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Wang Z, Nie K, Liang Y, Niu J, Yu X, Zhang O, Liu L, Shi X, Wang Y, Feng X, Zhu Y, Wang P, Cheng G. A mosquito salivary protein-driven influx of myeloid cells facilitates flavivirus transmission. EMBO J 2024; 43:1690-1721. [PMID: 38378891 PMCID: PMC11066113 DOI: 10.1038/s44318-024-00056-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 01/29/2024] [Accepted: 02/02/2024] [Indexed: 02/22/2024] Open
Abstract
Mosquitoes transmit many disease-relevant flaviviruses. Efficient viral transmission to mammalian hosts requires mosquito salivary factors. However, the specific salivary components facilitating viral transmission and their mechanisms of action remain largely unknown. Here, we show that a female mosquito salivary gland-specific protein, here named A. aegypti Neutrophil Recruitment Protein (AaNRP), facilitates the transmission of Zika and dengue viruses. AaNRP promotes a rapid influx of neutrophils, followed by virus-susceptible myeloid cells toward mosquito bite sites, which facilitates establishment of local infection and systemic dissemination. Mechanistically, AaNRP engages TLR1 and TLR4 of skin-resident macrophages and activates MyD88-dependent NF-κB signaling to induce the expression of neutrophil chemoattractants. Inhibition of MyD88-NF-κB signaling with the dietary phytochemical resveratrol reduces AaNRP-mediated enhancement of flavivirus transmission by mosquitoes. These findings exemplify how salivary components can aid viral transmission, and suggest a potential prophylactic target.
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Affiliation(s)
- Zhaoyang Wang
- New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, 100084, China
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, 518000, China
- Institute of Pathogenic Organisms, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China
| | - Kaixiao Nie
- Department of Pathogen Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, China
| | - Yan Liang
- New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, 100084, China
- School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Jichen Niu
- New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, 100084, China
| | - Xi Yu
- New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, 100084, China
- School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Oujia Zhang
- Department of Pathogen Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100086, China
| | - Long Liu
- Institute of Virology, Hubei University of Medicine, Shiyan, 442000, China
- Department of Infectious Diseases, Renmin Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, China
| | - Xiaolu Shi
- Institute of Pathogenic Organisms, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China
| | - Yibaina Wang
- China National Center for Food Safety Risk Assessment, Beijing, 100022, China
| | - Xuechun Feng
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, 518000, China
| | - Yibin Zhu
- New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, 100084, China
- Institute of Pathogenic Organisms, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China
| | - Penghua Wang
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Gong Cheng
- New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, 100084, China.
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, 518000, China.
- Institute of Pathogenic Organisms, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China.
- Southwest United Graduate School, Kunming, 650092, China.
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Annamalai P, Thangam EB. Vitex trifolia L. modulates inflammatory mediators via down-regulation of the NF-κB signaling pathway in carrageenan-induced acute inflammation in experimental rats. JOURNAL OF ETHNOPHARMACOLOGY 2022; 298:115583. [PMID: 36028166 DOI: 10.1016/j.jep.2022.115583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 07/23/2022] [Accepted: 07/25/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Vitex trifolia L. (V. trifolia L.), commonly known as the three-leaved chaste tree, is extensively employed in traditional Chinese medicine (TCM) to treat various conditions associated with inflammation. AIM OF THE STUDY The present study aimed to delineate the molecular mechanisms responsible for the anti-inflammatory effect of V. trifolia L. in carrageenan (CA)-induced acute inflammation in experimental rats. MATERIALS AND METHODS CA-induced rat paw edema model was adopted to investigate the anti-inflammatory effect of methanolic extract from leaves of V. trifolia L. (VTME) in vivo. Leukocyte infiltration into the site of inflammation was determined by histopathological analysis. Further, the effect of VTME on CA-induced local and systemic levels of specific cytokines was quantified by enzyme-linked immunosorbent assay (ELISA). Moreover, its impact on the nuclear translocation of nuclear factor Kappa B (NF-κB) was analyzed by employing the western blotting technique. RESULTS VTME at the doses of 100 mg/kg and 200 mg/kg significantly inhibited the paw edema induced by CA (p < 0.05) and effectively reduced the inflammatory leukocyte infiltration. Further, VTME markedly inhibited the CA-induced levels of Interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α in tissue, and that of cytokine-induced neutrophil chemoattractant (CINC)-2/C-X-C motif chemokine (CXCL)3 and CINC-3/CXCL2 in tissue as well as in serum. On the other hand, VTME significantly upregulated the tissue concentration of anti-inflammatory cytokine IL-10. Moreover, VTME significantly attenuated the CA-induced IκBα degradation and nuclear translocation of NF-κB p65. CONCLUSIONS Our results demonstrate the potent anti-inflammatory effect of V. trifolia L. in vivo, providing insight into its molecular mechanism, which is mediated through down-regulation of NF-κB signal transduction.
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Affiliation(s)
- Parvathi Annamalai
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India.
| | - Elden Berla Thangam
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India.
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Lee HY, You DJ, Taylor-Just AJ, Linder KE, Atkins HM, Ralph LM, De la Cruz G, Bonner JC. Pulmonary exposure of mice to ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX) suppresses the innate immune response to carbon black nanoparticles and stimulates lung cell proliferation. Inhal Toxicol 2022; 34:244-259. [PMID: 35704474 DOI: 10.1080/08958378.2022.2086651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Per- and polyfluoroalkyl substances (PFAS) have been associated with respiratory diseases in humans, yet the mechanisms through which PFAS cause susceptibility to inhaled agents is unknown. Herein, we investigated the effects of ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX), an emerging PFAS, on the pulmonary immune response of mice to carbon black nanoparticles (CBNP). We hypothesized that pulmonary exposure to GenX would increase susceptibility to CBNP through suppression of innate immunity. METHODS Male C57BL/6 mice were exposed to vehicle, 4 mg/kg CBNP, 10 mg/kg GenX, or CBNP and GenX by oropharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) was collected at 1 and 14 days postexposure for cytokines and total protein. Lung tissue was harvested for histopathology, immunohistochemistry (Ki67 and phosphorylated (p)-STAT3), western blotting (p-STAT3 and p-NF-κB), and qRT-PCR for cytokine mRNAs. RESULTS CBNP increased CXCL-1 and neutrophils in BALF at both time points evaluated. However, GenX/CBNP co-exposure reduced CBNP-induced CXCL-1 and neutrophils in BALF. Moreover, CXCL-1, CXCL-2 and IL-1β mRNAs were increased by CBNP in lung tissue but reduced by GenX. Western blotting showed that CBNP induced p-NF-κB in lung tissue, while the GenX/CBNP co-exposed group displayed decreased p-NF-κB. Furthermore, mice exposed to GenX or GenX/CBNP displayed increased numbers of BALF macrophages undergoing mitosis and increased Ki67 immunostaining. This was correlated with increased p-STAT3 by western blotting and immunohistochemistry in lung tissue from mice co-exposed to GenX/CBNP. CONCLUSIONS Pulmonary exposure to GenX suppressed CBNP-induced innate immune response in the lungs of mice yet promoted the proliferation of macrophages and lung epithelial cells.
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Affiliation(s)
- Ho Young Lee
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Dorothy J You
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Alexia J Taylor-Just
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Keith E Linder
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, USA
| | - Hannah M Atkins
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, USA.,Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Lauren M Ralph
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Gabriela De la Cruz
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - James C Bonner
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
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Takeda T, Yamano S, Goto Y, Hirai S, Furukawa Y, Kikuchi Y, Misumi K, Suzuki M, Takanobu K, Senoh H, Saito M, Kondo H, Daghlian G, Hong YK, Yoshimatsu Y, Hirashima M, Kobashi Y, Okamoto K, Kishimoto T, Umeda Y. Dose-response relationship of pulmonary disorders by inhalation exposure to cross-linked water-soluble acrylic acid polymers in F344 rats. Part Fibre Toxicol 2022; 19:27. [PMID: 35395797 PMCID: PMC8994297 DOI: 10.1186/s12989-022-00468-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/30/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND In Japan, six workers handling cross-linked water-soluble acrylic acid polymer (CWAAP) at a chemical plant suffered from lung diseases, including fibrosis, interstitial pneumonia, emphysema, and pneumothorax. We recently demonstrated that inhalation of CWAAP-A, one type of CWAAP, causes pulmonary disorders in rats. It is important to investigate dose-response relationships and recoverability from exposure to CWAAPs for establishing occupational health guidelines, such as setting threshold limit value for CWAAPs in the workplace. METHODS Male and female F344 rats were exposed to 0.3, 1, 3, or 10 mg/m3 CWAAP-A for 6 h/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. At 1 h, 4 weeks, and 13 weeks after the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. In a second experiment, male rats were pre-treated with clodronate liposome or polymorphonuclear leukocyte-neutralizing antibody to deplete macrophages or neutrophils, respectively, and exposed to CWAAP-A for 6 h/day for 2 days. RESULTS CWAAP-A exposure damaged only the alveoli. The lowest observed adverse effect concentration (LOAEC) was 1 mg/m3 and the no observed adverse effect concentration (NOAEC) was 0.3 mg/m3. Rats of both sexes were able to recover from the tissue damage caused by 13 weeks exposure to 1 mg/m3 CWAAP-A. In contrast, tissue damage caused by exposure to 3 and 10 mg/m3 was irreversible due to the development of interstitial lung lesions. There was a gender difference in the recovery from CWAAP-A induced pulmonary disorders, with females recovering less than males. Finally, acute lung effects caused by CWAAP-A were significantly reduced by depletion of alveolar macrophages. CONCLUSIONS Pulmonary damage caused by inhalation exposure to CWAAP-A was dose-dependent, specific to the lung and lymph nodes, and acute lung damage was ameliorated by depleting macrophages in the lungs. CWAAP-A had both a LOAEC and a NOAEC, and tissue damage caused by exposure to 1 mg/m3 CWAAP-A was reversible: recovery in female rats was less than for males. These findings indicate that concentration limits for CWAAPs in the workplace can be determined.
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Affiliation(s)
- Tomoki Takeda
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan.
| | - Shotaro Yamano
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan.
| | - Yuko Goto
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan
| | - Shigeyuki Hirai
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan
| | - Yusuke Furukawa
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan
| | - Yoshinori Kikuchi
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan
| | - Kyohei Misumi
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan
| | - Masaaki Suzuki
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan
| | - Kenji Takanobu
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan
| | - Hideki Senoh
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan
| | - Misae Saito
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan
| | - Hitomi Kondo
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan
| | - George Daghlian
- Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Young-Kwon Hong
- Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yasuhiro Yoshimatsu
- Division of Pharmacology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Masanori Hirashima
- Division of Pharmacology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Yoichiro Kobashi
- Department of Pathology, Tenri Hospital, Tenri, Nara, 632-8552, Japan
| | - Kenzo Okamoto
- Department of Pathology, Hokkaido Chuo Rosai Hospital, Japan Organization of Occupational Health and Safety, Iwamizawa, Hokkaido, 068-0004, Japan
| | - Takumi Kishimoto
- Director of Research and Training Center for Asbestos-Related Diseases, Okayama, Okayama, 702-8055, Japan
| | - Yumi Umeda
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Hadano, Kanagawa, 257-0015, Japan
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Nakatake R, Hishikawa H, Kotsuka M, Ishizaki M, Matsui K, Nishizawa M, Yoshizawa K, Kaibori M, Okumura T. The Proton Pump Inhibitor Lansoprazole Has Hepatoprotective Effects in In Vitro and In Vivo Rat Models of Acute Liver Injury. Dig Dis Sci 2019; 64:2854-2866. [PMID: 30989463 DOI: 10.1007/s10620-019-05622-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 04/08/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS The proton pump inhibitor lansoprazole (LPZ) is clinically used to reduce gastric acid secretion, but little is known about its possible hepatoprotective effects. This study aimed to investigate the hepatoprotective effects of LPZ and its potential mechanisms using in vitro and in vivo rat models of liver injury. METHODS For the in vitro model of liver injury, primary cultured rat hepatocytes were treated with interleukin-1β in the presence or absence of LPZ. The influence of LPZ on inducible nitric oxide synthase (iNOS) induction and nitric oxide (NO) production and on the associated signaling pathways was analyzed. For the in vivo model, rats were treated with D-galactosamine (GalN) and lipopolysaccharide (LPS). The effects of LPZ on survival and proinflammatory mediator expression (including iNOS and tumor necrosis factor-α) in these rats were examined. RESULTS LPZ inhibited iNOS induction partially through suppression of the nuclear factor-kappa B signaling pathway in hepatocytes, thereby reducing potential liver injury from excessive NO levels. Additionally, LPZ increased survival by 50% and decreased iNOS, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-1 mRNA expression in the livers of GalN/LPS-treated rats. LPZ also inhibited nuclear factor-kappa B activation by GalN/LPS. CONCLUSIONS LPZ inhibits the induction of several inflammatory mediators (including cytokines, chemokines, and NO) partially through suppression of nuclear factor-kappa B, resulting in the prevention of fulminant liver failure. The therapeutic potential of LPZ for liver injuries warrants further investigation.
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Affiliation(s)
- Richi Nakatake
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
| | - Hidehiko Hishikawa
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Masaya Kotsuka
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Morihiko Ishizaki
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Kosuke Matsui
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Mikio Nishizawa
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan
| | - Katsuhiko Yoshizawa
- Laboratory of Environmental Sciences, Department of Food Sciences and Nutrition, School of Human Environmental Sciences, Mukogawa Women's University, 6-46 Ikebiraki-cho, Nishinomiya, Hyogo, 663-8558, Japan
| | - Masaki Kaibori
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Tadayoshi Okumura
- Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.,Research Organization of Science and Technology, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan
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Chandler JD, Hu X, Ko EJ, Park S, Fernandes J, Lee YT, Orr ML, Hao L, Smith MR, Neujahr DC, Uppal K, Kang SM, Jones DP, Go YM. Low-dose cadmium potentiates lung inflammatory response to 2009 pandemic H1N1 influenza virus in mice. ENVIRONMENT INTERNATIONAL 2019; 127:720-729. [PMID: 30999129 PMCID: PMC6536378 DOI: 10.1016/j.envint.2019.03.054] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 03/08/2019] [Accepted: 03/24/2019] [Indexed: 05/04/2023]
Abstract
Cadmium (Cd) is a toxic, pro-inflammatory metal ubiquitous in the diet that accumulates in body organs due to inefficient elimination. Responses to influenza virus infection are variable, particularly severity of pneumonia. We used a murine model of chronic low-dose oral exposure to Cd to test if increased lung tissue Cd worsened inflammation in response to sub-lethal H1N1 infection. The results show that Cd-treated mice had increased lung tissue inflammatory cells, including neutrophils, monocytes, T lymphocytes and dendritic cells, following H1N1 infection. Lung genetic responses to infection (increasing TNF-α, interferon and complement, and decreasing myogenesis) were also exacerbated. To reveal the organization of a network structure, pinpointing molecules critical to Cd-altered lung function, global correlations were made for immune cell counts, leading edge gene transcripts and metabolites. This revealed that Cd increased correlation of myeloid immune cells with pro-inflammatory genes, particularly interferon-γ and metabolites. Together, the results show that Cd burden in mice increased inflammation in response to sub-lethal H1N1 challenge, which was coordinated by genetic and metabolic responses, and could provide new targets for intervention against lethal inflammatory pathology of clinical H1N1 infection.
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Affiliation(s)
- Joshua D Chandler
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States of America
| | - Xin Hu
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States of America
| | - Eun-Ju Ko
- Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30303, United States of America
| | - Soojin Park
- Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30303, United States of America
| | - Jolyn Fernandes
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States of America
| | - Young-Tae Lee
- Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30303, United States of America
| | - Michael L Orr
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States of America
| | - Li Hao
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States of America
| | - M Ryan Smith
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States of America
| | - David C Neujahr
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States of America
| | - Karan Uppal
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States of America
| | - Sang-Moo Kang
- Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30303, United States of America
| | - Dean P Jones
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States of America.
| | - Young-Mi Go
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States of America.
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Jin J, Xu W, Wan B, Wang X, Zhou Z, Miao Y, Lv T, Song Y. Topotecan Alleviates Lipopolysaccharide-Mediated Acute Lung Injury Via the NF-κB Signaling Pathway. J Surg Res 2019; 235:83-92. [DOI: 10.1016/j.jss.2018.08.057] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 07/30/2018] [Accepted: 08/24/2018] [Indexed: 12/14/2022]
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8
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Zhang K, Shi MJ, Niu Z, Chen X, Wei JY, Miao ZW, Zhao WD, Chen YH. Activation of brain endothelium by Escherichia coli K1 virulence factor cglD promotes polymorphonuclear leukocyte transendothelial migration. Med Microbiol Immunol 2018; 208:59-68. [DOI: 10.1007/s00430-018-0560-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 08/29/2018] [Indexed: 12/01/2022]
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9
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Gal Y, Mazor O, Falach R, Sapoznikov A, Kronman C, Sabo T. Treatments for Pulmonary Ricin Intoxication: Current Aspects and Future Prospects. Toxins (Basel) 2017; 9:E311. [PMID: 28972558 PMCID: PMC5666358 DOI: 10.3390/toxins9100311] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 09/26/2017] [Accepted: 09/29/2017] [Indexed: 12/13/2022] Open
Abstract
Ricin, a plant-derived toxin originating from the seeds of Ricinus communis (castor beans), is one of the most lethal toxins known, particularly if inhaled. Ricin is considered a potential biological threat agent due to its high availability and ease of production. The clinical manifestation of pulmonary ricin intoxication in animal models is closely related to acute respiratory distress syndrome (ARDS), which involves pulmonary proinflammatory cytokine upregulation, massive neutrophil infiltration and severe edema. Currently, the only post-exposure measure that is effective against pulmonary ricinosis at clinically relevant time-points following intoxication in pre-clinical studies is passive immunization with anti-ricin neutralizing antibodies. The efficacy of this antitoxin treatment depends on antibody affinity and the time of treatment initiation within a limited therapeutic time window. Small-molecule compounds that interfere directly with the toxin or inhibit its intracellular trafficking may also be beneficial against ricinosis. Another approach relies on the co-administration of antitoxin antibodies with immunomodulatory drugs, thereby neutralizing the toxin while attenuating lung injury. Immunomodulators and other pharmacological-based treatment options should be tailored according to the particular pathogenesis pathways of pulmonary ricinosis. This review focuses on the current treatment options for pulmonary ricin intoxication using anti-ricin antibodies, disease-modifying countermeasures, anti-ricin small molecules and their various combinations.
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Affiliation(s)
- Yoav Gal
- Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 76100, Israel.
| | - Ohad Mazor
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 76100, Israel.
| | - Reut Falach
- Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 76100, Israel.
| | - Anita Sapoznikov
- Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 76100, Israel.
| | - Chanoch Kronman
- Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 76100, Israel.
| | - Tamar Sabo
- Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 76100, Israel.
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10
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Elental® amino acid component has protective effects on primary cultured hepatocytes and a rat model of acute liver injury. Nutr Res 2017. [PMID: 28633873 DOI: 10.1016/j.nutres.2017.04.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Amino acids can exert protective effects on the liver either when administered as a medication or following an operation. In this study, we examined the protective effects of amino acids on the liver using in vitro and in vivo models by studying their influence on the induction of inducible nitric oxide synthase (iNOS) and nitric oxide production as a liver injury marker in cultured hepatocytes and liver-protective effects in d-galactosamine and lipopolysaccharide (GalN/LPS)-treated rats, respectively. Primary cultured rat hepatocytes were treated with interleukin (IL)-1β in the presence or absence of Elental® amino acid component (EleAA; 17 amino acids). Rats were pretreated with either EleAA or a diet containing selected amino acids followed by GalN/LPS injection. Survival rate and mRNA expression were analyzed. EleAA inhibited iNOS induction through reduction of mRNA synthesis and stability in cultured hepatocytes, indicating prevention of liver injury, but did not show a liver-protective effect in GalN/LPS rats. Among EleAA, Lys, Trp, His, and Arg (4AA) markedly decreased nitric oxide production and inhibited nuclear factor-κB (NF-κB) activation. In GalN/LPS rats, 4AA (3% of each amino acid in diet) increased survival rate by 50% and decreased mRNA expression of iNOS, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-1 in the liver. 4AA reduced NF-κB activation induced by GalN/LPS. 4AA inhibited the expression of inflammatory mediators, in part through inhibition of NF-κB activation in cultured hepatocytes and GalN/LPS-treated rats. The results suggest that EleAA has therapeutic potential for organ injuries including liver.
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Calkins CM, Bensard DD, Shames BD, Pulido EJ, Abraham E, Fernandez N, Xianzhong Meng, Dinarello CA, McIntyre RC. IL-1 regulates in vivo C—X—C chemokine induction and neutrophil sequestration following endotoxemia. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519020080010601] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The influx of neutrophils into tissues in response to inflammatory stimuli involves C—X—C chemokines. Interleukin-1 (IL-1) stimulates chemokine production in vitro , but its role in vivo on chemokine production is not as clearly understood. We hypothesized that IL-1 mediates in vivo tissue C—X—C chemokine production induced by systemic lipopolysaccharide (LPS). IL-1 activity was blockedbyIL-1 receptor antagonist (IL-1Ra). Rats were injected with Salmonella typhi LPS (0.5 mg/kg) with and without prior administration of IL-1Ra. Cytokine-induced neutrophil chemoattractant-1 (CINC-1) and macrophage inflammatory protein-2 (MIP-2) protein and mRNA levels, tissue neutrophil accumulation, and indices of organ injury were measured. LPS administration resulted in increased plasma, lung, and liver IL-1β that was decreased by IL-1Ra. LPS also induced an increase in plasma, lung, and liver CINC-1 and MIP-2 protein and mRNA. However, IL-1Ra had no effect on LPS-induced plasma or lung tissue CINC-1 levels. In contrast, IL-1Ra pretreatment did significantly decrease CINC-1 protein expression in the liver (45% decrease) and MIP-2 protein expression in plasma (100% decrease), lung (72% decrease) and liver (100% decrease) compared to LPS-treated controls. Steady-state mRNA levels by Northern blot analysis of both CINC-1 and MIP-2 in lung and liver were similar to the protein findings. Pretreatment with IL-1Ra also resulted in a 47% and 59% decrease in lung and liver neutrophil accumulation, respectively, following LPS. In addition, indices of both lung and liver injury were decreased in animals pretreated with IL-1Ra. In summary, LPS induces IL-1β and MIP-2 expression in the lung and liver, both of which are IL-1 dependent. Although lung neutrophil accumulation in both lung and liver after LPS is also IL-1 mediated, lung CINC-1 levels were unaffected by IL-1Ra. These data suggest that IL-1 regulates tissue chemokine expression and neutrophil accumulation after LPS.
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Affiliation(s)
- Casey M. Calkins
- Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,
| | - Denis D. Bensard
- Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,, Division of Pediatric Surgery, The Children's Hospital, and Department of Medicine,
| | - Brian D. Shames
- Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,
| | - Edward J. Pulido
- Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,
| | | | - Nathan Fernandez
- Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,
| | - Xianzhong Meng
- Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,
| | - Charles A. Dinarello
- Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA
| | - Robert C. McIntyre
- Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,
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Fonai F, Priber JK, Jakus PB, Kalman N, Antus C, Pollak E, Karsai G, Tretter L, Sumegi B, Veres B. Lack of cyclophilin D protects against the development of acute lung injury in endotoxemia. Biochim Biophys Acta Mol Basis Dis 2015; 1852:2563-73. [PMID: 26385159 DOI: 10.1016/j.bbadis.2015.09.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 09/04/2015] [Accepted: 09/12/2015] [Indexed: 01/19/2023]
Abstract
Sepsis caused by LPS is characterized by an intense systemic inflammatory response affecting the lungs, causing acute lung injury (ALI). Dysfunction of mitochondria and the role of reactive oxygen (ROS) and nitrogen species produced by mitochondria have already been proposed in the pathogenesis of sepsis; however, the exact molecular mechanism is poorly understood. Oxidative stress induces cyclophilin D (CypD)-dependent mitochondrial permeability transition (mPT), leading to organ failure in sepsis. In previous studies mPT was inhibited by cyclosporine A which, beside CypD, inhibits cyclophilin A, B, C and calcineurin, regulating cell death and inflammatory pathways. The immunomodulatory side effects of cyclosporine A make it unfavorable in inflammatory model systems. To avoid these uncertainties in the molecular mechanism, we studied endotoxemia-induced ALI in CypD(-/-) mice providing unambiguous data for the pathological role of CypD-dependent mPT in ALI. Our key finding is that the loss of this essential protein improves survival rate and it can intensely ameliorate endotoxin-induced lung injury through attenuated proinflammatory cytokine release, down-regulation of redox sensitive cellular pathways such as MAPKs, Akt, and NF-κB and reducing the production of ROS. Functional inhibition of NF-κB was confirmed by decreased expression of NF-κB-mediated proinflammatory genes. We demonstrated that impaired mPT due to the lack of CypD reduces the severity of endotoxemia-induced lung injury suggesting that CypD specific inhibitors might have a great therapeutic potential in sepsis-induced organ failure. Our data highlight a previously unknown regulatory function of mitochondria during inflammatory response.
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Affiliation(s)
- Fruzsina Fonai
- Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary
| | - Janos K Priber
- Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary
| | - Peter B Jakus
- Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary
| | - Nikoletta Kalman
- Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary
| | - Csenge Antus
- Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary
| | - Edit Pollak
- Department of Comparative Anatomy and Developmental Biology, Faculty of Sciences, University of Pecs, Pecs, Hungary
| | - Gergely Karsai
- Department of Comparative Anatomy and Developmental Biology, Faculty of Sciences, University of Pecs, Pecs, Hungary
| | - Laszlo Tretter
- Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary
| | - Balazs Sumegi
- Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary; Szentagothai Research Center, University of Pecs, Pecs, Hungary; MTA-PTE Nuclear and Mitochondrial Interactions Research Group, Pecs, Hungary
| | - Balazs Veres
- Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary.
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Xu Y, Zhang S, Niu H, Ye Y, Hu F, Chen S, Li X, Luo X, Jiang S, Liu Y, Chen Y, Li J, Xiang R, Li N. STIM1 accelerates cell senescence in a remodeled microenvironment but enhances the epithelial-to-mesenchymal transition in prostate cancer. Sci Rep 2015; 5:11754. [PMID: 26257076 PMCID: PMC4530453 DOI: 10.1038/srep11754] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 06/01/2015] [Indexed: 12/19/2022] Open
Abstract
The importance of store-operated Ca2+ entry (SOCE) and the role of its key molecular regulators, STIM1 and ORAI1, in the development of cancer are emerging. Here, we report an unexpected dual function of SOCE in prostate cancer progression by revealing a decrease in the expression of STIM1 in human hyperplasia and tumor tissues of high histological grade and by demonstrating that STIM1 and ORAI1 inhibit cell growth by arresting the G0/G1 phase and enhancing cell senescence in human prostate cancer cells. In addition, STIM1 and ORAI1 inhibited NF-κB signaling and remodeled the tumor microenvironment by reducing the formation of M2 phenotype macrophages, possibly creating an unfavorable tumor microenvironment and inhibiting cancer development. However, STIM1 also promoted cell migration and the epithelial-to-mesenchymal transition by activating TGF-β, Snail and Wnt/β-Catenin pathways. Thus, our study revealed novel regulatory effects and the mechanisms by which STIM1 affects cell senescence, tumor migration and the tumor microenvironment, revealing that STIM1 has multiple functions in prostate cancer cells.
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Affiliation(s)
- Yingxi Xu
- 1] School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China [2] State Key Lab of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin 300020, China
| | - Shu Zhang
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
| | - Haiying Niu
- Department of Obstetrics and Gynecology, First Central Hospital Clinic Institute, Tianjin Medical University, 24 Fukang Road, Tianjin 300192 China
| | - Yujie Ye
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
| | - Fen Hu
- School of Physics, Nankai University, 94 Weijin Road, Tianjin 300071, China
| | - Si Chen
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
| | - Xuefei Li
- Beijing Health Vocational College, 94 Nanhengxijie Street, Beijing, 100053 China
| | - Xiaohe Luo
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
| | - Shan Jiang
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
| | - Yanhua Liu
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
| | - Yanan Chen
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
| | - Junying Li
- Department of Obstetrics and Gynecology, First Central Hospital Clinic Institute, Tianjin Medical University, 24 Fukang Road, Tianjin 300192 China
| | - Rong Xiang
- 1] School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China [2] Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Tianjin 300071, China [3] Collaborative Innovation Center for Biotherapy, Nankai University, 94 Weijin Road, Tianjin 300071, China
| | - Na Li
- 1] School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China [2] Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Tianjin 300071, China [3] Collaborative Innovation Center for Biotherapy, Nankai University, 94 Weijin Road, Tianjin 300071, China
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Tanaka Y, Kaibori M, Miki H, Nakatake R, Tokuhara K, Nishizawa M, Okumura T, Kwon AH. Alpha-lipoic acid exerts a liver-protective effect in acute liver injury rats. J Surg Res 2015; 193:675-83. [DOI: 10.1016/j.jss.2014.08.057] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 07/19/2014] [Accepted: 08/28/2014] [Indexed: 01/23/2023]
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Stellari FF, Sala A, Donofrio G, Ruscitti F, Caruso P, Topini TM, Francis KP, Li X, Carnini C, Civelli M, Villetti G. Azithromycin inhibits nuclear factor-κB activation during lung inflammation: an in vivo imaging study. Pharmacol Res Perspect 2014; 2:e00058. [PMID: 25505605 PMCID: PMC4186419 DOI: 10.1002/prp2.58] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Revised: 05/08/2014] [Accepted: 05/21/2014] [Indexed: 12/26/2022] Open
Abstract
We studied in vivo the potential involvement of nuclear factor-κB (NF-κB) pathway in the molecular mechanism of the anti-inflammatory and immunomodulatory activity of azithromycin in the lung. Mice transiently transfected with the luciferase gene under the control of a NF-κB responsive element were used to assess in vivo NF-κB activation by bioluminescence imaging. Bioluminescence as well as inflammatory cells and concentrations of proinflammatory cytokines in bronchoalveolar lavage fluids, were monitored in an acute model of pulmonary inflammation resulting from intratracheal instillation of lipopolysaccharide. Lipopolysaccharide (LPS) instillation induced a marked increase in lung bioluminescence in mice transiently transfected with the luciferase gene under the control of an NF-κB responsive element, with significant luciferase expression in resident cells such as endothelial and epithelial cells, as assessed by duoplex immunofluorescence staining. Activation of NF-κB and inflammatory cell lung infiltration linearly correlated when different doses of bortezomib were used to inhibit NF-κB activation. Pretreatment with azithromycin significantly decreased lung bioluminescence and airways cell infiltration induced by LPS, also reducing proinflammatory cytokines concentrations in bronchoalveolar lavages and inhibiting NF-κB nuclear translocation. The results obtained using a novel approach to monitor NF-κB activation, provided, for the first time, in vivo evidence that azithromycin treatment results in pulmonary anti-inflammatory activity associated with the inhibition of NF-κB activation in the lung.
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Affiliation(s)
| | - Angelo Sala
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano Milano, Italy ; Consiglio Nazionale delle Ricerche, IBIM Palermo, Italy
| | - Gaetano Donofrio
- Dipartimento di Scienze Medico-Veterinarie, Università di Parma Parma, Italy
| | - Francesca Ruscitti
- Dipartimento di Scienze Biomediche, Biotecnologiche e Traslazionali, Università di Parma Parma, Italy
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Tan YC, Xie F, Zhang HL, Zhu YL, Chen K, Tan HM, Hu BS, Yang JM, Tan JW. Hydrogen-rich saline attenuates postoperative liver failure after major hepatectomy in rats. Clin Res Hepatol Gastroenterol 2014; 38:337-45. [PMID: 24502885 DOI: 10.1016/j.clinre.2013.11.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Revised: 10/31/2013] [Accepted: 11/21/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS A major hepatectomy occasionally lead to acute liver failure and death. We demonstrated the anti-oxidative and anti-inflammatory effects and functional mechanisms of hydrogen-rich saline (HS), a novel antioxidant, on an experimental model of rats after a partial hepatectomy (PH). METHODS The rats underwent a 90% hepatectomy. HS was given intraperitoneally after the operation and every 8hours after. RESULTS HS markedly improved the survival rate of two experimental groups after the massive hepatectomy and inhibited increases in serum levels of TBIL, DBIL, ALT and AST. The histopathological analysis demonstrated that HS attenuated inflammatory changes in the liver. HS administration markedly lowered the massive hepatectomy induced elevation of the serum hyaluronic acid (HA) concentrations. HS inhibited the formation of one of the markers of oxidative damage, malondialdehyde (MDA), and increased the activities of superoxide dismutase (SOD) in liver tissue. In the HS-treated group, increases in inflammatory cytokines, such as TNF-α, IL-6 and HMGB-1, were inhibited in the liver tissue. The NF-κB p65 staining revealed that HS inhibited the activation of the transcription factor nuclear factor kappa B (NF-kB). CONCLUSIONS HS attenuates the massive hepatectomy induced liver injury not only by attenuating oxidative damage, but also by reducing the production of inflammatory cytokines, such as TNF-α, IL-6 and HMGB-1, in part through the inhibition of NF-kB activation.
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Affiliation(s)
- Yun Chang Tan
- General Surgery Department, Jiujiang University Clinical Medical College, Jiujiang university hospital, 332000 Jiujiang City, China; Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China.
| | - Feng Xie
- Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China
| | - Hui Lu Zhang
- Department of Digestive Disease, Huashan Hospital, Fudan University, 200438 Shanghai, China
| | - Yu Li Zhu
- Laboratory Department, Jiujiang University Clinical Medical College, Jiujiang university hospital, 332000 Jiujiang City, China
| | - Ke Chen
- General Surgery Department, Jiujiang University Clinical Medical College, Jiujiang university hospital, 332000 Jiujiang City, China
| | - Hua Min Tan
- General Surgery Department, Jiujiang University Clinical Medical College, Jiujiang university hospital, 332000 Jiujiang City, China
| | - Ben Shun Hu
- General Surgery Department, Jiujiang University Clinical Medical College, Jiujiang university hospital, 332000 Jiujiang City, China
| | - Jia Mei Yang
- Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, China.
| | - Jing Wang Tan
- Institute of Hepatobiliary Surgery, The First Affiliated Hospital of Chinese PLA General Hospital, 100038 Beijing, China
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Platonin mitigates lung injury in a two-hit model of hemorrhage/resuscitation and endotoxemia in rats. J Trauma Acute Care Surg 2012; 72:660-70. [PMID: 22491550 DOI: 10.1097/ta.0b013e3182318551] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Traumatic hemorrhagic shock and subsequent resuscitation may promote bacteria translocation and cause endotoxemia, a two-hit process that will induce severe lung injury. The pathogenesis involves oxidative stress, neutrophil infiltration, and inflammatory response. Platonin, a potent antioxidant, possesses potent anti-inflammation capacity. We sought to elucidate whether platonin could mitigate acute lung injury in a two-hit model of traumatic hemorrhage/resuscitation and subsequent endotoxemia. METHODS Adult male rats were randomized to receive traumatic hemorrhage/resuscitation plus lipopolysaccharide (HS/L) alone or HS/L plus platonin (200 μg/kg; n = 12 in each group). Sham groups were used simultaneously. At 6 hours after resuscitation, rats were killed and the levels of lung injury were assayed. RESULTS Rats treated with HS/L alone had severe lung injury as evidenced by significant alterations in lung function (i.e., arterial blood gas and alveolar-arterial oxygen difference) and histology. Significant increases in polymorphonuclear leukocytes/alveoli ratio (neutrophil infiltration index) and significant increases in the concentrations of inflammatory molecules (including chemokine, cytokine, and prostaglandin E2) and malondialdehyde (lipid peroxidation index) revealed that HS/L caused significant oxidative stress, neutrophil infiltration, and inflammatory response in rat lungs. Moreover, our data revealed that the levels of functional and histologic alteration as well as polymorphonuclear leukocytes/alveoli ratio and the concentrations of inflammatory molecules and malondialdehyde in rats treated with HS/L plus platonin (200 μg/kg) were significantly lower than those treated with HR/L alone. CONCLUSIONS Platonin mitigates lung injury in a two-hit model of traumatic hemorrhage/resuscitation and endotoxemia in rats.
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Murugan V, Peck MJ. Signal transduction pathways linking the activation of alveolar macrophages with the recruitment of neutrophils to lungs in chronic obstructive pulmonary disease. Exp Lung Res 2010; 35:439-85. [PMID: 19842832 DOI: 10.1080/01902140902759290] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem. It is predicted by the World Health Organization to become the third most common cause of death and the fifth most common cause of disability in the world by 2020. COPD is a complex inflammatory disease involving several types of inflammatory cells and multiple inflammatory mediators. Although abnormal numbers of inflammatory cells such as macrophages, dendritic cells, neutrophils, and T lymphocytes have been documented in COPD, the relationship between these cell types and the sequence of their appearance and persistence is largely unknown. Alveolar macrophages have been identified as one of the major cell types that plays a key role in orchestrating the inflammatory events associated with the pathophysiology of COPD. One of the major functions of macrophages is the secretion of chemotactic factors and this function is markedly increased on exposure to cigarette smoke (CS). This enhanced release of chemoattractants results in increased lung neutrophil infiltration, which is thought to be a key event in the development of COPD. The molecular basis for this amplified inflammatory response is not very clear, but it could be due to an alteration in signal transduction pathways within the macrophage. Based on existing literature, an attempt has been made to create a comprehensive review of the signal transduction pathways that link the activation of macrophages with the increased recruitment of neutrophils into the airways. Some of the major stimuli that activate macrophages and cause them to secrete chemotactic factors have been identified as CS, wood smoke, ozone, bacterial endotoxin, and proinflammatory cytokines such as interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. These stimuli seem to activate mainly redox-sensitive transcription factors such as nuclear factor (NF)-kappa B and activator protein (AP)-1, both of which play a major role in the synthesis and secretion of chemotactic factors such as IL-8 and leukotriene B(4) (LTB(4)). The pathways involved in the synthesis and secretion of other factors such as macrophage chemotactic protein-1 (MCP-1) and growth-related oncogene-alpha (Gro-alpha) have also been reviewed.
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Abstract
Acute lung injury (ALI) has been documented clinically following several pathological states such as trauma, septic shock and pneumonia. The histopathological characteristics, paired with the production of a number of cellular pro-inflammatory mediators, play a crucial role in the progression of ALI. During ALI, polymorphonuclear neutrophil (PMN)-mediated apoptosis is delayed by macrophages, possibly via effects on the Fas/FasL mediated pathway, leading to the accumulation of these cells at the site of injury and inflammation. The transcriptional regulation of NFκB, CREB, and AP-1 also regulates the pathogenesis of ALI. During sepsis and septic shock, we found evidence of infiltrating leukocytes in the alveolar spaces along with an increased number of TUNEL-positive cells in the lung sections. We also observed an increased expression of TRADD and Bax/Bcl2 ratio at 7 days post-sepsis. In contrast, the NFκB/IκB ratio increased at 1 day post-sepsis. Together, these data provide evidence illustrating the induction of apoptosis in lung tissues subsequent to the onset of polymicrobial sepsis. The results support the concept that the upregulation of apoptosis following lung inflammation plays a crucial role in the development of acute lung injury and related disorders such as ARDS.
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Hong SB, Huang Y, Moreno-Vinasco L, Sammani S, Moitra J, Barnard JW, Ma SF, Mirzapoiazova T, Evenoski C, Reeves RR, Chiang ET, Lang GD, Husain AN, Dudek SM, Jacobson JR, Ye SQ, Lussier YA, Garcia JGN. Essential role of pre-B-cell colony enhancing factor in ventilator-induced lung injury. Am J Respir Crit Care Med 2008; 178:605-17. [PMID: 18658108 PMCID: PMC2542434 DOI: 10.1164/rccm.200712-1822oc] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2007] [Accepted: 06/27/2008] [Indexed: 12/25/2022] Open
Abstract
RATIONALE We previously demonstrated pre-B-cell colony enhancing factor (PBEF) as a biomarker in sepsis and sepsis-induced acute lung injury (ALI) with genetic variants conferring ALI susceptibility. OBJECTIVES To explore mechanistic participation of PBEF in ALI and ventilator-induced lung injury (VILI). METHODS Two models of VILI were utilized to explore the role of PBEF using either recombinant PBEF or PBEF(+/-) mice. MEASUREMENTS AND MAIN RESULTS Initial in vitro studies demonstrated recombinant human PBEF (rhPBEF) as a direct rat neutrophil chemotactic factor with in vivo studies demonstrating marked increases in bronchoalveolar lavage (BAL) leukocytes (PMNs) after intratracheal injection in C57BL/6J mice. These changes were accompanied by increased BAL levels of PMN chemoattractants (KC and MIP-2) and modest increases in lung vascular and alveolar permeability. We next explored the potential synergism between rhPBEF challenge (intratracheal) and a model of limited VILI (4 h, 30 ml/kg tidal volume) and observed dramatic increases in BAL PMNs, BAL protein, and cytokine levels (IL-6, TNF-alpha, KC) compared with either challenge alone. Gene expression profiling identified induction of ALI- and VILI-associated gene modules (nuclear factor-kappaB, leukocyte extravasation, apoptosis, Toll receptor pathways). Heterozygous PBEF(+/-) mice were significantly protected (reduced BAL protein, BAL IL-6 levels, peak inspiratory pressures) when exposed to a model of severe VILI (4 h, 40 ml/kg tidal volume) and exhibited significantly reduced expression of VILI-associated gene expression modules. Finally, strategies to reduce PBEF availability (neutralizing antibody) resulted in significant protection from VILI. CONCLUSIONS These studies implicate PBEF as a key inflammatory mediator intimately involved in both the development and severity of ventilator-induced ALI.
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Affiliation(s)
- Sang-Bum Hong
- Department of Medicine, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, W604, Chicago, IL 60637, USA
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Ishizaki M, Kaibori M, Uchida Y, Hijikawa T, Tanaka H, Ozaki T, Tokuhara K, Matsui K, Kwon AH, Kamiyama Y, Nishizawa M, Okumura T. PROTECTIVE EFFECT OF FR183998, A Na+/H+ EXCHANGER INHIBITOR, AND ITS INHIBITION OF iNOS INDUCTION IN HEPATIC ISCHEMIA-REPERFUSION INJURY IN RATS. Shock 2008; 30:311-7. [DOI: 10.1097/shk.0b013e318164ef14] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Schmerbach K, Schefe JH, Krikov M, Müller S, Villringer A, Kintscher U, Unger T, Thoene-Reineke C. Comparison between single and combined treatment with candesartan and pioglitazone following transient focal ischemia in rat brain. Brain Res 2008; 1208:225-33. [PMID: 18378216 DOI: 10.1016/j.brainres.2008.02.032] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2007] [Revised: 02/14/2008] [Accepted: 02/15/2008] [Indexed: 10/22/2022]
Abstract
Angiotensin AT1 receptor blockers (ARBs) and thiazolidinediones (TZDs) have become well established drugs for the treatment of major risk factors of stroke. Since several studies provided evidence that ARBs and TZDs also have additional anti-inflammatory effects, we hypothesized that a combined treatment with the ARB, candesartan, and the TZD, pioglitazone, ameliorates ischemia-induced brain injury and inflammation by synergistic anti-inflammatory actions. Normotensive Wistar rats were pre-treated for 5 days with vehicle (0.9% NaCl), 0.2 mg/kg/day candesartan (s.c.), and/or 2 and/or 20 mg/kg/day pioglitazone (p.o.), respectively and underwent 90 min of middle cerebral artery occlusion (MCAO) with successive reperfusion. Neurological deficits and infarct size were determined 24 h and 48 h after MCAO, respectively, followed by tissue sampling. Animals treated with candesartan, pioglitazone, and the combination of candesartan and pioglitazone had reduced neurological deficits 24 h and 48 h after MCAO, respectively (P<0.05-0.01). Infarct size was reduced by treatment of candesartan, pioglitazone, and their respective combination (each P<0.05) 48 h after stroke compared to vehicle. Treatment with candesartan, pioglitazone, and their combination resulted in significantly reduced mRNA expression of the inflammatory markers CXCL1 and TNFalpha in vivo (P<0.01). The combination of candesartan plus pioglitazone is equally effective compared to their single applications concerning neuroprotection and attenuation of inflammation after MCAO. Therefore, we conclude that a direct synergistic neuroprotective action of parallel ARB and TZD treatment is unlikely.
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Affiliation(s)
- Kristin Schmerbach
- Center for Cardiovascular Research/Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Tanaka H, Uchida Y, Kaibori M, Hijikawa T, Ishizaki M, Yamada M, Matsui K, Ozaki T, Tokuhara K, Kamiyama Y, Nishizawa M, Ito S, Okumura T. Na+/H+ exchanger inhibitor, FR183998, has protective effect in lethal acute liver failure and prevents iNOS induction in rats. J Hepatol 2008; 48:289-99. [PMID: 18096265 DOI: 10.1016/j.jhep.2007.09.017] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2007] [Revised: 08/20/2007] [Accepted: 09/11/2007] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS Selective inhibition of Na(+)/H(+) exchanger (NHE) improves organ dysfunctions including heart ischemia-reperfusion injury. In vivo and in vitro studies were designed to investigate whether NHE inhibitor has a protective effect in lethal acute liver failure, and if so, what are the mechanisms involved. METHODS NHE inhibitor (FR183998) was administered to rats treated with d-galactosamine/lipopolysaccharide (GalN/LPS), or incubated with cultured hepatocytes stimulated by pro-inflammatory cytokine, interleukin (IL)-1beta. RESULTS FR183998 reduced the increases of pro-inflammatory cytokines such as TNF-alpha, interferon-gamma and CINC-1, but enhanced the anti-inflammatory cytokine, IL-10, leading to the prevention of liver injury and increased survival rate in GalN/LPS-treated animals. FR183998 prevented the activation of transcription factor NF-kappaB induced by GalN/LPS. In vivo and in vitro experiments revealed that FR183998 reduced inducible nitric oxide synthase (iNOS) induction and NO production. Further FR183998 decreased levels of iNOS antisense-transcript in GalN/LPS-treated liver and IL-1beta-treated hepatocytes. CONCLUSIONS FR183998 may reduce a variety of inflammatory mediators such as cytokines and NO in part through the inhibition of NF-kappaB activation, resulting in the prevention of fulminant liver failure, and may inhibit iNOS gene expression at steps of iNOS promoter transactivation and its mRNA stabilization through NF-kappaB and iNOS antisense-transcript, respectively.
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Affiliation(s)
- Hironori Tanaka
- Department of Surgery, Kansai Medical University, Moriguchi, Osaka, Japan
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Uchida Y, Kaibori M, Hijikawa T, Ishizaki M, Ozaki T, Tanaka H, Matsui K, Tokuhara K, Kwon AH, Kamiyama Y, Okumura T. Protective effect of neutrophil elastase inhibitor (FR136706) in lethal acute liver failure induced by D-galactosamine and lipopolysaccharide in rats. J Surg Res 2007; 145:57-65. [PMID: 17936791 DOI: 10.1016/j.jss.2007.04.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2006] [Revised: 03/13/2007] [Accepted: 04/01/2007] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS It has been reported that liver dysfunction with ischemia-reperfusion is improved through selective inhibition of neutrophil elastase (NE) by NE inhibitor. This study was designed to investigate whether NE inhibitor has protective effect in lethal acute liver failure. MATERIALS AND METHODS Rats were treated with D-galactosamine plus lipopolysaccharide (GalN/LPS) to induce acute liver failure. NE inhibitor (FR136706) was administered intravenously before GalN/LPS injection. RESULTS NE inhibitor increased the survival rate to approximately 80% compared with less than 10% in GalN/LPS-treated rats. NE inhibitor prevented GalN/LPS-induced increase of enzymes and total bilirubin in serum, which are related to liver injury. Histopathological analysis revealed that NE inhibitor decreased the incidence of hepatic apoptosis and neutrophil infiltration in the liver. NE inhibitor inhibited the increased concentration of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-6 and interferon-gamma), and chemokines (CINC-1 and MIP-2) in serum or liver caused by GalN/LPS, and enhanced anti-inflammatory cytokine, interleukin-10 concentration. NE inhibitor prevented the activation of the transcription factor, nuclear factor-kappa B, induced by GalN/LPS. NE inhibitor also reduced the induction of inducible nitric oxide synthase mRNA and its protein in GalN/LPS-treated liver, and resulted in a decrease in nitric oxide production. CONCLUSIONS These results indicate that NE inhibitor, FR136706, inhibits the induction of a variety of inflammatory mediators such as cytokines, chemokines, and nitric oxide, in part through the inhibition of nuclear factor-kappa B activation, resulting in the prevention of fulminant liver failure.
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Affiliation(s)
- Yoichiro Uchida
- Department of Surgery, Kansai Medical University, Osaka, Japan
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Nagasaka R, Chotimarkorn C, Shafiqul IM, Hori M, Ozaki H, Ushio H. Anti-inflammatory effects of hydroxycinnamic acid derivatives. Biochem Biophys Res Commun 2007; 358:615-9. [PMID: 17499610 DOI: 10.1016/j.bbrc.2007.04.178] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2007] [Accepted: 04/30/2007] [Indexed: 01/05/2023]
Abstract
NF-kappaB family of transcription factors are involved in numerous cellular processes, including differentiation, proliferation, and inflammation. It was reported that hydroxycinnamic acid derivatives (HADs) are inhibitors of NF-kappaB activation. Rice bran oil contains a lot of phytosteryl ferulates, one of HADs. We have investigated effects of phytosteryl ferulates on NF-kappaB activation in macrophage. Cycloartenyl ferulate (CAF), one of phytosteryl ferulates, significantly reduced lipopolysaccharide (LPS)-induced NO production and mRNA expression of inducible NO synthase and cyclooxygenese-2 but upregulated SOD activity. Electrophoresis mobility shift assay revealed that CAF inhibited DNA-binding of NF-kappaB. CAF and phytosteryl ferulates probably have potentially anti-inflammatory properties.
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Affiliation(s)
- Reiko Nagasaka
- Department of Food Science & Technology, Tokyo University of Marine Science and Technology, 5-7 Konan 4, Minato, Tokyo, Japan
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Auten RL, Mason SN, Whorton MH, Lampe WR, Foster WM, Goldberg RN, Li B, Stamler JS, Auten KM. Inhaled ethyl nitrite prevents hyperoxia-impaired postnatal alveolar development in newborn rats. Am J Respir Crit Care Med 2007; 176:291-9. [PMID: 17478622 PMCID: PMC1994219 DOI: 10.1164/rccm.200605-662oc] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
RATIONALE Inhaled nitric oxide (NO) has been used to prevent bronchopulmonary dysplasia, but with variable results. Ethyl nitrite (ENO) forms S-nitrosothiols more readily than does NO, and resists higher-order nitrogen oxide formation. Because S-nitrosylation is a key pathway mediating many NO biological effects, treatment with inhaled ENO may better protect postnatal lung development from oxidative stress than NO. OBJECTIVES To compare inhaled NO and ENO on hyperoxia-impaired postnatal lung development. METHODS We treated newborn rats beginning at birth to air or 95% O(2) +/- 0.2-20.0 ppm ENO for 8 days, or to 10 ppm NO for 8 days. Pups treated with the optimum ENO dose, 10 ppm, and pups treated with 10 ppm NO were recovered in room air for 6 more days. MEASUREMENTS AND MAIN RESULTS ENO and NO partly prevented 95% O(2)-induced airway neutrophil influx in lavage, but ENO had a greater effect than did NO in prevention of lung myeloperoxidase accumulation, and in expression of cytokine-induced neutrophil chemoattractant-1. Treatment with 10 ppm ENO, but not NO, for 8 days followed by recovery in air for 6 days prevented 95% O(2)-induced impairments of body weight, lung compliance, and alveolar development. CONCLUSIONS Inhaled ENO conferred protection superior to inhaled NO against hyperoxia-induced inflammation. ENO prevented hyperoxia impairments of lung compliance and postnatal alveolar development in newborn rats.
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Affiliation(s)
- Richard L Auten
- Division of Neonatal Medicine, Department of Pediatrics, Neonatal-Perinatal Research Institute, University Medical Center, Durham, North Carolina 27710, USA.
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Oba K, Yamashita H, Waragai A, Kawano T. NF-kappaB in the lungs of premature rabbits during mechanical ventilation--comparison between conventional mechanical ventilation (CMV) and high-frequency oscillation (HFO). Pediatr Pulmonol 2007; 42:446-51. [PMID: 17394254 DOI: 10.1002/ppul.20580] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The purpose of this study is to compare pulmonary nuclear factor-kappaB (NF-kappaB) activity of conventional mechanical ventilation (CMV) with that of high-frequency oscillation (HFO) in premature rabbit lungs. For surfactant-depleted model, we used premature rabbits in order to exclude the effect of lung lavage on the activation of NF-kappaB. The premature rabbits were delivered at a gestational age of 27 days by hysterotomy. Both modes of the ventilator were set at the same MAP and FiO(2). We used animals that had PCO(2) levels of approximately 50-mmHg. Animals were sacrificed after 1-hr ventilation with CMV or HFO. Then activity of pulmonary NF-kappaB was assessed. We observed that NF-kappaB activity was higher in the lungs of CMV compared with those of HFO, as measured by Western blot analysis. The activity level of NF-kappaB in the lungs measured by ELISA was significantly higher in CMV group than in HFO group. We conclude that a higher level of NF-kappaB activation was associated with CMV when compared to HFO.
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Affiliation(s)
- Kunihiro Oba
- Department of Pediatrics, Kyorin University School of Medicine, Mitaka-City, Tokyo, Japan.
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Waragai A, Yamashita H, Hosoi K, Hoshina H, Noda E, Yan K, Kawano T. High-frequency oscillation (HFO) prevents activation of NF-kappaB found with conventional mechanical ventilation (CMV) in surfactant-depleted rabbit lung. Pediatr Pulmonol 2007; 42:440-5. [PMID: 17427897 DOI: 10.1002/ppul.20444] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
High-frequency oscillation (HFO) has been recognized as an effective ventilatory strategy to minimize lung injury during respiratory support. Conventional mechanical ventilation (CMV) compared with HFO was shown to result in an increased number of PMNs and inflammatory cytokines in the lung lavage fluid. However how mechanical forces can be sensed by cells and converted into biochemical signals for intracellular signal transduction is still unknown. In this current study, we sought to determine whether the activation of Nuclear factor-kappa B (NF-kappaB) might be involved in the lung injury caused by CMV. Surfactant-depleted Japanese white rabbits received 1- or 4-hr CMV or 1- or 4-hr HFO. Then, activation of NF-kappaB in the lungs was assessed by conducting electrophoretic mobility shift assays (EMSA). In the experiment with whole lungs, NF-kappaB activity was much higher in the 4-hr CMV lungs than in the 4-hr HFO lungs. To clarify the origin of the cells in which NF-kappaB was activated, we did a second lung lavage at the end of ventilation and washed out the cells that had infiltrated the alveoli. The levels of NF-kappaB activity were the similar in the lungs of 4-hr HFO rabbits and in those of 4-hr CMV ones. On the other hand, NF-kappaB activity was much higher in the 4-hr CMV lungs than in the 4-hr HFO lungs in the experiment with the lung lavage fluid cells. These results show that the increase in NF-kappaB activity in the lungs of 4-hr CMV rabbits was due mainly to the cells that had infiltrated the alveoli.
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Affiliation(s)
- Aki Waragai
- Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan.
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Chen D, Pan J, Du B, Sun D. Induction of the heat shock response in vivo inhibits NF-kappaB activity and protects murine liver from endotoxemia-induced injury. J Clin Immunol 2006; 25:452-61. [PMID: 16160914 DOI: 10.1007/s10875-005-5636-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2005] [Accepted: 05/02/2005] [Indexed: 12/31/2022]
Abstract
Liver plays an important role in the pathogenesis of sepsis by releasing various cytokines and producing acute phase proteins. Heat shock preconditioning is reported to be effective in protection of lung and liver from injury in sepsis and in endotoxemia models, but the exact mechanism is still not fully understood. We report here on the effects of the heat shock response (HSR) induced by sodium arsenite on endotoxemia-induced liver injury as well as hepatic NF-kappaB activation and proinflammatory cytokine expression. Prior induction of HSR significantly attenuated endotoxemia-induced histological changes, inhibited hepatic NF-kappaB activation and IkappaBalpha degradation and decreased mortality. Expression of mRNA coding for TNF-alpha and IL-6 in liver was significantly lower in arsenite-pretreated animals. We conclude that attenuation of endotoxin-induced hepatic NF-kappaB activation and subsequent proinflammatory cytokine production may be one of the mechanisms of the beneficial effect of the heat shock response.
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Affiliation(s)
- Dechang Chen
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing
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Everhart MB, Han W, Sherrill TP, Arutiunov M, Polosukhin VV, Burke JR, Sadikot RT, Christman JW, Yull FE, Blackwell TS. Duration and intensity of NF-kappaB activity determine the severity of endotoxin-induced acute lung injury. THE JOURNAL OF IMMUNOLOGY 2006; 176:4995-5005. [PMID: 16585596 DOI: 10.4049/jimmunol.176.8.4995] [Citation(s) in RCA: 199] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Activation of innate immunity in the lungs can lead to a self-limited inflammatory response or progress to severe lung injury. We investigated whether specific parameters of NF-kappaB pathway activation determine the outcome of acute lung inflammation using a novel line of transgenic reporter mice. Following a single i.p. injection of Escherichia coli LPS, transient NF-kappaB activation was identified in a variety of lung cell types, and neutrophilic inflammation resolved without substantial tissue injury. However, administration of LPS over 24 h by osmotic pump (LPS pump) implanted into the peritoneum resulted in sustained, widespread NF-kappaB activation and neutrophilic inflammation that culminated in lung injury at 48 h. To determine whether intervention in the NF-kappaB pathway could prevent progression to lung injury in the LPS pump model, we administered a specific IkappaB kinase inhibitor (BMS-345541) to down-regulate NF-kappaB activation following the onset of inflammation. Treatment with BMS-345541 beginning at 20 h after osmotic pump implantation reduced lung NF-kappaB activation, concentration of KC and MIP-2 in lung lavage, neutrophil influx, and lung edema measured at 48 h. Therefore, sustained NF-kappaB activation correlates with severity of lung injury, and interdiction in the NF-kappaB pathway is beneficial even after the onset of lung inflammation.
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Affiliation(s)
- M Brett Everhart
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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Handa O, Naito Y, Yoshikawa T. Rat Cytokine-Induced Neutrophil Chemoattractant-1 (CINC-1) in Inflammation. J Clin Biochem Nutr 2006. [DOI: 10.3164/jcbn.38.51] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Hang CH, Shi JX, Li JS, Li WQ, Wu W. Expressions of intestinal NF-kappaB, TNF-alpha, and IL-6 following traumatic brain injury in rats. J Surg Res 2005; 123:188-93. [PMID: 15680377 DOI: 10.1016/j.jss.2004.08.002] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2004] [Indexed: 01/04/2023]
Abstract
BACKGROUND NF-kappaB regulates a large number of genes involved in the inflammatory response to critical illness, but it is not well known if and how NF-kappaB is activated in the gut following traumatic brain injury (TBI) and what is the role of cytokine-mediated inflammation in the pathogenesis of acute gut mucosal injury. MATERIALS AND METHODS Male Wistar rats were randomly divided into control and TBI groups, each of which was subgrouped at hours 3, 12, 24, and 72 and on day 7. Parietal brain contusion was produced by a free-falling weight on the exposed dura of the right parietal lobe. NF-kappaB binding activity in jejunal tissue was measured using EMSA and the concentrations of TNF-alpha and IL-6 were detected using ELISA. RESULTS NF-kappaB binding activity in the jejunum was significantly increased at 3 h following TBI, was maximal at 72 h, and remained elevated by 7 days postinjury. TNF-alpha and IL-6 concentrations were also significantly increased by 3 h postinjury, but peaked at 24 h and remained elevated on Day 7 postinjury. CONCLUSIONS TBI induced a rapid and persistent up-regulation of NF-kappaB and proinflammatory cytokines in the gut, which may play an important role in the pathogenesis of acute gut mucosal injury mediated by inflammation.
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Affiliation(s)
- Chun-Hua Hang
- Department of Neurosurgery, Clinical School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China.
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Hang CH, Shi JX, Li JS, Li WQ, Yin HX. Up-regulation of intestinal nuclear factor kappa B and intercellular adhesion molecule-1 following traumatic brain injury in rats. World J Gastroenterol 2005; 11:1149-54. [PMID: 15754395 PMCID: PMC4250704 DOI: 10.3748/wjg.v11.i8.1149] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Nuclear factor kappa B (NF-κB) regulates a large number of genes involved in the inflammatory response to critical illnesses, but it is not known if and how NF-κB is activated and intercellular adhesion molecule-1 (ICAM-1) expressed in the gut following traumatic brain injury (TBI). The aim of current study was to investigate the temporal pattern of intestinal NF-κB activation and ICAM-1 expression following TBI.
METHODS: Male Wistar rats were randomly divided into six groups (6 rats in each group) including controls with sham operation and TBI groups at hours 3, 12, 24, and 72, and on d 7. Parietal brain contusion was adopted using weight-dropping method. All rats were decapitated at corresponding time point and mid-jejunum samples were taken. NF-κB binding activity in jejunal tissue was measured using EMSA. Immunohistochemistry was used for detection of ICAM-1 expression in jejunal samples.
RESULTS: There was a very low NF-κB binding activity and little ICAM-1 expression in the gut of control rats after sham surgery. NF-κB binding activity in jejunum significantly increased by 160% at 3 h following TBI (P<0.05 vs control), peaked at 72 h (500% increase) and remained elevated on d 7 post-injury by 390% increase. Compared to controls, ICAM-1 was significantly up-regulated on the endothelia of microvessels in villous interstitium and lamina propria by 24 h following TBI and maximally expressed at 72 h post-injury (P<0.001). The endothelial ICAM-1 immunoreactivity in jejunal mucosa still remained strong on d 7 post-injury. The peak of NF-κB activation and endothelial ICAM-1 expression coincided in time with the period during which secondary mucosal injury of the gut was also at their culmination following TBI.
CONCLUSION: TBI could induce an immediate and persistent up-regulation of NF-κB activity and subsequent up-regulation of ICAM-1 expression in the intestine. Inflammatory response mediated by increased NF-κB activation and ICAM-1 expression may play an important role in the pathogenesis of acute gut mucosal injury following TBI.
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Affiliation(s)
- Chun-Hua Hang
- Department of Neurosurgery, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China.
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Tsuji K, Kwon AH, Yoshida H, Qiu Z, Kaibori M, Okumura T, Kamiyama Y. Free radical scavenger (edaravone) prevents endotoxin-induced liver injury after partial hepatectomy in rats. J Hepatol 2005; 42:94-101. [PMID: 15629513 DOI: 10.1016/j.jhep.2004.09.018] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2004] [Revised: 09/15/2004] [Accepted: 09/21/2004] [Indexed: 01/05/2023]
Abstract
BACKGROUND/AIMS Infection after major surgery, such as massive hepatectomy, induces liver dysfunction, occasionally leading to multiple organ failure and death. We demonstrated the anti-inflammatory effects and functional mechanisms of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), a newly synthesized free radical scavenger, on an experimental model of endotoxemia after partial hepatectomy in rats. METHODS Rats were treated with lipopolysaccharide (LPS) 48h after 70% hepatectomy. Edaravone was administered intravenously before LPS-treatment. RESULTS Edaravone markedly improved the survival rate of LPS-treated rats after hepatectomy and inhibited increases in serum levels of AST and LDH. Histopathological analysis demonstrated that edaravone prevented inflammatory changes in the liver, kidney and spleen. Edaravone inhibited the formation of one of the markers of oxidative damage, malondialdehyde. Increases in inflammatory cytokines and cytokine-induced neutrophil chemoattractant (CINC) in serum and liver tissue were inhibited in the edaravone-treated group. An electrophoretic mobility shift assay revealed that edaravone inhibited the activation of the transcription factor, nuclear factor-kappa B (NF-kappaB). Edaravone also reduced the induction of inducible nitric oxide synthase (iNOS). CONCLUSIONS Edaravone prevents endotoxin-induced liver injury after partial hepatectomy not only by attenuating oxidative damage, but also by reducing the production of inflammatory cytokines, CINC and iNOS, in part through the inhibition of NF-kappaB activation.
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Affiliation(s)
- Katsushige Tsuji
- Department of Surgery, Kansai Medical University, 10-15 Fumizono, Moriguchi, Osaka 570-8507, Japan
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Takaki M, Ushikai M, Deguchi K, Nishimoto K, Matsune S, Kurono Y. The role of nuclear factor-kappa B in interleukin-8 expression by human adenoidal fibroblasts. Laryngoscope 2003; 113:1378-85. [PMID: 12897563 DOI: 10.1097/00005537-200308000-00021] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES/HYPOTHESIS The production of cytokines by adenoids is known to be associated with inflammation of nasopharynx and the pathogenesis of otitis media with effusion. However, the role of adenoids in producing inflammatory cytokines such as interleukin-8 (IL-8) is not yet clear. In the present study, expression of IL-8 in adenoidal fibroblasts was investigated at the level of transcription factors. Further, the effects of clarithromycin, a 14-member ring macrolide, on IL-8 gene expression and nuclear factor-kappa B (NF-kappa B) activation in adenoidal fibroblasts were evaluated. STUDY DESIGN In vitro study for the production of inflammatory cytokine from human adenoidal fibroblasts. METHODS Adenoidal fibroblasts were incubated with nontypeable Haemophilus influenzae endotoxin or interleukin-1 beta. Then the expression of IL-8 and the influence of NF-kappa B inhibitor and clarithromycin were evaluated. Interleukin-8 protein production was assessed by ELISA, and IL-8 messenger RNA production was measured by Northern blot analysis and reverse transcriptase-polymerase chain reaction. Activation of NF-kappa B and inhibition of its activation were determined by electrophoretic mobility shift assay. RESULTS The expression of both IL-8 protein and messenger RNA in adenoidal fibroblasts was enhanced by Haemophilus influenzae endotoxin and interleukin-1 beta and was positively correlated with increases in NF-kappa B activity. Treatment of cells with the NF-kappa B inhibitor N-tosyl-(L)-phenylalanine chloromethyl ketone, as well as with clarithromycin, reduced expression of IL-8 and NF-kappa B activity in a dose-dependent manner. CONCLUSIONS Results suggest that adenoidal fibroblasts produce IL-8 in response to endotoxin through NF-kappa B activation. The inhibitory effects of clarithromycin on NF-kappa B activation and IL-8 production in adenoidal fibroblasts might explain, in part, the mechanism of this drug in improving otitis media with effusion.
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Affiliation(s)
- Minoru Takaki
- Department of Otolarynology, Faculty of Medicine, Kagoshima University, Sakuragaoka, Japan
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Shields CJ, O'Sullivan AW, Wang JH, Winter DC, Kirwan WO, Redmond HP. Hypertonic saline enhances host response to bacterial challenge by augmenting receptor-independent neutrophil intracellular superoxide formation. Ann Surg 2003; 238:249-57. [PMID: 12894019 PMCID: PMC1422699 DOI: 10.1097/01.sla.0000080827.77985.fc] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE This study sought to determine whether hypertonic saline (HTS) infusion modulates the host response to bacterial challenge. METHODS Sepsis was induced in 30 Balb-C mice by intraperitoneal injection of Escherichia coli (5 x 107 organisms per animal). In 10 mice, resuscitation was performed at 0 and 24 hours with a 4 mL/kg bolus of HTS (7.5% NaCl), 10 animals received 4 mL/kg of normal saline (0.9% NaCl), and the remaining animals received 30 mL/kg of normal saline. Samples of blood, spleen, and lung were cultured at 8 and 36 hours. Polymorphonucleocytes were incubated in isotonic or hypertonic medium before culture with E. coli. Phagocytosis was assessed by flow cytometry, whereas intracellular bacterial killing was measured after inhibition of phagocytosis with cytochalasin B. Intracellular formation of free radicals was assessed by the molecular probe CM-H(2)DCFDA. Mitogen-activated protein (MAP) kinase p38 and ERK-1 phosphorylation, and nuclear factor kappa B (NFkappaB) activation were determined. Data are represented as means (SEM), and an analysis of variance test was performed to gauge statistical significance. RESULTS Significantly reduced bacterial culture was observed in the animals resuscitated with HTS when compared with their NS counterparts, in blood (51.8 +/- 4.3 vs. 82.0 +/- 3.3 and 78.4 +/- 4.8, P = 0.005), lung (40.0 +/- 4.1 vs. 93.2 +/- 2.1 and 80.9 +/- 4.7, P = 0.002), and spleen (56.4 +/- 3.8 vs. 85.4 +/- 4.2 and 90.1 +/- 5.9, P = 0.05). Intracellular killing of bacteria increased markedly (P = 0.026) and superoxide generation was enhanced upon exposure to HTS (775.78 +/- 23.6 vs. 696.57 +/- 42.2, P = 0.017) despite inhibition of MAP kinase and NFkappaB activation. CONCLUSIONS HTS significantly enhances intracellular killing of bacteria while attenuating receptor-mediated activation of proinflammatory cascades.
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Affiliation(s)
- Conor J Shields
- Department of Academic Surgery, Cork University Hospital and National University of Ireland, Cork, Ireland
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Kataoka M, Shimizu H, Mitsuhashi N, Ohtsuka M, Wakabayashi Y, Ito H, Kimura F, Nakagawa K, Yoshidome H, Shimizu Y, Miyazaki M. Effect of cold-ischemia time on C-X-C chemokine expression and neutrophil accumulation in the graft liver after orthotopic liver transplantation in rats. Transplantation 2002; 73:1730-5. [PMID: 12084994 DOI: 10.1097/00007890-200206150-00007] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND The precise mechanisms leading to polymorphonuclear neutrophil (PMN) recruitment and activation in the extended cold-preserved liver after transplantation are not yet fully understood. METHODS We histologically evaluated the number of accumulated PMNs in graft livers, with varying time periods of cold ischemia (1, 6, and 24 hr in University of Wisconsin solution at 4 degrees C), after liver transplantation in rats. Intragraft expression of macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) mRNA, as well as immunohistochemical expression of MIP-2 and CINC in the graft liver, were investigated after reperfusion. The levels of MIP-2 and CINC in the hepatic vein, and tumor necrosis factor (TNF)-alpha, which stimulates these chemokine production, were also monitored. RESULTS The number of accumulated PMNs in sinusoids significantly increased in the 24-hr cold-ischemia group within 3 hr after reperfusion, compared with the 1-hr and 6-hr groups. Serum MIP-2 levels in the 24-hr group significantly increased at 3, 6, and 12 hr after reperfusion, compared with the other groups. Intragraft MIP-2 mRNA was also up-regulated to a greater extent in the 24-hr group. Similarly, serum CINC levels in the 24-hr group significantly increased at 3 hr, compared with the 1-hr group. CINC mRNA also increased as cold-ischemia time was prolonged. Immunohistochemical staining revealed that hepatocytes were the main source of both MIP-2 and CINC protein. In addition, TNF-alpha in the hepatic vein was detected only in the 24-hr group after reperfusion. CONCLUSION Extended cold preservation of the graft liver might up-regulate MIP-2 and CINC expression of hepatocytes, most probably through elevated TNF-alpha, and might contribute to PMN recruitment and activation after reperfusion.
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Affiliation(s)
- Masaaki Kataoka
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-0856, Japan
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Shields CJ, Winter DC, Redmond HP. Lung injury in acute pancreatitis: mechanisms, prevention, and therapy. Curr Opin Crit Care 2002; 8:158-63. [PMID: 12386518 DOI: 10.1097/00075198-200204000-00012] [Citation(s) in RCA: 107] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Lung injury is the most pertinent manifestation of extra-abdominal organ dysfunction in pancreatitis. The propensity of this retroperitoneal inflammatory condition to engender a diffuse and life-threatening lung injury is significant. Approximately one third of patients will develop acute lung injury and acute respiratory distress syndrome, which account for 60% of all deaths within the first week. The variability in the clinical course of pancreatitis renders it a vexing entity and makes demonstration of the efficacy of any specific intervention difficult. The distinct pathologic entity of pancreatitis-associated lung injury is reviewed with a focus on etiology and potential therapeutic maneuvers.
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Affiliation(s)
- Conor J Shields
- Department of Academic Surgery, Cork University Hospital, and National University of Ireland, Cork, Ireland
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Abstract
Acute lung injury occurs as a result of a cascade of cellular events initiated by either infectious or noninfectious inflammatory stimuli. An elevated level of proinflammatory mediators combined with a decreased expression of anti-inflammatory molecules is a critical component of lung inflammation. Expression of proinflammatory genes is regulated by transcriptional mechanisms. Nuclear factor-kappa B (NF-kappa B) is one critical transcription factor required for maximal expression of many cytokines involved in the pathogenesis of acute lung injury. Activation and regulation of NF-kappa B are tightly controlled by a complicated signaling cascade. In acute lung injury caused by infection of bacteria, Toll-like receptors play a central role in initiating the innate immune system and activating NF-kappa B. Anti-inflammatory cytokines such as interleukin-10 and interleukin-13 have been shown to suppress inflammatory processes through inhibiting NF-kappa B activation. NF-kappa B can interact with other transcription factors, and these interactions thereby lead to greater transcriptional selectivity. Modification of transcription is likely to be a logical therapeutic target for acute lung injury.
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Affiliation(s)
- J Fan
- Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
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Puruckherr M, Gupta K, Youngberg G, Krishnaswamy G, Roy T. A 76-year-old woman with polymyalgia, polyarthralgia, and interstitial lung disease. Ann Allergy Asthma Immunol 2001; 87:113-6. [PMID: 11529256 DOI: 10.1016/s1081-1206(10)62203-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- M Puruckherr
- Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City 37604, USA
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42
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Ojo-Amaize EA, Kapahi P, Kakkanaiah VN, Takahashi T, Shalom-Barak T, Cottam HB, Adesomoju AA, Nchekwube EJ, Oyemade OA, Karin M, Okogun JI. Hypoestoxide, a novel anti-inflammatory natural diterpene, inhibits the activity of IkappaB kinase. Cell Immunol 2001; 209:149-57. [PMID: 11446747 DOI: 10.1006/cimm.2001.1798] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Most inflammatory agents activate nuclear factor-kappaB (NF-kappaB), resulting in induction of genes coding for cytokines, chemokines, and enzymes involved in amplification and perpetuation of inflammation. Hypoestoxide (a bicyclo [9,3,1] pentadecane) is a diterpene from Hypoestes rosea, a tropical shrub in the family Acanthacea, several members of which are used in folk medicine in Nigeria. Here, we demonstrate that hypoestoxide (HE) abrogates the production of pro-inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) in lipopolysaccharide (LPS)-activated normal human peripheral blood mononuclear cells. Moreover, HE inhibits the production of nitric oxide (NO) by IL-1beta- or IL-17-stimulated normal human chondrocytes. In vivo, oral administration of HE to mice significantly ameliorated hind paw edema induced by antibodies to type II collagen plus LPS. Furthermore, topical administration of HE to mice also significantly inhibited phorbol ester-induced ear inflammation. The anti-inflammatory activity of HE may be due in part to its ability to inhibit NF-kappaB activation through direct inhibition of IkappaB kinase (IKK) activity. Thus, HE could be useful in treating various inflammatory diseases and may represent a prototype of a novel class of IKK inhibitors.
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Affiliation(s)
- E A Ojo-Amaize
- Immune Modulation, Incorporated, Bloomington, California 92316, USA.
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Ohta N, Shimaoka M, Imanaka H, Nishimura M, Taenaka N, Kiyono H, Yoshiya I. Glucocorticoid suppresses neutrophil activation in ventilator-induced lung injury. Crit Care Med 2001; 29:1012-6. [PMID: 11378614 DOI: 10.1097/00003246-200105000-00027] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To investigate, in a rat model, the role of the Mac-1/ICAM-1 pathway and the anti-inflammatory activity of steroid in ventilator-induced lung injury. DESIGN Prospective, randomized controlled study. SETTING Animal investigation using Wistar rats. INTERVENTION Rats in three randomly assigned groups of 18, a total of 54 animals, were subject to the following: Two groups received high peak inspiratory pressure (35 cm H2O) ventilation after pretreatment with methylprednisolone (high-methylprednisolone group) or pretreatment with methylprednisolone vehicle (high-vehicle group). The third group of animals received low peak inspiratory pressure (7 cm H2O) ventilation after pretreatment with methylprednisolone vehicle (low-vehicle group). Except for animals previously killed to establish baseline values, after 40 mins of mechanical ventilation, the animals in each group were killed. Some animals provided histological samples, and the rest received total lung lavage. MEASUREMENT We measured flow cytometry of lavage fluid, cell counts of tissue samples, and pressure-volume curves before and after mechanical ventilation. RESULTS In the groups that received high peak inspiratory pressure ventilation, both the number of neutrophils that infiltrated the lungs and the expression of Mac-1 and ICAM-1 on neutrophils and macrophages increased significantly more than in the low-vehicle group. Static lung compliance was reduced in the high peak inspiratory pressure groups. In the high peak inspiratory pressure groups, there were significantly fewer neutrophils in samples from the high-methylprednisolone group (0.412 +/- 0.1 x 10(5)) than from the high-vehicle group (1.10 +/- 0.1 x 10(5); p < .05). The high-vehicle group showed greater expression of CD11b on neutrophils, but this was significantly decreased by methylprednisolone (mean fluorescence intensity: high-vehicle, 118.4 +/- 34.3; high-methylprednisolone, 25.8 +/- 4.2; p < .05). The lung mechanics measured by pressure-volume curve analysis were deteriorated less in the high-methylprednisolone group. CONCLUSION Our study suggests that a neutrophil-endothelium interaction via the Mac-1/ICAM-1 pathway is involved in the activation and recruitment of neutrophils in ventilator-induced lung injury. Activation and recruitment of neutrophils were lessened by pretreatment with methylprednisolone, which might have contributed to the improvement of lung dysfunction after mechanical ventilation.
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Affiliation(s)
- N Ohta
- Intensive Care Unit, Osaka University Hospital, Suita, Osaka, Japan.
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Mowlavi A, Ghavami A, Song YH, Neumeister M. Limited use of cyclosporin A in skeletal muscle ischemia--reperfusion injury. Ann Plast Surg 2001; 46:426-30. [PMID: 11324887 DOI: 10.1097/00000637-200104000-00013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Reperfusion injury is propagated by an inflammatory-mediated tissue edema and damage after reestablishment of vascular flow following an initial ischemic insult. In the field of transplantation, cyclosporin A(CsA) provides protection against chronic graft rejection through lymphocyte immunosuppression. Evidence for an independent protective effect of CsA against ischemia-reperfusion (IR) injury during organ transfer has prompted studies showing the benefit of CsA in various ischemia-exposed visceral organs. The authors hypothesized that CsA administration may similarly benefit IR injury after skeletal muscle amputations. To determine the effects of CsA on IR injury the authors induced 4 hours of ischemia on the gracilis muscle in a rat model. CsA (15 mg per kilogram orally) was administered in two experimental groups: (1) preischemic (N = 6): 48, 24, and 3 hours before ischemia; and (2) postischemic (N = 6): 30 minutes after induction of ischemia. The effects of CsA on IR muscle injury were observed in each of the experimental groups as well as a control group (N = 6) exposed to similar ischemia and administered a saline vehicle. Muscle viability (nitro blue tetrazolium staining) and muscle edema (wet-to-dry weight ratio) were assessed 24 hours after reperfusion. The preischemic CsA-treated gracilis muscle group demonstrated improved muscle viability (39.1 +/- 4.8%) when compared with the ischemic control muscle group (23.8 +/- 7.1%; p = 0.039). Furthermore, the preischemic CsA-treated muscle group demonstrated decreased edema (1.137 +/- 0.095 times the contralateral nonischemic muscle) when compared with the control ischemic muscle group (1.248 +/- 0.045 times the contralateral nonischemic muscle; p = 0.011). Although a trend toward improved muscle viability (32.1 +/- 4.2%) and decreased edema formation (1.200 +/- 0.062 times the contralateral nonischemic muscle) was observed in the peri-ischemic CsA-treated group when compared with the control ischemic muscle group, these differences were not significant. These observations confirm the beneficial effects of preischemic CsA therapy observed in organ transplantation research and suggest limited clinical use of peri-ischemic CsA therapy for patients with musculoskeletal amputations.
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Affiliation(s)
- A Mowlavi
- Southern Illinois University, Institute for Plastic and Reconstructive Surgery, Springfield, USA
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Finsnes F, Lyberg T, Christensen G, Skjønsberg OH. Effect of endothelin antagonism on the production of cytokines in eosinophilic airway inflammation. Am J Physiol Lung Cell Mol Physiol 2001; 280:L659-65. [PMID: 11238005 DOI: 10.1152/ajplung.2001.280.4.l659] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Endothelin (ET)-1 has been launched as an important mediator in bronchial asthma, which is an eosinophilic airway inflammation. However, the interplay between ET-1 and other proinflammatory mediators during the development of airway inflammation has not been elucidated. We wanted to study 1) whether the production of ET-1 precedes the production of other proinflammatory mediators and 2) whether ET-1 stimulates the production of these mediators within the airways. These hypotheses were studied during the development of an eosinophilic airway inflammation in rats. The increase in ET-1 mRNA level in lung tissue preceded the increase in mRNA levels of tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-8. Treatment of the animals with the ET receptor antagonist bosentan resulted in a substantial decrease in the concentrations of tumor necrosis factor-alpha, IL-4, IL-1beta, interferon-gamma, and ET-1 in bronchoalveolar lavage fluid. In conclusion, the synthesis of ET-1 as measured by increased mRNA level precedes the synthesis of other proinflammatory cytokines of importance for the development of an eosinophilic airway inflammation, and ET antagonism inhibits the production of these mediators within the airways. Whether treatment with ET antagonists will prove beneficial for patients with eosinophilic airway inflammations like bronchial asthma is not yet known.
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Affiliation(s)
- F Finsnes
- Department of Pulmonary Medicine, Ullevål Hospital, University of Oslo, 0407 Oslo, Norway.
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46
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Calkins CM, Bensard DD, Heimbach JK, Meng X, Shames BD, Pulido EJ, McIntyre RC. L-arginine attenuates lipopolysaccharide-induced lung chemokine production. Am J Physiol Lung Cell Mol Physiol 2001; 280:L400-8. [PMID: 11159022 DOI: 10.1152/ajplung.2001.280.3.l400] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Chemokines stimulate the influx of leukocytes into tissues. Their production is regulated by nuclear factor-kappaB (NF-kappaB), an inducible transcription factor under the control of inhibitory factor kappaB-alpha (IkappaB-alpha). We have previously demonstrated that L-arginine (L-Arg) attenuates neutrophil accumulation and pulmonary vascular injury after administration of lipopolysaccharide (LPS). We hypothesized that L-Arg would attenuate the production of lung chemokines by stabilizing IkappaB-alpha and preventing NF-kappaB DNA binding. We examined the effect of L-Arg on chemokine production, IkappaB-alpha degradation, and NF-kappaB DNA binding in the lung after systemic LPS. To block nitric oxide (NO) production, a NO synthase inhibitor was given before L-Arg. LPS induced the production of chemokine protein and mRNA. L-Arg attenuated the production of chemokine protein and mRNA, prevented the decrease in IkappaB-alpha levels, and inhibited NF-kappaB DNA binding. NO synthase inhibition abolished the effects of L-Arg on all measured parameters. Our results suggest that L-Arg abrogates chemokine protein and mRNA production in rat lung after LPS. This effect is dependent on NO and is mediated by stabilization of IkappaB-alpha levels and inhibition of NF-kappaB DNA binding.
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Affiliation(s)
- C M Calkins
- Department of Surgery, University of Colorado Health Sciences Center and The Veterans Affairs Hospital, Denver, Colorado 80262, USA
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Lancaster LH, Christman JW, Blackwell TR, Koay MA, Blackwell TS. Suppression of lung inflammation in rats by prevention of NF-kappaB activation in the liver. Inflammation 2001; 25:25-31. [PMID: 11293663 DOI: 10.1023/a:1007071527408] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Activation of NF-kappaB and production of NF-kappaB-dependent chemokines are thought to be involved in the pathogenesis of neutrophilic lung inflammation. Calpain-1 inhibitor (CI-1) blocks activation of NF-kappaB by preventing proteolysis of the inhibitory protein IkappaB-alpha by the ubiquitin/proteasome pathway. We hypothesized that inhibition of proteasome function with CI-1 would block NF-kappaB activation in vivo after intraperitoneal (i.p.) treatment with bacterial lipopolysaccharide (LPS), and that NF-kappaB inhibition would be associated with suppression of chemokine gene expression and attenuation of neutrophilic alveolitis. We treated rats with a single i.p. injection of CI-1 (10 mg/kg) two hours prior to i.p. LPS (7 mg/kg). Treatment with Cl-1 prevented degradation of IkappaB-alpha and activation of NF-kappaB in the liver in response to LPS; however, Cl-1 treatment had no detected effect on NF-kappaB activation in lung tissue. CI-1 treatment prior to LPS resulted in 40% lower MIP-2 concentration in lung lavage fluid compared to rats treated with vehicle prior to LPS (502 +/- 112 pg/ml vs. 859 +/-144 pg/ml, P < 0.05). In addition, CI-1 treatment substantially inhibited LPS-induced neutrophilic alveolitis (2.7+ /- 1.2 x 10(5) vs. 43.7 +/- 12.2 x 10(5) lung lavage neutrophils, P < 0.01). These data indicate that NF-kappaB inhibition in the liver can alter lung inflammation induced by systemic LPS treatment and suggest that a liver-lung interaction contributes to the inflammatory response of the lung.
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Affiliation(s)
- L H Lancaster
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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Paul-Clark MJ, Gilroy DW, Willis D, Willoughby DA, Tomlinson A. Nitric oxide synthase inhibitors have opposite effects on acute inflammation depending on their route of administration. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2001; 166:1169-77. [PMID: 11145698 DOI: 10.4049/jimmunol.166.2.1169] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The bulk of published data has shown that NO is proinflammatory. However, there also exists the conflicting notion that NO may be protective during an inflammatory insult. In an attempt to resolve this issue, we have compared the effects on inflammation of a range of NO synthase (NOS) inhibitors given either directly to the site of the inflammatory lesion or systemically. It was found that in the carrageenin-induced pleurisy, a single intrapleural injection of the selective inducible NO inhibitors S-(2-aminoethyl) isothiourea (AE-ITU; 3 and 10 mg/kg) and N-(3-(aminomethyl)-benzyl) acetamidine (1400W; 10 mg/kg) or the selective endothelial cell NOS inhibitor L-N(5)(1-iminoethyl)-ornithine (10 mg/kg) not only exacerbated inflammation at the very early stages of the lesion (1-6 h), but also prevented inflammatory resolution. By contrast, administering NOS inhibitors systemically ameliorated the severity of inflammation throughout the reaction. To elucidate the mechanisms by which inhibition of NO synthesis locally worsened inflammation, we found an increase in histamine, cytokine-induced neutrophil chemoattractant, superoxide, and leukotriene B(4) levels at the inflammatory site. In conclusion, this work shows that the local production of NO is protective by virtue of its ability to regulate the release of typical proinflammatory mediators and, importantly, that NOS inhibitors have differential anti-inflammatory effects depending on their route of administration.
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Affiliation(s)
- M J Paul-Clark
- Department of Experimental Pathology, The William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London, United Kingdom
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Yamaguchi Y, Ohshiro H, Nagao Y, Odawara K, Okabe K, Hidaka H, Ishihara K, Uchino S, Furuhashi T, Yamada S, Mori K, Ogawa M. Urinary trypsin inhibitor reduces C-X-C chemokine production in rat liver ischemia/reperfusion. J Surg Res 2000; 94:107-15. [PMID: 11104650 DOI: 10.1006/jsre.2000.5999] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND AIM Protease inhibitors attenuate ischemia/reperfusion injury. However, the underlying mechanisms by which protease inhibitors prevent reperfusion injury remain obscure. Neutrophils play an important role in reperfusion injury. We studied the effects of urinary trypsin inhibitor (UTI) on production of the C-X-C chemokine, cytokine-induced neutrophil chemoattractant (CINC), by Kupffer cells during ischemia/reperfusion of the liver. METHODS Liver ischemia was induced in rats by occlusion of the portal vein for 30 min. UTI (50,000 U/kg) was injected intravenously 5 min before vascular clamping. Serum CINC concentrations were measured by enzyme-linked immunosorbent assay. Levels of CINC mRNA in the liver were determined by Northern blot analysis. We also examined the inhibitory effects of UTI on in vitro CINC production by peritoneal macrophages in response to neutrophil elastase (NE). RESULTS Serum CINC concentrations increased and peaked 6 h after reperfusion. However, pretreatment of animals with UTI blunted this increase in CINC and significantly reduced CINC mRNA levels in the liver after ischemia/reperfusion. UTI also decreased neutrophil accumulation in the liver 24 h after reperfusion. In vitro CINC production by Kupffer cells from rats pretreated with UTI 3 h after ischemia/reperfusion was significantly decreased compared to those from untreated animals. UTI reduced NE activity in vitro in a dose-dependent manner, and UTI significantly reduced in vitro CINC production by peritoneal macrophages stimulated with NE. CONCLUSION UTI reduces the production of CINC by Kupffer cells stimulated with NE, attenuating ischemia/reperfusion injury of the liver.
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Affiliation(s)
- Y Yamaguchi
- Department of Surgery II, Kumamoto University Medical School, Kumamoto, Japan
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Chong IW, Shi MM, Love JA, Christiani DC, Paulauskis JD. Regulation of chemokine mRNA expression in a rat model of vanadium-induced pulmonary inflammation. Inflammation 2000; 24:505-17. [PMID: 11128049 DOI: 10.1023/a:1007021322323] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Environmental and occupational exposure to vanadium dusts results in toxic effects mainly confined to the respiratory system. Using a rat model of acute lung inflammation induced by intratracheal instillation of sodium metavanadate (NaVO3) at the dose of 200 microg V/kg, we investigated the relationship between the cytologic characterization of pulmonary inflammation and the expression of chemokine mRNA. Significant polymorphonuclear leukocyte (PMN) influx (P < 0.01) into the lung was noted 4 h after NaVO3 instillation, whereas alveolar macrophages (AMs) in bronchoalveolar lavage (BAL) cells appeared to decrease significantly. In contrast, neither PMNs nor AMs changed substantially 1 h after NaVO3 instillation. By Northern analysis, macrophage inflammatory protein (MIP)-2 mRNA in BAL cells increased markedly 1 h after NaVO3 instillation and reduced a little bit at 4 h, whereas MIP-1alpha mRNA in BAL cells was expressed relatively high 1 h after NaVO3 instillation, although a basal expression was detected in control group, and returned rapidly nearly to control level at 4 h. Since MIP-2 is a potent PMN chemoattractant and MIP-1alpha is a potent macrophage/monocyte chemoattractant has been well known. The facts that PMN influx was preceded by increased MIP-2 mRNA expression, suggesting that MIP-2 is involved in the development of NaVO3-induced pulmonary inflammation, whereas increased MIP-1alpha mRNA expression was followed by decreased AMs in BAL cells, suggesting AMs might be activated by MIP-1alpha, adherent to the lining surface of the airways and then resistant to be washed out. To delineate the mechanisms of transcriptional activation, we recently cloned the 5'-flanking region of the MIP-2 gene. The promotor region contains consensus binding sites for transcription factor nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1). Using electrophoretic mobility shift assay, increased nuclear NF-kappaB, not AP-1, binding activity was detected 1 h after NaVO3 instillation, which correlated with the induction of MIP-2 mRNA. p65 (Rel A) and p50 protein appears to be involved in MIP-2 NF-kappaB binding. Taken together, our studies suggest that MIP-2 is an important mediator of NaVO3-induced pulmonary inflammation in the rat model. In addition, elevated MIP-2 mRNA levels are accompanied by increased NF-kappaB binding activity in BAL cells, suggesting possible MIP-2 transcriptional regulation through NF-kappaB.
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Affiliation(s)
- I W Chong
- Department of Internal Medicine, Kaohsiung Medical University, Taiwan
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