Adipose tissue fibrosis, characterized by abnormal extracellular matrix deposition within adipose tissue, signifies a crucial indicator of adipose tissue malfunction, potentially leading to organ tissue dysfunction. Various factors, including a high-fat diet, non-alcoholic fatty liver disease, and insulin resistance, coincide with adipose tissue fibrosis. MicroRNAs (miRNAs) represent a class of small non-coding RNAs with significant influence on tissue fibrosis through diverse signaling pathways. For instance, in response to a high-fat diet, miRNAs can modulate signaling pathways such as TGF-β/Smad, PI3K/AKT, and PPAR-γ to impact adipose tissue fibrosis. Furthermore, miRNAs play roles in inhibiting fibrosis in different contexts: suppressing corneal fibrosis via the TGF-β/Smad pathway, mitigating cardiac fibrosis through the VEGF signaling pathway, reducing wound fibrosis via regulation of the MAPK signaling pathway, and diminishing fibrosis post-fat transplantation via involvement in the PDGFR-β signaling pathway. Notably, the secretome released by miRNA-transfected adipose-derived stem cells facilitates targeted delivery of miRNAs to evade host immune rejection, enhancing their anti-fibrotic efficacy. Hence, this study endeavors to elucidate the role and mechanism of miRNAs in adipose tissue fibrosis and explore the mechanisms and advantages of the secretome released by miRNA-transfected adipose-derived stem cells in combating fibrotic diseases.

Fibrosis-related disorders represent an increasing medical and economic burden on a worldwide scale, accounting for one-third of all disease-related deaths with limited therapeutic options. As central mediators in fibrosis development, myofibroblasts have been gaining increasing attention in the last 20 years as potential targets for fibrosis attenuation and reversal. While various aspects of myofibroblast physiology have been proposed as treatment targets, many of these approaches have shown limited long-term efficacy so far. However, ongoing research is uncovering new potential strategies for targeting myofibroblast activity, offering hope for more effective treatments in the future. The circadian molecular clock is a feature of almost every cell in the human body that dictates the rhythmic nature of various aspects of human physiology and behavior in response to changes in the surrounding environment. The dysregulation of these rhythms with aging is considered to be one of the underlying reasons behind the development of multiple aging-related chronic disorders, with fibrotic tissue scarring being a common pathological complication among the majority of them. Myofibroblast dysregulation due to skewed circadian clockwork might significantly contribute to fibrotic scar persistence. In the current review, we highlight the role of the circadian clock in the context of myofibroblast activation and deactivation and examine its dysregulation as a driver of fibrogenesis.

Mouse strain and sex variability may provide a better understanding of the isothiazolinone-associated respiratory toxicity profile; however, this remains poorly understood. In this study, we investigated and compared the respiratory effects of repeated exposure to a mixture of chloromethylisothiazolinone and methylisothiazolinone (CMIT/MIT) in two commonly used mouse strains, BALB/c and C57BL/6, including both males and females. CMIT/MIT-induced lung injury was analyzed after six times intratracheal instillation of CMIT/MIT using differential cell counts and cytokine measurements in bronchoalveolar lavage fluid (BALF), histological analysis, and gene expression profiling of lung tissue. In both female and male C57BL/6 mice, CMIT/MIT exposure led to increased infiltration of inflammatory cells, particularly eosinophils, and elevated levels of Type 2 helper T cell (Th2)-associated cytokines in BALF. Histopathological findings revealed granulomatous inflammation, mucinous cell hyperplasia, eosinophilic cell infiltration, and lung fibrosis in these mice. Female BALB/c mice exhibited similar but less severe pathological changes. In contrast, male BALB/c mice showed a predominance of macrophages and neutrophils, with no notable histopathological alterations. Gene expression analysis revealed upregulation of genes associated with inflammatory and fibrotic lung injury and Th2 signaling in female and male C57BL/6 mice and female BALB/c mice, but not in male BALB/c mice. Collectively, these findings indicate that C57BL/6 mice are more susceptible to CMIT/MIT-induced lung injury than BALB/c mice, which is closely associated with the genetic characteristics of increased eosinophil and Th2-mediated responses.

Biomaterial implants are a critical aspect of our medical therapies and biomedical research and come in various forms: stents, implantable glucose sensors, orthopedic implants, silicone implants, drug delivery systems, and tissue engineered scaffolds. Their implantation triggers a series of biological responses that often times lead to the foreign body response and subsequent fibrotic encapsulation, a dense ECM-rich capsule that isolates the biomaterial and renders it ineffective. These responses lead to the failure of biomaterials and is a major hurdle to overcome and in promoting their success. Much attention has been given to macrophage populations for the inflammatory component of these responses to biomaterials but recent work has identified an important role of T cells and their ability to modulate fibroblast activity and vice versa. In this review, we focus on T cell-fibroblast crosstalk by exploring T cell subsets, critical signaling pathways, and fibroblast populations that have been shown to dictate biomaterial-mediated fibrosis. We then highlight emerging technologies and model systems that enable new insights and avenues to T cell-fibroblast crosstalk that will improve biomaterial outcomes.

Thoracic tumours represent a significant proportion of malignant cancers. While radiotherapy (RT) improves prognosis, it can also lead to side effects such as radiation-induced pneumonitis (RP). Since SIRT6 is involved in DNA repair, energy metabolism and inflammation, this study aims to investigate the expression of SIRT6 in lymphocytes as a potential biomarker and therapeutic target for RP. This study included 170 patients diagnosed with thoracic tumours, all of whom underwent thoracic RT. RP was evaluated and classified as severe RP (SRP) and lower as non-severe RP (NSRP). Analyses were performed using SPSS version 26.0 and the R. Among 170 patients in this study, 124 developed NSRP, and 46 experienced SRP. The univariate analysis showed that SIRT6 expression (cOR, 0.33, 95%CI, 0.18-0.97 before RT and 0.31, 0.19-0.98 after RT), clinical factors, dosimetric parameters and haematological/serological parameters were associated with SRP before and after RT. Our multivariable logistic regression showed that SIRT6 expression was significantly associated with risk of SRP before (aOR, 0.32, 95%CI, 0.15-0.96) and after RT (aOR, 0.32, 95%CI, 0.18-0.99) after adjustment with other confounders. Moreover, the receiver operating characteristic curve analysis revealed that the combined multivariable model exhibited superior predictive capability compared to any single predictor (overall AUC, 0.93, 95%CI, 0.90-0.97 before RT and AUC, 0.91, 95%CI, 0.87-0.96 after RT). The expression of SIRT6 alone or in combination with other risk factors was associated with an increased risk of SRP, suggesting a novel approach for the prevention and treatment of radiation pneumonitis in clinical practice.

The immune system plays a major role in pulmonary fibrosis (PF), a devastating lung disease with limited treatment options. Myeloid-derived suppressor cells (MDSCs) are immune cells with remarkable immunosuppressive functions. We hypothesized that their anti-inflammatory activity may dampen PF by inhibiting inflammation and its transition to fibrosis. Here, we studied the emergence of both polymorphonuclear (PMN)- and monocytic (M)-MDSCs in a murine model of PF. We assessed immunological, histopathological, and clinical changes at days 3, 7, 14, and 21 following bleomycin challenge. A comprehensive overview of the role of MDSCs during the acute lung injury and chronic phase of pulmonary fibrosis is provided, along with the effects of MDSCs adoptive transfer and depletion. Inflammation and fibrosis increased over a period of 21 days after bleomycin administration. In the lung, the number of PMN-MDSCs increased, while M-MDSCs decreased over the time following bleomycin challenge. Especially, M-MDSCs showed enhanced suppressive activity on day 3 following bleomycin challenge. Adoptive transfer of PMN-MDSCs attenuated inflammation and fibrosis development. However, depletion of PMN-MDSCs did not lead to an exacerbation of PF. Our results suggest that adoptive transfer of PMN-MDSCs can ameliorate the inflammatory responses and thus the development of fibrosis in a bleomycin-induced pulmonary fibrosis model.

Fibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse progression of the disease. To find novel targets for fibrosis therapeutics, we developed a model for the differentiation of monocytes to myofibroblasts that allowed us to screen for proteins involved in myofibroblast differentiation. Inhibition of a novel protein target generated by our model, talin2, reduces myofibroblast-specific morphology, α-smooth muscle actin content, and collagen I content and lowers the pro-fibrotic secretome of myofibroblasts. We find that knockdown of talin2 de-differentiates myofibroblasts and reverses bleomycin-induced lung fibrosis in mice, and further that Tln2-/- mice are resistant to bleomycin-induced lung fibrosis and resistant to unilateral ureteral obstruction-induced kidney fibrosis. Talin2 inhibition is thus a potential treatment for reversing lung and kidney fibroses.

Ocular fibrosis is one of the leading causes of irreversible visual impairment or blindness. Currently, there is no effective drug available for such diseases. Therefore, understanding the underlying mechanisms is a prerequisite for finding better therapeutic strategies.

This study aims to investigate the role of the junctional adhesion molecule C (JAM-C) in ocular fibrosis.

The protein levels of JAM-C were determined in the vitreous humor samples of patients with ocular fibrosis using ELISA. Jam-c genetic deletion mice and ocular fibrosis mouse models were generated to study the role of JAM-C in vivo. EMT, proliferation, migration, and gel contraction capacities in RPE cells were examined after JAM-C knockdown by siRNAs. RNA sequencing, co-IP, ChIP-qPCR, and luciferase reporter assay were performed to investigate the underlying mechanisms. Subretinal injection of adeno-associated virus, immunofluorescence, western blot were performed to evaluate the potential of JAM-C in preventing ocular fibrosis in different mouse models.

Markedly reduced JAM-C expression was found in patients with ocular fibrosis. Genetic deletion of Jam-c in mice exacerbated ocular fibrosis, and JAM-C knockdown triggered the EMT process in RPE cells. Mechanistically, we reveal that JAM-C inhibits ocular fibrosis by suppressing the nuclear localization and function of TAZ, which otherwise binds to KLF6 to promote its expression and activity to initiate the EMT cascade. Importantly, AAV-mediated JAM-C augmentation alleviated ocular fibrosis in different mouse models.

Our findings unveil a novel function of JAM-C in preventing ocular fibrosis by inhibiting the TAZ/KLF6 pathway, and suggest new therapeutic possibilities for the treatment of fibrotic diseases.

Chronic hepatitis C (CHC), caused by the hepatitis C virus, commonly leads to liver fibrosis. CHC is also related to T-cell exhaustion, phenotypically manifesting as overexpression of inhibitory receptors (iRs), e.g., programmed death receptor-1 (PD-1), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and lymphocyte activation gene 3 (LAG-3), which have corresponding plasma-soluble analogs. Galectin-3 (Gal-3) is a pro-fibrotic and pro-inflammatory molecule, but its role in CHC is controversial. The study aimed to assess the relationship between plasma levels of soluble PD-1 (sPD-1), sTIM-3, sLAG-3 and Gal-3 and the degree of fibrosis in CHC and successful CHC treatment effect on these markers. The study comprised 98 CHC patients, qualified for treatment with direct-acting antivirals. Plasma samples were collected prior to and six months post-treatment. iRs were determined by ELISA. sPD-1 levels were significantly higher in more advanced fibrosis (F2 + F3 vs. F0/1). Regardless of the degree of fibrosis, sPD-1 and sLAG-3 levels significantly decreased after therapy. sTIM-3 levels also decreased, however, mostly in patients with no or mild (i.e., F0/1) fibrosis. Furthermore, Gal-3 increased in patients with more advanced fibrosis (F2 + F3). sPD-1 is associated with liver disease stage in CHC and effective treatment is related to the iRs levels reduction.

Fibrosis is one of the key healing responses to injury, especially within the heart, where it helps to maintain structural integrity following acute insults such as myocardial infarction. However, if it becomes dysregulated, then fibrosis can become maladaptive, leading to adverse remodelling, impaired cardiac function and heart failure. Fibroblast activation protein is exclusively expressed by activated fibroblasts, the key effector cells of fibrogenesis, and has a unique extracellular domain that is an ideal ligand for novel molecular imaging probes. Fibroblast activation protein inhibitor (FAPI) radiotracers have been developed for positron emission tomography (PET) imaging, demonstrating high selectivity for activated fibroblasts across a range of different pathologies and disparate organ systems. In this review, we will summarise the role of fibroblast activation protein in cardiovascular disease and how FAPI radiotracers might improve the assessment and treatment of patients with cardiovascular diseases.

Fibrosis, the replacement of healthy tissue with collagen-rich matrix, can occur following injury in almost every organ1,2. Mouse lungs follow a stereotyped sequence of fibrogenesis-to-resolution after bleomycin injury3, and we reasoned that profiling post-injury histological stages could uncover pro-fibrotic versus anti-fibrotic features with functional value for human fibrosis. Here we quantified spatiotemporally resolved matrix transformations for integration with multi-omic data. First, we charted stepwise trajectories of matrix aberration versus resolution, derived from a high-dimensional set of histological fibre features, that denoted a reversible transition in uniform-to-disordered histological architecture. Single-cell sequencing along these trajectories identified temporally enriched 'ECM-secreting' (Csmd1-expressing) and 'pro-resolving' (Cd248-expressing) fibroblasts at the respective post-injury stages. Visium-based spatial analysis further suggested divergent matrix architectures and spatial-transcriptional neighbourhoods by fibroblast subtype, identifying distinct fibrotic versus non-fibrotic biomolecular milieu. Critically, pro-resolving fibroblast instillation helped to ameliorate fibrosis in vivo. Furthermore, the fibroblast neighbourhood-associated factors SERPINE2 and PI16 functionally modulated human lung fibrosis ex vivo. Spatial phenotyping of idiopathic pulmonary fibrosis at protein level additionally uncovered analogous fibroblast subtypes and neighbourhoods in human disease. Collectively, these findings establish an atlas of pro- and anti-fibrotic factors that underlie lung matrix architecture and implicate fibroblast-associated biological features in modulating fibrotic progression versus resolution.

Systemic and organ-specific fibrotic disorders are a leading cause of death worldwide. Crosstalk between fibroblasts and macrophages has been suggested as a key event leading to either resolution or aberrant remodeling and fibrosis. This study sought to identify the impacts of the timing and effects of exposure to quiescent (basal) and transforming growth factor-β-stimulated (activated) fibroblast secreted products on macrophage polarization and function. Naïve (M0 macrophages), lipopolysaccharide/interferon-γ-stimulated (M1 macrophages), and IL-4-stimulated (M2 macrophages) macrophages were exposed to basal or activated fibroblast conditioned media (FBCM) for 24 hours before, after, or during macrophage polarization. Macrophage function and polarization were quantified by phagocytosis, nitric oxide, and arginase activity assays and by cytokine array. FBCM from activated fibroblasts led to a pronounced up-regulation of arginase-1 compared with that from quiescent fibroblasts in M0 macrophages. Moreover, treatment with FBCM from activated fibroblasts resulted in significant increases in arginase-1 immunoexpression as well as urea production in M2 macrophages when applied antecedent, concurrent, or subsequent to M2 macrophage polarizing cytokines. Activated FBCM enhanced several proinflammatory cytokines, such as IL-1β and IL-6, in all macrophage subsets while only increasing tumor necrosis factor-α in M1 macrophages. This study elucidates multiple proinflammatory and profibrotic effects of fibroblasts on M1 and M2 macrophages, providing insights into the complex orchestration of macrophage-fibroblast crosstalk in fibrosis and the critical role of fibroblasts in the inflammatory response to injury.

Fibrotic diseases are involved in 45% of deaths in the United States. In particular, fibrosis of the kidney and lung are major public health concerns due to their high prevalence and lack of existing treatment options. Here, we harness the pathophysiological features of fibrotic diseases, namely leaky vasculature and aberrant extracellular matrix (ECM) protein deposition (i.e. collagen), to target an anti-fibrotic biologic and a small molecule drug to disease sites of fibrosis, thus improving the therapeutic potential of both the biologic and small molecule in mouse models of both lung and kidney fibrosis. First, we identify and validate two collagen-targeting drug delivery systems that preferentially accumulate in fibrotic organs: von Willebrand Factor's A3 domain (VWF-A3) and decorin-derived collagen-binding peptide-conjugated micelles (CBP-micelles). We then engineer and recombinantly express novel candidate biologic therapies based on the anti-inflammatory cytokine IL-10: A3-IL-10 and A3-Serum Albumin-IL-10 (A3-SA-IL-10). Simultaneously, we stably encapsulate the potential anti-fibrotic water-insoluble drug, rapamycin, in CBP-micelles. We show that these novel formulations of therapeutics bind to collagen in vitro and that their efficacy in mouse models of lung and kidney fibrosis is improved, compared to free, untargeted drugs. Our results demonstrate that collagen-targeted anti-fibrotic drugs may be next generation therapies of high clinical potential.

Fibroblast activation protein (FAP) is a serine protease selectively expressed in cancer-associated fibroblasts (CAFs), fibrotic tissues, and areas of active tissue remodeling, making it an attractive target for diagnostic imaging across a spectrum of disease. FAP inhibitors (FAPIs) labeled with PET tracers have rapidly advanced as a novel imaging modality with broad clinical applications that offers several advantages, including rapid tumor accumulation, low background uptake, and high tumor-to-background ratios. In oncology, FAPI PET has demonstrated excellent performance in visualizing a wide range of malignancies, including those with low glycolytic activity, such as pancreatic cancer, cholangiocarcinoma, and certain sarcomas. Its high sensitivity and specificity for the stromal component enables improved tumor delineation, staging, and response assessment. Additionally, the potential to guide theranostic approaches, where the same tracer can be labeled with therapeutic radionuclides, positions FAPI as a key player in precision oncology. Beyond oncology, FAPI PET has shown promise in imaging conditions characterized by fibrotic and inflammatory processes. In the cardiovascular field, FAPI PET imaging is being investigated for its ability to detect myocardial fibrosis and active cardiac remodeling, crucial in conditions like heart failure, post-myocardial infarction remodeling, and hypertrophic cardiomyopathy. This review highlights the expanding clinical applications of FAPI-based PET imaging across oncology, inflammation, and cardiovascular disease. While the current data are promising, further large-scale studies and multicenter trials are essential to validate these findings and establish standardized protocols. The versatility and broad applicability of FAPI PET underscore its potential as a transformative tool in precision medicine.

Allogeneic stem cell transplantation represents the only curative option for many patients with high risk hematological malignancies but is associated with a number of severe complications. Of these, chronic graft versus host disease (cGVHD) is the leading cause of late non-relapse mortality and of much morbidity. For over 30 years, glucocorticoids have been the mainstay of first line therapy, yet approximately 50% patients are refractory or dependent and traditionally there have been few options for these patients. In recent years, newer treatments including ruxolitinib and belumosudil have shown success in the second and third line settings. However, further effective nontoxic treatments are a necessary to address this complex debilitating disease. Axatilimab is an antibody to colony stimulating factor 1 (CSF-1), a tyrosine kinase receptor. CSF1R signaling dependent macrophages and monocytes are key mediators of inflammation and fibrosis in chronic GVHD, and thus, this therapy offers a targeted approach. Here we summarize the key clinical studies that have been performed to date of this novel therapy.

In this study, a previously developed approach for creating a quantitative structure-activity relationship model anchored in an Adverse Outcome Pathway framework (AOP-anchored Nano-QSAR) is employed to develop a novel model capable of predicting transcriptomic responses triggered by the inhalation of multiwalled carbon nanotubes (MWCNTs). The acute phase response (AR) signaling pathway, which plays a crucial role in neutrophil influx and initiates the acute immune response is focused. This process involves recruiting pro-inflammatory cells into the lungs and can lead to lung fibrosis, as outlined in AOP33, or atherosclerosis, as per AOP237. To establish the relationship between the structural properties of a set of MWCNTs and the transcriptional benchmark dose level (BMDLAR) response of genes associated with the acute phase response signaling pathway, the locally weighted kernel linear regression algorithm is used. These findings emphasize the critical role of the aspect ratio and specific surface area of MWCNTs in initiating acute inflammation and, subsequently, lung pathologies and atherosclerosis through the inflammatory and acute phase response signaling pathways. This newly developed data-driven model extends the repertoire of transcriptomic-based, AOP-informed Nano-QSAR models, potentially serving as an in silico new approach methodology (NAM) to support the MWCNTs' safety assessment based on the weight of evidence.

Numerous studies have demonstrated that interleukin (IL) plays an essential role in the development of chronic inflammatory diseases, especially in pneumoconiosis. The association between various IL gene polymorphisms and pneumoconiosis susceptibility has been investigated extensively, but the results remain controversial. A literature search was conducted using PubMed, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang database to obtain relevant studies before 22 January 2025. Subsequently, odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of correlations. A sensitivity analysis was performed to evaluate the robustness and reliability of the included studies. Overall, there was a significant association between IL-1RA +2018 and IL-6 -634 with the risk of pneumoconiosis. The IL-1RA +2018 variant was positively associated with an increased risk of pneumoconiosis among both Asians and Caucasians. In contrast, the IL-6 -634 genotype was associated with a lower risk of pneumoconiosis among Asians. Additionally, the IL-1RA +2018 genotype was significantly linked to a predisposition to coal workers' pneumoconiosis (CWP) and silicosis. The IL-6 -634 mutant significantly decreased silicosis and CWP risk. Additional large-scale replication studies are needed to elucidate the precise role of various IL SNPs in the etiology of pneumoconiosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial lung disease characterized by high mortality rates. An expanding body of evidence highlights the critical role of targeted therapies in the management of IPF. Nevertheless, there is a paucity of bibliometric studies that have comprehensively assessed this domain. This study seeks to examine global literature production and research trends related to targeted therapies for IPF.

A literature search was conducted using the Web of Science Core Collection, encompassing publications from 2004 to 2024, focusing on targeted therapies for IPF. The bibliometric analysis utilized tools such as VOSviewer, CiteSpace, and the "bibliometrix" package in R.

A total of 2,779 papers were included in the analysis, demonstrating a general trend of continuous growth in the number of publications over time. The United States contributed the highest number of publications, totaling 1,052, while France achieved the highest average citation rate at 75.74. The University of Michigan Medical School was the leading institution in terms of publication output, with 88 papers. Principal Investigator Naftali Kaminski was identified as the most prolific researcher in the field. The American Journal of Respiratory Cell and Molecular Biology emerged as the journal with the highest number of publications, featuring 98 articles. In recent years, the research has emerged surrounding targeted therapies for IPF, particularly focusing on agents such as TGF-β, pathogenesis, and autotaxin inhibitor.

In this bibliometric study, we systematically analyze research trends related to targeted therapies for IPF, elucidating recent research frontiers and emerging directions. The selected keywords-idiopathic pulmonary fibrosis, targeted therapy, bibliometric analysis, transforming growth factor β, and autotaxin inhibitor-capture the essential aspects of this research domain. This analysis serves as a reference point for future investigations into targeted therapies.

Keloids are benign fibroproliferative tumors that cause significant physical and mental morbidity owing to their disfiguring appearance, chronic symptoms, and resistance to treatment. Although fibroblast hyperproliferation and excessive extracellular matrix deposition have been extensively studied, less attention has been paid to the role of vascular dysregulation and endothelial dysfunction (ED) in keloid pathogenesis. Emerging evidence highlights abnormal angiogenesis, vascular irregularities, and endothelial injury as critical drivers of fibrosis in keloids. This review explores the direct and indirect mechanisms of ED in keloid progression, including endothelial-to-mesenchymal transition, inflammation, immune cell crosstalk, and hypoxia. In addition, various treatment strategies targeting angiogenesis and ED, such as drugs, radiotherapy, hyperbaric oxygen therapy, compression, and laser treatments, are comprehensively reviewed. This review explores keloids through the lens of vasculature and endothelium, emphasizing the critical roles of vascular dysregulation and ED. It aims to provide insights into the mechanisms of keloid formation and serve as a reference for developing future therapeutic strategies.

Postoperative abdominal adhesions are the leading cause of bowel obstruction and a cause of chronic pain and infertility. Adhesion formation occurs after 50 to 90% of abdominal operations and has no proven preventative or treatment strategy. Abdominal adhesions derive primarily from the visceral peritoneum and are composed of polyclonally proliferating tissue-resident fibroblasts. We have previously shown that signaling of the transcription factor JUN regulates adhesiogenesis and that a small-molecule JUN inhibitor (T-5224) decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with antiadhesion properties for intraperitoneal postoperative delivery and sustained release of a JUN inhibitor for adhesion prevention. The material properties of the T-5224-hydrogel support its use for open or minimally invasive surgical application. We found this therapeutic system to be safe, well tolerated, and efficacious in murine and porcine preclinical models. T-5224-hydrogel minimized adhesion quantity and also diminished adhesion fibrosis at an ultrastructural level. Moving toward clinical translation, we developed a large mammal adhesion model in pigs with bowel resection. Single-cell transcriptomic analysis showed that JUN and associated pathway signaling were diminished in adhesion-derived fibroblasts treated with T-5224-hydrogel. The JUN-inhibiting T-5224-hydrogel provided robust prevention of adhesion without deleterious effects on bowel anastomosis or abdominal wall healing. Adhesion biology is similar across surgical sites, and, therefore, this formulation has potential for applicability across the body. The development of therapeutics to prevent adhesions is of paramount importance with potential for high-impact translation to patient care to address a common, unmet clinical need.

Fibrosis is a multifactorial process characterized by the excessive accumulation of extracellular matrix (ECM), increased tissue stiffness, and decreased elasticity. This study examined how individual cytokines and a cytokine combination alter collagen production and biomechanics in a 3D in vitro model of the human ECM.

Cultured human fibroblasts were seeded into a circular agarose trough molded in 24 well plates. The fibroblasts aggregated and formed a 3D ring-shaped tissue that synthesized de novo a collagen-rich human ECM complete with collagen fibrils. Unlike existing models, no macromolecular crowders were added, nor artificial scaffolds or exogenous ECM proteins. Rings were treated with TGF-β1, IL-13 or the combination of TGF-β1 and IL-13 for up to 3 weeks. Morphology, histology, collagen, DNA, fibril formation, gene expression and tensile properties of the rings were measured.

As the rings compacted, cellularity and total DNA decreased, whereas total collagen accumulated. TGF-β1 stimulated collagen accumulation and increased ring biomechanics at day 7, but these increases stalled and declined by day 21. When treated with IL-13, a cytokine exclusive to the immune system, there were no significant differences from control. However, when TGF-β1 was combined with IL-13, collagen levels and ring biomechanics increased over the entire three weeks to levels higher than TGF-β1 alone. Gene expression was differentially regulated by cytokine treatment over the entire three weeks suggesting that increased collagen accumulation was not due to upregulation of collagen gene expression.

These results suggest that TGF-β1 requires a second signal, such as IL-13, to sustain the long-term pathological increases in collagen accumulation and biomechanics that can compromise the function of fibrotic tissues.

Cardiac fibrosis is a physiological process that involves the formation of scar tissue in the heart in response to injury or damage. This process is initially a protective measure characterized by enhanced fibroblasts, which are responsible for producing extracellular matrix proteins that provide structural support to the heart. However, when fibrosis becomes excessive, it can lead to adverse outcomes, including increasing tissue stiffness and impaired cardiac function, which can ultimately result in heart failure with a poor prognosis. While fibroblasts are the primary cells involved in cardiac fibrosis, immune cells have also been found to play a vital role in its progression. Recent research has shown that immune cells exert multifaceted effects besides regulation of inflammatory response. Advanced research techniques such as single-cell sequencing and multiomics have provided insights into the specific subsets of immune cells involved in fibrosis and the complex regulation of the process. Targeted immunotherapy against fibrosis is gaining traction as a potential treatment option, but it is still unclear how immune cells achieve this regulation and whether distinct subsets are involved in different roles. To better understand the role of immune cells in cardiac fibrosis, it is essential to examine the classical signaling pathways that are closely related to fibrosis formation. We have also focused on the unique properties of diverse immune cells in cardiac fibrosis and their specific intercommunications. Therefore, this review will delve into the plasticity and heterogeneity of immune cells and their specific roles in cardiac fibrosis, which propose insights to facilitate the development of anti-fibrosis therapeutic strategies.

Frailty is one of the most common symptoms in patients with cirrhosis. Many researchers have identified it as a prognostic factor for patients with cirrhosis. However, no quantitative meta-analysis has evaluated the prognostic value of frailty in patients with cirrhosis.

This systematic review and meta-analysis aimed to assess the prognostic significance of frailty in patients with cirrhosis.

The systematic review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations. We conducted a comprehensive search of the literature using databases such as PubMed, Cochrane Library, Embase, and Web of Science, as well as China National Knowledge Infrastructure, encompassing the period from inception to 22 December 2023. Data were extracted for frailty to predict adverse outcomes in patients with cirrhosis. RevMan (version 5.3) and R (version 4.2.2) were used to assess the extracted data.

A total of 26 studies with 9597 patients with cirrhosis were included. Compared with patients having low or no frailty, the frail group had a higher mortality rate (relative ratio, RR=2.07, 95% CI 1.82-2.34, P<.001), higher readmission rate (RR=1.50, 95% CI 1.22-1.84, P<.001), and lower quality of life (RR=5.78, 95% CI 2.25-14.82, P<.001). The summary receiver operator characteristic (SROC) curve of frailty for mortality in patients with cirrhosis showed that the false positive rate (FPR) was 0.25 (95% CI 0.17-0.34), diagnostic odds ratio (DOR) was 4.17 (95% CI 2.93-5.93), sensitivity was 0.54 (95% CI 0.39-0.69), and specificity was 0.73 (95% CI 0.64-0.81). The SROC curve of readmission showed that the FPR, DOR, sensitivity, and specificity were 0.39 (95% CI 0.17-0.66), 1.38 (95% CI 0.64-2.93), 0.46 (95% CI 0.28-0.64), and 0.60 (95% CI 0.28-0.85), respectively.

This meta-analysis demonstrated that frailty is a reliable prognostic predictor of outcomes in patients with cirrhosis. To enhance the prognosis of patients with cirrhosis, more studies on frailty screening are required.

This study aimed to investigate the impact of residual ethmoidal laminae after endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP).

This retrospective cohort included 66 patients with CRSwNP who received 300mg of dupilumab every 2weeks for 16weeks between August 2020 and March 2022. Patients were categorized into the no-lamina or residual-lamina groups based on postoperative sinus computed tomography scans. Clinical parameters, including the Lund-Mackay score (primary endpoint), nasal polyp score, T&T olfactometer threshold, and SNOT-22 scores (secondary endpoints), were assessed at baseline and 16weeks posttreatment.

Of 66 patients who received dupilumab, 51 met the inclusion criteria. The no-lamina (n=23) and residual-lamina (n=28) groups exhibited similar baseline characteristics. At 16weeks, the Lund-Mackay Score significant improved in the no-lamina group compared with the residual-lamina group (5±4 vs. 9±4; P=0.004). Non-significant differences were observed in nasal polyp score (2.6±1.6 vs. 3.3±2.0; P=0.22), T&T olfactometer threshold test score, (3.2±1.8 vs. 3.3±1.4; P=0.78) SNOT-22 score, (18±11 vs. 24±13; P=0.15).

This study suggests an association between the absence of residual ethmoidal laminae and an enhanced dupilumab response in CRSwNP. Residual laminae in the anterior ethmoid affect the effectiveness of dupilumab in targeting inflammatory pathways. Meticulous clearance, particularly in the anterior ethmoidal region, optimizes the efficacy of dupilumab. Understanding the influence of residual ethmoidal laminae on dupilumab outcomes is crucial for refining post-ESS treatment strategies for patients with CRSwNP.

Trichinella spiralis infection is a serious parasitic zoonosis in which a collagenous capsule surrounding the larva is developed in the striated muscle cells. However, the mechanism of T. spiralis encapsulation is currently poorly understood. It has been reported that T. spiralis infection can induce the production of IL-13 via the NLRP3 inflammasome, and it has also been suggested IL-13 thus produced may be involved in T. spiralis encapsulation. This research aimed to clarify the involvement of NLRP3 and IL-13 in the T. spiralis capsule formation process. IL-13 and NLRP3 inhibitors were used in a T. spiralis infected mouse model and in C2C12 cells to analyze the role of IL-13 and NLRP3 in encapsulation. The results showed that T. spiralis infection significantly increased the expression levels of IL-13 and collagen IV and VI. The production of collagen around the T. spiralis encapsulation zone was significantly inhibited when an IL-13 inhibitor was applied. Moreover, the expression levels of IL-13 and collagen IV and VI were significantly decreased by the NLRP3 inhibitor in vitro and in vivo. The above results indicated that NLRP3 can participate in the development of T. spiralis encapsulation by regulating IL-13 expression and stimulating collagen IV and VI synthesis during T. spiralis infection.

Airway stenosis (AS) is a fibroinflammatory disease characterized by abnormal activation of fibroblasts and excessive synthesis of extracellular matrix, which has puzzled many doctors despite its relatively low prevalence. Traditional treatment such as endoscopic surgery, open surgery, and adjuvant therapy have many disadvantages and are limited in the treatment of patients with recurrent AS. Therefore, it is urgent to reveal the pathogenesis of AS and accelerate its clinical transformation. Based on the discovered pathogenesis, including fibrosis, inflammation, epithelial-mesenchymal transition, metabolic reprogramming, microbiome, genetic susceptibility, and other mechanisms, researchers have developed a series of treatments, such as drug therapy, gene therapy, stem cell therapy, growth factor therapy, protein therapy, and photodynamic therapy. This review introduces the classification of AS, explores the existing pathogenesis and preclinical treatments developed based on the pathogenesis, and finally summarizes the current clinical management. In addition, the prospect of exploring the interaction between different types of cells and between microorganisms and cells to identify the intersection of multiple mechanisms based on single-cell RNA sequencing, 16S rRNA gene sequencing and shotgun metagenomic sequencing is worth looking forward to.

Pulmonary fibrosis (PF) is progressive and terminal lung disease, which is also the most common sequelae of Corona Virus Disease (2019) (COVID-19) survivors. Unfortunately, there is currently no cure for PF. ShaShen-MaiDong decoction (SMT), a traditional Chinese medicine, has been employed in treating various lung diseases, which may offer potential therapeutic benefits for PF.

To investigate the antifibrotic efficacy of SMT and its major active ingredients as well as the underlying mechanisms for treating PF.

Fist, we build the UPLC-MS based qualitative and quantitative profiling for the quality control of SMT. Then, the antifibrotic efficacy of SMT was investigated in bleomycin (BLM)-induced PF mice model. Network pharmacology was used to predict the mechanism and active components of SMT for the treatment of PF, which was further verified in vitro and in vivo.

SMT improved the weight loss and attenuated hydroxyproline, inflammatory cytokines, and collagen deposition in BLM-induced PF mice model in a dose-dependent manner. Mechanistically, as predicted by network pharmacology analysis, SMT and its active compounds (kaempferol, quercetin, and isorhamnetin) regulated the mitogen-activated protein kinase (MAPK) signaling pathways, TGF-β/Smad signaling pathway, and YAP/TAZ signaling pathway, which was further verified in the PF mice and TGF-β-induced A549 cell model. Moreover, SMT balanced the proportions of increased CD4+ and decreased CD8+ T cells in the peripheral blood of PF mice model.

Considering the high mortality and complex pathogenesis of fibrotic diseases, our results provide novel evidence that SMT would be beneficial for pulmonary fibrosis therapy by modulating MAPK, TGF-β/Smad, and YAP/TAZ signaling pathways at same time.

During skin fibrosis, extracellular matrix proteins are overproduced, and resident lipid-filled mature dermal adipocytes are depleted in both human disease and mouse models. However, the mechanisms underlying this reduction in lipid-filled adipocytes during fibrosis are poorly understood. In this study, we found that adipocyte lipolysis through the rate-limiting enzyme Atgl is required for loss of adipose tissue during skin fibrosis in mice. We found that in 2 fibrotic mouse models, adipocyte lipolysis occurred early during skin fibrosis development, and lipid storage was re-established during fibrosis recovery. In mice lacking Atgl in adipocytes, maintenance of adipocyte lipid storage occurs in both chemical and genetic models of fibrosis development. Transcriptional analysis revealed the upregulation of lipid metabolism/lipolysis genes in the skin of patients with fibrosis. Interestingly, the loss of adipocyte Atgl-driven lipolysis resulted in precocious fibrotic remodeling of the dermal extracellular matrix in bleomycin-treated mice, as indicated by histological and transcriptional changes. These data suggest that dermal adipocyte-derived fatty acids prevent fibrotic extracellular matrix remodeling in fibroblasts during the development of fibrosis. Thus, we suggest that dermal adipocyte-derived fatty acids are released during fibrosis development and delay fibroblast fibrogenic responses, which may hold therapeutic potential for treating fibrotic diseases.

Interleukin-33 (IL-33) is a nuclear factor and member of the IL-1 cytokine family. IL-33 is mainly expressed by epithelial and endothelial cells and exerts its function through interaction with various immune cells, and binding to its receptor can form the IL-33/Suppression of tumorigenicity 2 (ST2) signaling pathway. While most cytokines are actively synthesized within cells, IL-33 is produced passively in response to tissue damage or cell necrosis, indicating its role as a signaling molecule following cellular infection, stress, or trauma. IL-33/ST2 signaling pathway has been proved to play diverse role in the pathological process of central nervous system disorders, cancer, fibrosis, autoimmune diseases, etc. Although research on the IL-33/ST2 signaling pathway has deepened recently, relevant treatment strategies have been proposed, and even targeted drugs are in the preclinical stage; further research on the effect of the IL-33/ST2 signaling pathway in different diseases is still necessary, to provide a clearer understanding of the different roles of IL-33/ST2 in disease progression and to develop new drugs and treatment strategies. Because IL-33/ST2 plays an important role in the occurrence and progression of diseases, the study of therapeutic drugs targeting this pathway is also necessary. This review focused on recent studies on the positive or negative role of IL-33/ST2 in different diseases, as well as the current related drugs targeting IL-33/ST2 in the preclinical and clinical stage. The mechanism of IL-33/ST2 in different diseases and its mediating effect on different immune cells have been summarized, as well as the antibody drugs targeting IL-33 or ST2, natural compounds with a mediating effect, and small molecule substances targeting relative pathway. We aim to provide new ideas and treatment strategies for IL-33/ST2-related drugs to treat different diseases.

Macrophages are innate immune cells present in all tissues and play an important role in almost all aspects of the biology of living organisms. Extracellular vesicles (EVs) are released by cells and transport their contents (micro RNAs, mRNA, proteins, and long noncoding RNAs) to nearby or distant cells for cell-to-cell communication. Numerous studies have shown that macrophage-derived extracellular vesicles (M-EVs) and their contents play an important role in a variety of diseases and show great potential as biomarkers, therapeutics, and drug delivery vehicles for diseases. This article reviews the biological functions and mechanisms of M-EVs and their contents in chronic non-communicable diseases such as cardiovascular diseases, metabolic diseases, cancer, inflammatory diseases and bone-related diseases. In addition, the potential application of M-EVs as drug delivery systems for various diseases have been summarized.

Tissue fibrosis results from a dysregulated and chronic wound healing response accompanied by chronic inflammation and angiogenesis. Regardless of the affected organ, fibrosis shares the following common hallmarks: the recruitment of immune cells, fibroblast activation/proliferation, and excessive extracellular matrix deposition. Chemokines play a pivotal role in initiating and advancing these fibrotic processes. CCL24 (eotaxin-2) is a chemokine secreted by immune cells and epithelial cells, which promotes the trafficking of immune cells and the activation of profibrotic cells through CCR3 receptor binding. Higher levels of CCL24 and CCR3 were found in the tissue and sera of patients with fibro-inflammatory diseases, including primary sclerosing cholangitis (PSC), systemic sclerosis (SSc), and metabolic dysfunction-associated steatohepatitis (MASH). This review delves into the intricate role of CCL24 in fibrotic diseases, highlighting its impact on fibrotic, immune, and vascular pathways. We focus on the preclinical and clinical evidence supporting the therapeutic potential of blocking CCL24 in diseases that involve excessive inflammation and fibrosis.

Chitosan, a biodegradable and biocompatible natural polymer composed of β-(1-4)-linked N-acetyl glucosamine (GlcNAc) and d-glucosamine (GlcN) and derived from crustacean shells, has been widely studied for various biomedical applications, including drug delivery, cartilage repair, wound healing, and tissue engineering, because of its unique physicochemical properties. One of the most promising areas of research is the investigation of the immunomodulatory properties of chitosan, since the biopolymer has been shown to modulate the maturation, activation, cytokine production, and polarization of dendritic cells and macrophages, two key immune cells involved in the initiation and regulation of innate and adaptive immune responses, leading to enhanced immune responses. Several signaling pathways, including the cGAS-STING, STAT-1, and NLRP3 inflammasomes, are involved in chitosan-induced immunomodulation. This review provides a comprehensive overview of the current understanding of the in vitro immunomodulatory effects of chitosan. This information may facilitate the development of chitosan-based therapies and vaccine adjuvants for various immune-related diseases.

Th1/Th2 polarisation and suppressor of cytokine signalling-3 (SOCS3) are important indicators of the humoral and cellular immune system activity in cows. The aim of this study was to determine the correlation of postpartum diseases with the levels of Th1/Th2 polarisation and SOCS3 at the time of parturition. The study examined 180 cows (90 with normal parturition [NP] and 90 with dystocia [D]). Blood samples were taken from the cows once at the time of calving. Two subgroups were created among cows with NP: those without the postpartum disease (NP [-], n = 45) and those with postpartum disease (NP [+], n = 45). Likewise, two subgroups were created among D cows: those without postpartum disease (D [-], n = 45) and those with postpartum disease (D [+], n = 45). Cytokine analyses were performed using species-specific commercial ELISA kits. In the NP (-) group, it was found that Th1/Th2 cytokine polarisation was in the Th1 direction due to the increase in the concentration of IFN-γ, TNF-α and IL-2 in four subgroups grouping with different types of parturition and diseases. It was concluded that it would be appropriate to strengthen cellular immunity. In cases of postpartum diseases, Th1/Th2 polarisation shifted towards Th2 due to the increase in IL-4 and IL-5 concentrations in cows that performed NP and developed mastitis in the postpartum period. These results suggest that it would be beneficial to support the Th2 aspect (i.e. humoral immunity) in cows that have undergone NP and develop mastitis in the postpartum period.

Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) constitute members of the dual-specificity family of protein phosphatases that dephosphorylate the MAPKs. MKP-5 dephosphorylates the stress-responsive MAPKs, p38 MAPK and JNK, and has been shown to promote tissue fibrosis. Here, we provide insight into how MKP-5 regulates the transforming growth factor-β (TGF-β) pathway, a well-established driver of fibrosis. We show that MKP-5-deficient fibroblasts in response to TGF-β are impaired in SMAD2 phosphorylation at canonical and non-canonical sites, nuclear translocation, and transcriptional activation of fibrogenic genes. Consistent with this, pharmacological inhibition of MKP-5 is sufficient to block TGF-β signaling, and that this regulation occurs through a JNK-dependent pathway. By utilizing RNA sequencing and transcriptomic analysis, we identify TGF-β signaling activators regulated by MKP-5 in a JNK-dependent manner, providing mechanistic insight into how MKP-5 promotes TGF-β signaling. This study elucidates a novel mechanism whereby MKP-5-mediated JNK inactivation is required for TGF-β signaling and provides insight into the role of MKP-5 in tissue fibrosis.

Juvenile systemic sclerosis (jSSc), the pediatric counterpart of systemic sclerosis (SSc), is a rare autoimmune disorder characterized by vasculopathy and fibrotic disorders. It ranks among the rheumatologic diseases with the highest rates of morbidity and mortality, predominantly impacting females. Although a universally accepted classification for jSSc remains elusive, a provisional classification proposed in 2007 integrates major and minor criteria, reflecting the involvement of diverse organs and tissues. Pulmonary manifestations are relatively common in jSSc, occurring in 36% to 55% of cases. Particularly lung complications include children s interstitial lung disease (chILD), pulmonary arterial hypertension (PAH) and nodules. The aim of this paper is to describe the main pulmonary manifestations of patients with jSSc in relation to SSc, highlighting fundamental pathophysiological, and clinical features based on the latest literature data.

Idiopathic pulmonary fibrosis (IPF) remains a challenging disease with no drugs available to change the trajectory. It is a condition associated with excessive and highly progressive scarring of the lungs with remodelling and extracellular matrix deposition. It is a highly "destructive" disease of the lungs. The diagnosis of IPF is challenging due to continuous evolution of the disease, which also makes early interventions very difficult. The role of vascular endothelial cells has not been explored in IPF in great detail. We do not know much about their contribution to arterial or vascular remodelling, extracellular matrix changes and contribution to pulmonary hypertension and lung fibrosis in general. Endothelial to mesenchymal transition appears to be central to such changes in IPF. Similarly, for epithelial changes, the process of epithelial to mesenchymal transition seem to be the key both for airway epithelial cells and type-2 pneumocytes. We focus here on endothelial and epithelial cell changes and its contributions to IPF. In this review we revisit the pathology of IPF, mechanistic signalling pathways, clinical definition, update on diagnosis and new advances made in treatment of this disease. We discuss ongoing clinical trials with mode of action. A multidisciplinary collaborative approach is needed to understand this treacherous disease for new therapeutic targets.

Interleukin-4 (IL-4), which is traditionally associated with inflammation, has emerged as a key player in tissue regeneration. Produced primarily by T-helper 2 (Th2) and other immune cells, IL-4 activates endogenous lymphocytes and promotes M2 macrophage polarization, both of which are crucial for tissue repair. Moreover, IL-4 stimulates the proliferation and differentiation of various cell types, contributing to efficient tissue regeneration, and shows promise for promoting tissue regeneration after injury. This review explores the multifaceted roles of IL-4 in tissue repair, summarizing its mechanisms and potential for clinical application. This review delves into the multifaceted functions of IL-4, including its immunomodulatory effects, its involvement in tissue regeneration, and its potential therapeutic applications. We discuss the mechanisms underlying IL-4-induced M2 macrophage polarization, a crucial process for tissue repair. Additionally, we explore innovative strategies for delivering IL-4, including gene therapy, protein-based therapies, and cell-based therapies. By leveraging the regenerative properties of IL-4, we can potentially develop novel therapies for various diseases, including chronic inflammatory disorders, autoimmune diseases, and organ injuries. While early research has shown promise for the application of IL-4 in regenerative medicine, further studies are needed to fully elucidate its therapeutic potential and optimize its use.