well as relevant emerging therapies currently being evaluated for IPF treatment.
Collapse
Affiliation(s)
- Moez Ghumman
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
| | - Dinesh Dhamecha
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
| | - Andrea Gonsalves
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
| | - Lauren Fortier
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
| | - Parand Sorkhdini
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA
| | - Yang Zhou
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
| | - Jyothi U Menon
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
| |
Collapse
|
|
26
|
Bos S, De Sadeleer LJ, Vanstapel A, Beeckmans H, Sacreas A, Yserbyt J, Wuyts WA, Vos R. Antifibrotic drugs in lung transplantation and chronic lung allograft dysfunction: a review. Eur Respir Rev 2021; 30:30/160/210050. [PMID: 34415849 DOI: 10.1183/16000617.0050-2021] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/02/2021] [Indexed: 12/30/2022] Open
Abstract
This review aims to provide an overview of pre-transplant antifibrotic therapy on peri-transplant outcomes and to address the possible role of antifibrotics in lung transplant recipients with chronic lung allograft dysfunction.Lung transplantation is an established treatment modality for patients with various end-stage lung diseases, of which idiopathic pulmonary fibrosis and other progressive fibrosing interstitial lung diseases are growing indications. Theoretically, widespread use of antifibrotics prior to lung transplantation may increase the risk of bronchial anastomotic complications and impaired wound healing.Long-term graft and patient survival are still hampered by development of chronic lung allograft dysfunction, on which antifibrotics may have a beneficial impact.Antifibrotics until the moment of lung transplantation proved to be safe, without increasing peri-transplant complications. Currently, best practice is to continue antifibrotics until time of transplantation. In a large multicentre randomised trial, pirfenidone did not appear to have a beneficial effect on lung function decline in established bronchiolitis obliterans syndrome. The results of antifibrotic therapy in restrictive allograft syndrome are eagerly awaited, but nonrandomised data from small case reports/series are promising.
Collapse
Affiliation(s)
- Saskia Bos
- Dept of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Laurens J De Sadeleer
- Dept of Respiratory Diseases, Ziekenhuis Oost-Limburg, Genk, Belgium.,Dept of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Arno Vanstapel
- Dept of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Hanne Beeckmans
- Dept of Internal Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Annelore Sacreas
- Dept of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Jonas Yserbyt
- Dept of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.,Dept of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Wim A Wuyts
- Dept of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.,Dept of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Robin Vos
- Dept of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.,Dept of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| |
Collapse
|
|
27
|
H. sinensis mycelium inhibits epithelial-mesenchymal transition by inactivating the midkine pathway in pulmonary fibrosis. Front Med 2021; 15:313-329. [PMID: 33908025 DOI: 10.1007/s11684-020-0737-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Accepted: 11/27/2019] [Indexed: 09/29/2022]
Abstract
The medical fungus Hirsutella sinensis has been used as a Chinese folk health supplement because of its immunomodulatory properties. Our previous studies established the antifibrotic action of Hirsutella sinensis mycelium (HSM) in the lung. The epithelial-mesenchymal transition (EMT) is involved in the pathogenesis of idiopathic pulmonary fibrosis. The present study investigates the role of HSM in mediating EMT during the development of pulmonary fibrosis. HSM significantly inhibits bleomycin (BLM)-induced pulmonary fibrosis by blocking the EMT. In addition, the expression levels of midkine are increased in the lungs of the BLM-induced group. Further analysis of the results indicates that the mRNA level of midkine correlated positively with EMT. HSM markedly abrogates the transforming growth factor β-induced EMT-like phenotype and behavior in vitro. The activation of midkine related signaling pathway is ameliorated following HSM treatment, whereas this extract also caused an effective attenuation of the induction of EMT (caused by midkine overexpression) in vitro. Results further confirm that oral medication of HSM disrupted the midkine pathway in vivo. Overall, findings suggest that the midkine pathway and the regulation of the EMT may be considered novel candidate therapeutic targets for the antifibrotic effects caused by HSM.
Collapse
|
|
28
|
Cochrane A, Li X. What is the role of surgical lung biopsy in interstitial lung disease? ANZ J Surg 2021; 91:223-224. [PMID: 33740307 DOI: 10.1111/ans.16646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 01/25/2021] [Indexed: 11/26/2022]
Affiliation(s)
- Andrew Cochrane
- Department of Cardiothoracic Surgery, Monash Medical Centre & Department of Surgery, Monash University, Clayton, Victoria
| | - Xun Li
- Lung and Sleep Unit, Monash Medical Centre, Clayton, Victoria
| |
Collapse
|
|
29
|
Increased Levels of ER Stress and Apoptosis in a Sheep Model for Pulmonary Fibrosis Are Alleviated by In Vivo Blockade of the KCa3.1 Ion Channel. Can Respir J 2021; 2021:6683195. [PMID: 33828632 PMCID: PMC8004363 DOI: 10.1155/2021/6683195] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 03/04/2021] [Accepted: 03/10/2021] [Indexed: 12/26/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease, characterized by progressive damage to the lung tissues. Apoptosis and endoplasmic reticulum stress (ER stress) in type II alveolar epithelial cells (AECs) and lung macrophages have been linked with the development of IPF. Therefore, apoptosis- and ER stress-targeted therapies have drawn attention as potential avenues for treatment of IPF. The calcium-activated potassium ion channel KCa3.1 has been proposed as a potential therapeutic target for fibrotic diseases including IPF. While KCa3.1 is expressed in AECs and macrophages, its influence on ER stress and apoptosis during the disease process is unclear. We utilized a novel sheep model of pulmonary fibrosis to demonstrate that apoptosis and ER stress occur in type II AECs and macrophages in sheep with bleomycin-induced lung fibrosis. Apoptosis in type II AEC and macrophages was identified using the TUNEL method of tagging fragmented nuclear DNA, while ER stress was characterized by increased expression of GRP-78 ER chaperone proteins. We demonstrated that apoptosis and ER stress in type II AECs and macrophages increased significantly 2 weeks after the final bleomycin infusion and remained high for up to 7 weeks post-bleomycin injury. Senicapoc treatment significantly reduced the rates of ER stress in type II AECs and macrophages that were resident in bleomycin-infused lung segments. There were also significant reductions in the rates of apoptosis of type II AECs and macrophages in the lung segments of senicapoc-treated sheep. In vivo blockade of the KCa3.1 ion channel alleviates the ER stress and apoptosis in type II AECs and macrophages, and this effect potentially contributes to the anti-fibrotic effects of senicapoc.
Collapse
|
|
30
|
Velázquez-Díaz P, Nakajima E, Sorkhdini P, Hernandez-Gutierrez A, Eberle A, Yang D, Zhou Y. Hermansky-Pudlak Syndrome and Lung Disease: Pathogenesis and Therapeutics. Front Pharmacol 2021; 12:644671. [PMID: 33841163 PMCID: PMC8028140 DOI: 10.3389/fphar.2021.644671] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/11/2021] [Indexed: 12/19/2022] Open
Abstract
Hermansky-Pudlak Syndrome (HPS) is a rare, genetic, multisystem disorder characterized by oculocutaneous albinism (OCA), bleeding diathesis, immunodeficiency, granulomatous colitis, and pulmonary fibrosis. HPS pulmonary fibrosis (HPS-PF) occurs in 100% of patients with subtype HPS-1 and has a similar presentation to idiopathic pulmonary fibrosis. Upon onset, individuals with HPS-PF have approximately 3 years before experiencing signs of respiratory failure and eventual death. This review aims to summarize current research on HPS along with its associated pulmonary fibrosis and its implications for the development of novel treatments. We will discuss the genetic basis of the disease, its epidemiology, and current therapeutic and clinical management strategies. We continue to review the cellular processes leading to the development of HPS-PF in alveolar epithelial cells, lymphocytes, mast cells, and fibrocytes, along with the molecular mechanisms that contribute to its pathogenesis and may be targeted in the treatment of HPS-PF. Finally, we will discuss emerging new cellular and molecular approaches for studying HPS, including lentiviral-mediated gene transfer, induced pluripotent stem cells (iPSCs), organoid and 3D-modelling, and CRISPR/Cas9-based gene editing approaches.
Collapse
Affiliation(s)
| | - Erika Nakajima
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States
| | - Parand Sorkhdini
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States
| | | | - Adam Eberle
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States
| | - Dongqin Yang
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States
| | - Yang Zhou
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States
| |
Collapse
|
|
31
|
Li S, Shao L, Fang J, Zhang J, Chen Y, Yeo AJ, Lavin MF, Yu G, Shao H. Hesperetin attenuates silica-induced lung injury by reducing oxidative damage and inflammatory response. Exp Ther Med 2021; 21:297. [PMID: 33717240 PMCID: PMC7885076 DOI: 10.3892/etm.2021.9728] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 12/11/2020] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress and the inflammatory response are two important mechanisms of silica-induced lung injury. Hesperetin (HSP) is a natural flavonoid compound that is found in citrus fruits and has been indicated to exhibit strong antioxidant and anti-inflammatory properties. The current study evaluated the protective effect of HSP on lung injury in rats exposed to silica. The results indicated that the degree of alveolitis and pulmonary fibrosis in the HSP-treated group was significantly decreased compared with the silica model group. The content of hydroxyproline (HYP) was also revealed to decrease overall in the HSP treated group compared with the silica model group, indicating that the degree of pulmonary fibrosis was decreased compared with the silica model group. The present study also demonstrated that HSP reduced oxidation levels of malondialdehyde (MDA) and increased the activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-PX). Total antioxidant capacity (T-AOC) was also increased following HSP treatment, indicating that HSP can alleviate oxidative stress in the lung tissue of silica-exposed rats. In addition, HSP was revealed to inhibit the synthesis and secretion of fibrogenic factor TGF-β1, reduce the production of pro-inflammatory cytokines IL-1β, IL-4, TNF-α and increase the levels of anti-inflammatory factors IFN-γ and IL-10. The current study demonstrated that HSP can effectively attenuate silica-induced lung injury by reducing oxidative damage and the inflammatory response.
Collapse
Affiliation(s)
- Shuxian Li
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China
| | - Linlin Shao
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Jinguo Fang
- Primary Health Department, Linqing Health Bureau, Linqing, Shandong 252600, P.R. China
| | - Juan Zhang
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China
| | - Yanqin Chen
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China
| | - Abrey J Yeo
- Centre for Clinical Research, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Martin F Lavin
- Centre for Clinical Research, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Gongchang Yu
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China
| | - Hua Shao
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China
| |
Collapse
|
|
32
|
Araki K, Kinoshita R, Tomonobu N, Gohara Y, Tomida S, Takahashi Y, Senoo S, Taniguchi A, Itano J, Yamamoto KI, Murata H, Suzawa K, Shien K, Yamamoto H, Okazaki M, Sugimoto S, Ichimura K, Nishibori M, Miyahara N, Toyooka S, Sakaguchi M. The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis. J Mol Med (Berl) 2020; 99:131-145. [PMID: 33169236 DOI: 10.1007/s00109-020-02001-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/12/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023]
Abstract
In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.
Collapse
Affiliation(s)
- Kota Araki
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Rie Kinoshita
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Nahoko Tomonobu
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yuma Gohara
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shuta Tomida
- Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan
| | - Yuta Takahashi
- Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Satoru Senoo
- Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Akihiko Taniguchi
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Junko Itano
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Ken-Ichi Yamamoto
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hitoshi Murata
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Ken Suzawa
- Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazuhiko Shien
- Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiromasa Yamamoto
- Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Mikio Okazaki
- Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Seiichiro Sugimoto
- Department of Organ Transplant Center, Okayama University Hospital, Okayama, Japan
| | - Kouichi Ichimura
- Department of Pathology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Masahiro Nishibori
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Nobuaki Miyahara
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.,Department of Medical Technology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shinichi Toyooka
- Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
| | - Masakiyo Sakaguchi
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
| |
Collapse
|
|
33
|
Glass DS, Grossfeld D, Renna HA, Agarwala P, Spiegler P, Kasselman LJ, Glass AD, DeLeon J, Reiss AB. Idiopathic pulmonary fibrosis: Molecular mechanisms and potential treatment approaches. Respir Investig 2020; 58:320-335. [PMID: 32487481 DOI: 10.1016/j.resinv.2020.04.002] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 03/17/2020] [Accepted: 04/13/2020] [Indexed: 06/11/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease with high mortality that commonly occurs in middle-aged and older adults. IPF, characterized by a decline in lung function, often manifests as exertional dyspnea and cough. Symptoms result from a fibrotic process driven by alveolar epithelial cells that leads to increased migration, proliferation, and differentiation of lung fibroblasts. Ultimately, the differentiation of fibroblasts into myofibroblasts, which synthesize excessive amounts of extracellular matrix proteins, destroys the lung architecture. However, the factors that induce the fibrotic process are unclear. Diagnosis can be a difficult process; the gold standard for diagnosis is the multidisciplinary conference. Practical biomarkers are needed to improve diagnostic and prognostic accuracy. High-resolution computed tomography typically shows interstitial pneumonia with basal and peripheral honeycombing. Gas exchange and diffusion capacity are impaired. Treatments are limited, although the anti-fibrotic drugs pirfenidone and nintedanib can slow the progression of the disease. Lung transplantation is often contraindicated because of age and comorbidities, but it improves survival when successful. The incidence and prevalence of IPF has been increasing and there is an urgent need for improved therapies. This review covers the detailed cellular and molecular mechanisms underlying IPF progression as well as current treatments and cutting-edge research into new therapeutic targets.
Collapse
Affiliation(s)
- Daniel S Glass
- Department of Medicine and Winthrop Research Institute, NYU Long Island School of Medicine and NYU Winthrop Hospital, Mineola, NY, USA.
| | - David Grossfeld
- Department of Medicine and Winthrop Research Institute, NYU Long Island School of Medicine and NYU Winthrop Hospital, Mineola, NY, USA.
| | - Heather A Renna
- Department of Medicine and Winthrop Research Institute, NYU Long Island School of Medicine and NYU Winthrop Hospital, Mineola, NY, USA.
| | - Priya Agarwala
- Department of Medicine and Winthrop Research Institute, NYU Long Island School of Medicine and NYU Winthrop Hospital, Mineola, NY, USA.
| | - Peter Spiegler
- Department of Medicine and Winthrop Research Institute, NYU Long Island School of Medicine and NYU Winthrop Hospital, Mineola, NY, USA.
| | - Lora J Kasselman
- Department of Medicine and Winthrop Research Institute, NYU Long Island School of Medicine and NYU Winthrop Hospital, Mineola, NY, USA.
| | - Amy D Glass
- Department of Medicine and Winthrop Research Institute, NYU Long Island School of Medicine and NYU Winthrop Hospital, Mineola, NY, USA.
| | - Joshua DeLeon
- Department of Medicine and Winthrop Research Institute, NYU Long Island School of Medicine and NYU Winthrop Hospital, Mineola, NY, USA.
| | - Allison B Reiss
- Department of Medicine and Winthrop Research Institute, NYU Long Island School of Medicine and NYU Winthrop Hospital, Mineola, NY, USA.
| |
Collapse
|
|
34
|
The natural course of lung function decline in asbestos exposed subjects with pleural plaques and asbestosis. Respir Med 2019; 154:82-85. [DOI: 10.1016/j.rmed.2019.06.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Revised: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 11/23/2022]
|
|
35
|
Ullah A, Wang K, Wu P, Oupicky D, Sun M. CXCR4-targeted liposomal mediated co-delivery of pirfenidone and AMD3100 for the treatment of TGFβ-induced HSC-T6 cells activation. Int J Nanomedicine 2019; 14:2927-2944. [PMID: 31118614 PMCID: PMC6501422 DOI: 10.2147/ijn.s171280] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 03/19/2019] [Indexed: 12/15/2022] Open
Abstract
Background: Liver fibrosis is a chronic liver disease associated with an excessive accumulation of extracellualr matrix (ECM) proteins which ultimately lead to cirrohosis and hepatocellular carcinoma. Purpose: Liver fibrosis therapies that use combination approaches with the ability to affect multiple disease pathways have proven higher efficacies. This study aimed at optimizing and characterizing the co-encapsulation of pirfenidone (PF) and AMD3100 (AMD) into CXCR4-targeted combination liposomes (CTC liposome) for CXCR4 targeting, and the inhibition of major molecular culprits ie α-SMA, CXCR4, TGFβ, and P-p38 involved in liver fibrosis in-vitro. Methods: The CTC liposomes were prepared using the thin-film hydration method. The concentration of encapsulated AMD and PF was measured by HPLC and UV spectrophotometry, respectively. Tramsmission electron microscopy (TEM) was used to determine the liposomal morphology. The CXCR4 targeting ability was determined by CXCR4 redistribution assay. Confocal microscopy and flowcytometry were used to determine the CXCR4 mediated cell uptake. The apoptosis inducing and protein downreguating ability of CTC liposomes were determined by apoptosis assay and western blot analysis, respectively. In-vivo biodistribution and Hoechst staining were used to confirm the feasibility of CTC liposome for the in-vivo applications and drug targeted accumulation, respectively. Results: The TEM studies revealed that CTC liposomes were spherical in shape. The cumulative release of AMD and PF from CTC liposome was 67% and 84%, respectively, at 48 h. Compared to the free drug counterparts, encapsulated drugs displayed higher cell viability. The CXCR4 redistribution assay confirmed the CXCR4 targeting and antagonistic ability of CTC liposomes. The CTC liposomes were internalized more effectively via caveolae-mediated endocytic pathways. CTC liposomes displayed aggressive apoptosis (87.3%) in TGFβ-induced activated HSC-T6 cells suggesting a propensity to fibrosis regression. Also, CTC liposomes significantly reduced α-SMA (65%), CXCR4 (77%), TGFβ (89%), and P-p38 (66%) expressions, better than free drugs. CTC@IR780 liposomes (CTC liposomes incorporating IR780 dye) were more accumulated in fibrotic livers compared to free IR780, as judged by in-vivo imaging, biodistribution analysis, and Hoechst staining. These findings suggest that this simple and stable CTC liposomal system holds a great promise for the treatment and prevention of liver fibrosis.
Collapse
Affiliation(s)
- Aftab Ullah
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Kaikai Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Pengkai Wu
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - David Oupicky
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People's Republic of China.,Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Minjie Sun
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| |
Collapse
|
|
36
|
Kass DJ. Treatment of interstitial lung disease: Do the ends justify the means? Respirology 2019; 24:508-509. [DOI: 10.1111/resp.13526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 02/20/2019] [Indexed: 12/28/2022]
Affiliation(s)
- Daniel J. Kass
- Dorothy P. and Richard P. Simmons Center for Interstitial Lung DiseaseUniversity of Pittsburgh Pittsburgh PA USA
| |
Collapse
|
|
37
|
Karampitsakos T, Vraka A, Bouros D, Liossis SN, Tzouvelekis A. Biologic Treatments in Interstitial Lung Diseases. Front Med (Lausanne) 2019; 6:41. [PMID: 30931306 PMCID: PMC6425869 DOI: 10.3389/fmed.2019.00041] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 02/13/2019] [Indexed: 12/17/2022] Open
Abstract
Interstitial lung diseases (ILD) represent a group of heterogeneous parenchymal lung disorders with complex pathophysiology, characterized by different clinical and radiological patterns, ultimately leading to pulmonary fibrosis. A considerable proportion of these disease entities present with no effective treatment, as current therapeutic regimens only slow down disease progression, thus leaving patients, at best case, with considerable functional disability. Biologic therapies have emerged and are being investigated in patients with different forms of ILD. Unfortunately, their safety profile has raised many concerns, as evidence shows that they might cause or exacerbate ILD status in a subgroup of patients. This review article aims to summarize the current state of knowledge on their role in patients with ILD and highlight future perspectives.
Collapse
Affiliation(s)
- Theodoros Karampitsakos
- 5th Department of Pneumonology, General Hospital for Thoracic Diseases Sotiria, Athens, Greece
| | - Argyro Vraka
- First Academic Department of Pneumonology, Hospital for Thoracic Diseases, Sotiria Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Demosthenes Bouros
- First Academic Department of Pneumonology, Hospital for Thoracic Diseases, Sotiria Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Stamatis-Nick Liossis
- Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, Patras, Greece
| | - Argyris Tzouvelekis
- First Academic Department of Pneumonology, Hospital for Thoracic Diseases, Sotiria Medical School, National and Kapodistrian University of Athens, Athens, Greece
| |
Collapse
|
|
38
|
Zinter MS, Delucchi KL, Kong MY, Orwoll BE, Spicer AS, Lim MJ, Alkhouli MF, Ratiu AE, McKenzie AV, McQuillen PS, Dvorak CC, Calfee CS, Matthay MA, Sapru A. Early Plasma Matrix Metalloproteinase Profiles. A Novel Pathway in Pediatric Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 2019; 199:181-189. [PMID: 30114376 PMCID: PMC6353006 DOI: 10.1164/rccm.201804-0678oc] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 08/10/2018] [Indexed: 12/12/2022] Open
Abstract
RATIONALE MMPs (Matrix metalloproteinases) and their endogenous tissue inhibitors may contribute to lung injury through extracellular matrix degradation and modulation of inflammation and fibrosis. OBJECTIVES To test for an association between MMP pathway proteins and inflammation, endothelial dysfunction, and clinical outcomes. METHODS We measured MMPs in plasma collected on acute respiratory distress syndrome (ARDS) Day 1 from 235 children at five hospitals between 2008 and 2017. We used latent class analysis to identify patients with distinct MMP profiles and then associated those profiles with markers of inflammation (IL-1RA, -6, -8, -10, and -18; macrophage inflammatory protein-1α and -1β; tumor necrosis factor-α and -R2), endothelial injury (angiopoietin-2, von Willebrand factor, soluble thrombomodulin), impaired oxygenation (PaO2/FiO2 [P/F] ratio, oxygenation index), morbidity, and mortality. MEASUREMENTS AND MAIN RESULTS In geographically distinct derivation and validation cohorts, approximately one-third of patients demonstrated an MMP profile characterized by elevated MMP-1, -2, -3, -7, and -8 and tissue inhibitor of metalloproteinase-1 and -2; and depressed active and total MMP-9. This MMP profile was associated with multiple markers of inflammation, endothelial injury, and impaired oxygenation on Day 1 of ARDS, and conferred fourfold increased odds of mortality or severe morbidity independent of the P/F ratio and other confounders (95% confidence interval, 2.1-7.6; P < 0.001). Logistic regression using both the P/F ratio and MMP profiles was superior to the P/F ratio alone in prognosticating mortality or severe morbidity (area under the receiver operating characteristic curve, 0.75; 95% confidence interval, 0.68-0.82 vs. area under the receiver operating characteristic curve, 0.66; 95% confidence interval, 0.58-0.73; P = 0.009). CONCLUSIONS Pediatric patients with ARDS have specific plasma MMP profiles associated with inflammation, endothelial injury, morbidity, and mortality. MMPs may play a role in the pathobiology of children with ARDS.
Collapse
Affiliation(s)
| | | | - Michele Y. Kong
- Division of Critical Care Medicine, Department of Pediatrics, University of Alabama School of Medicine, Birmingham, Alabama; and
| | | | | | - Michelle J. Lim
- Division of Critical Care, Department of Pediatrics, Mattel Children’s Hospital, University of California Los Angeles Geffen School of Medicine, Los Angeles, California
| | | | - Anna E. Ratiu
- Division of Critical Care, Department of Pediatrics, Mattel Children’s Hospital, University of California Los Angeles Geffen School of Medicine, Los Angeles, California
| | | | | | - Christopher C. Dvorak
- Division of Allergy, Immunology, and Blood & Marrow Transplantation, Department of Pediatrics, Benioff Children’s Hospital
| | - Carolyn S. Calfee
- Department of Anesthesia and
- Department of Medicine, Cardiovascular Research Institute, University of California San Francisco School of Medicine, San Francisco, California
| | - Michael A. Matthay
- Department of Anesthesia and
- Department of Medicine, Cardiovascular Research Institute, University of California San Francisco School of Medicine, San Francisco, California
| | - Anil Sapru
- Division of Critical Care and
- Division of Critical Care, Department of Pediatrics, Mattel Children’s Hospital, University of California Los Angeles Geffen School of Medicine, Los Angeles, California
| |
Collapse
|
|
39
|
Niclosamide alleviates pulmonary fibrosis in vitro and in vivo by attenuation of epithelial-to-mesenchymal transition, matrix proteins & Wnt/β-catenin signaling: A drug repurposing study. Life Sci 2019; 220:8-20. [PMID: 30611787 DOI: 10.1016/j.lfs.2018.12.061] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 12/31/2018] [Accepted: 12/31/2018] [Indexed: 01/09/2023]
Abstract
Drug repurposing off late has been emerging as an inspiring alternative approach to conventional, exhaustive and arduous process of drug discovery. It is a process of identifying new therapeutic values for a drug already established for the treatment of a certain condition. Our current study is aimed at repurposing the old anti-helimenthic drug Niclosamide as an anti-fibrotic drug against pulmonary fibrosis (PF). PF is most common lethal interstitial lung disease hallmarked by deposition of extracelluar matrix and scarring of lung. Heterogenous nature, untimely diagnosis and lack of appropriate treatment options make PF an inexorable lung disorder. Prevailing void in PF treatment and drug repositioning strategy of drugs kindled our interest to demonstrate the anti-fibrotic activity of Niclosamide. Our study is aimed at investigating the anti-fibrotic potential of Niclosamide in TGF-β1 induced in vitro model of PF and 21-day model of Bleomycin induced PF in vivo respectively. Our study results showed that Niclosamide holds the potential to exert anti-fibrotic effect by hampering fibroblast migration, attenuating EMT, inhibiting fibrotic signaling and by regulating WNT/β-catenin signaling as evident from protein expression studies. Our study findings can give new directions to development of Niclosamide as an anti-fibrotic agent for treatment of pulmonary fibrosis.
Collapse
|
|
40
|
Pasciuto G, Inchingolo R, Condoluci C, Magnini D, Iovene B, Richeldi L. Approved and Experimental Therapies for Idiopathic Pulmonary Fibrosis. CURRENT PULMONOLOGY REPORTS 2018. [DOI: 10.1007/s13665-018-0209-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
41
|
Kim YI, Shin HW, Chun YS, Cho CH, Koh J, Chung DH, Park JW. Epithelial cell-derived cytokines CST3 and GDF15 as potential therapeutics for pulmonary fibrosis. Cell Death Dis 2018; 9:506. [PMID: 29724997 PMCID: PMC5938700 DOI: 10.1038/s41419-018-0530-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 03/20/2018] [Accepted: 03/27/2018] [Indexed: 12/22/2022]
Abstract
While wound healing is completed, the epithelium functions to normalize the interstitial context by eliminating fibroblasts excited during matrix reconstruction. If not, tissues undergo pathologic fibrosis. Pulmonary fibrosis is a fatal and hardly curable disorder. We here tried to identify epithelium-derived cytokines capable of ameliorating pulmonary fibrosis. Human lung fibroblasts were inactivated in epithelial cell-conditioned media. Cystatin C (CST3) and growth differentiation factor 15 (GDF15) were found to be enriched in the conditioned media and to inhibit the growth and activation of lung fibroblasts by inactivating the TGF–Smad pathway. In mouse and human lungs with interstitial fibrosis, CST3 and GDF15 expressions were markedly reduced, and the restoration of these cytokines alleviated the fibrotic changes in mouse lungs. These results suggest that CST3 and GDF15 are bona fide regulators to prevent excessive proliferation and activation of fibroblasts in injured lungs. These cytokines could be potential therapeutics for ameliorating interstitial lung fibrosis.
Collapse
Affiliation(s)
- Young-Im Kim
- Department of Biomedical Sciences, BK21-plus Education Program, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun-Woo Shin
- Department of Biomedical Sciences, BK21-plus Education Program, Seoul National University College of Medicine, Seoul, Korea.,Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yang-Sook Chun
- Department of Biomedical Sciences, BK21-plus Education Program, Seoul National University College of Medicine, Seoul, Korea.,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Chung-Hyun Cho
- Department of Biomedical Sciences, BK21-plus Education Program, Seoul National University College of Medicine, Seoul, Korea.,Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jaemoon Koh
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Doo Hyun Chung
- Department of Biomedical Sciences, BK21-plus Education Program, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Jong-Wan Park
- Department of Biomedical Sciences, BK21-plus Education Program, Seoul National University College of Medicine, Seoul, Korea. .,Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea. .,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
| |
Collapse
|
|
42
|
Varone F, Sgalla G, Iovene B, Bruni T, Richeldi L. Nintedanib for the treatment of idiopathic pulmonary fibrosis. Expert Opin Pharmacother 2018; 19:167-175. [DOI: 10.1080/14656566.2018.1425681] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Francesco Varone
- Polo Scienze Cardiovascolari e Toraciche, Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giacomo Sgalla
- Polo Scienze Cardiovascolari e Toraciche, Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Bruno Iovene
- Polo Scienze Cardiovascolari e Toraciche, Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Teresa Bruni
- Polo Scienze Cardiovascolari e Toraciche, Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luca Richeldi
- Polo Scienze Cardiovascolari e Toraciche, Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| |
Collapse
|
|
43
|
Chen C, Wang YY, Wang YX, Cheng MQ, Yin JB, Zhang X, Hong ZP. Gentiopicroside ameliorates bleomycin-induced pulmonary fibrosis in mice via inhibiting inflammatory and fibrotic process. Biochem Biophys Res Commun 2018; 495:2396-2403. [DOI: 10.1016/j.bbrc.2017.12.112] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Accepted: 12/20/2017] [Indexed: 01/22/2023]
|
|
44
|
Steiner CA, Higgins PDR. Anti-Fibrotic Therapies from Other Organs: What the Gut Can Learn from the Liver, Skin, Lung and Heart. FIBROSTENOTIC INFLAMMATORY BOWEL DISEASE 2018:347-385. [DOI: 10.1007/978-3-319-90578-5_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
45
|
Monitoring and manipulating cellular crosstalk during kidney fibrosis inside a 3D in vitro co-culture. Sci Rep 2017; 7:14490. [PMID: 29101326 PMCID: PMC5670242 DOI: 10.1038/s41598-017-12683-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 09/14/2017] [Indexed: 01/10/2023] Open
Abstract
In pharmacological research the development of promising lead compounds requires a detailed understanding of the dynamics of disease progression. However, for many diseases, such as kidney fibrosis, gaining such understanding requires complex real-time, multi-dimensional analysis of diseased and healthy tissue. To allow for such studies with increased throughput we established a dextran hydrogel-based in vitro 3D co-culture as a disease model for kidney fibrosis aimed at the discovery of compounds modulating the epithelial/mesenchymal crosstalk. This platform mimics a simplified pathological renal microenvironment at the interface between tubular epithelial cells and surrounding quiescent fibroblasts. We combined this 3D technology with epithelial reporter cell lines expressing fluorescent biomarkers in order to visualize pathophysiological cell state changes resulting from toxin-mediated chemical injury. Epithelial cell damage onset was robustly detected by image-based monitoring, and injured epithelial spheroids induced myofibroblast differentiation of co-cultured quiescent human fibroblasts. The presented 3D co-culture system therefore provides a unique model system for screening of novel therapeutic molecules capable to interfere and modulate the dialogue between epithelial and mesenchymal cells.
Collapse
|