Cytokine mediated tissue fibrosis Borthwick, Lee A.; Wynn, Thomas A.; Fisher, Andrew J.
Biochimica et biophysica acta,
07/2013, Letnik:
1832, Številka:
7
Journal Article
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Acute inflammation is a recognised part of normal wound healing. However, when inflammation fails to resolve and a chronic inflammatory response is established this process can become dysregulated ...resulting in pathological wound repair, accumulation of permanent fibrotic scar tissue at the site of injury and the failure to return the tissue to normal function. Fibrosis can affect any organ including the lung, skin, heart, kidney and liver and it is estimated that 45% of deaths in the western world can now be attributed to diseases where fibrosis plays a major aetiological role. In this review we examine the evidence that cytokines play a vital role in the acute and chronic inflammatory responses that drive fibrosis in injured tissues. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
► Fibrosis can affect any organ including the lung, skin, heart, kidney and liver. ► 45% of deaths can now be attributed to diseases where fibrosis plays a major role. ► Acute or chronic inflammatory responses are critical in driving fibrosis. ► Here we examine the evidence for cytokines driving fibrosis in injured tissue.
Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial ...tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
Novel insights into the epigenetic control of chronic liver diseases are now emerging. Recent advances in our understanding of the critical roles of DNA methylation, histone modifications and ncRNA ...may now be exploited to improve management of fibrosis/cirrhosis and cancer. Furthermore, improved technologies for the detection of epigenetic markers from patients' blood and tissues will vastly improve diagnosis, treatment options and prognostic tracking. The aim of this review is to present recent findings from the field of liver epigenetics and to explore their potential for translation into therapeutics to prevent disease promoting epigenome reprogramming and reverse epigenetic changes.
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Precision cut liver slices (PCLSs) retain the structure and cellular composition of the native liver and represent an improved system to study liver fibrosis compared to two‐dimensional mono‐ or ...co‐cultures. The aim of this study was to develop a bioreactor system to increase the healthy life span of PCLSs and model fibrogenesis. PCLSs were generated from normal rat or human liver, or fibrotic rat liver, and cultured in our bioreactor. PCLS function was quantified by albumin enzyme‐linked immunosorbent assay (ELISA). Fibrosis was induced in PCLSs by transforming growth factor beta 1 (TGFβ1) and platelet‐derived growth factor (PDGFββ) stimulation ± therapy. Fibrosis was assessed by gene expression, picrosirius red, and α‐smooth muscle actin staining, hydroxyproline assay, and soluble ELISAs. Bioreactor‐cultured PCLSs are viable, maintaining tissue structure, metabolic activity, and stable albumin secretion for up to 6 days under normoxic culture conditions. Conversely, standard static transwell‐cultured PCLSs rapidly deteriorate, and albumin secretion is significantly impaired by 48 hours. TGFβ1/PDGFββ stimulation of rat or human PCLSs induced fibrogenic gene expression, release of extracellular matrix proteins, activation of hepatic myofibroblasts, and histological fibrosis. Fibrogenesis slowly progresses over 6 days in cultured fibrotic rat PCLSs without exogenous challenge. Activin receptor‐like kinase 5 (Alk5) inhibitor (Alk5i), nintedanib, and obeticholic acid therapy limited fibrogenesis in TGFβ1/PDGFββ‐stimulated PCLSs, and Alk5i blunted progression of fibrosis in fibrotic PCLS. Conclusion: We describe a bioreactor technology that maintains functional PCLS cultures for 6 days. Bioreactor‐cultured PCLSs can be successfully used to model fibrogenesis and demonstrate efficacy of antifibrotic therapies.
Thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25), and IL-33 are important initiators of type 2-associated mucosal inflammation and immunity. However, their role in the maintenance of ...progressive type 2 inflammation and fibrosis is much less clear. Using chronic models of helminth infection and allergic lung inflammation, we show that collective disruption of TSLP, IL-25, and IL-33 signaling suppresses chronic and progressive type 2 cytokine-driven inflammation and fibrosis. In a schistosome lung granuloma model or during chronic Schistosoma mansoni infection in the liver, individual ablation of TSLP, IL-25, or IL-33/ST2 had no impact on the development of IL-4/IL-13-dependent inflammation or fibrosis. However, significant reductions in granuloma-associated eosinophils, hepatic fibrosis, and IL-13-producing type 2 innate lymphoid cells (ILC2s) were observed when signaling of all three mediators was simultaneously disrupted. Combined blockade through monoclonal antibody (mAb) treatment also reduced IL-5 and IL-13 expression during primary and secondary granuloma formation in the lungs. In a model of chronic house dust mite-induced allergic lung inflammation, combined mAb treatment did not decrease established inflammation or fibrosis. TSLP/IL-33 double-knockout mice treated with anti-IL-25 mAb during priming, however, displayed decreased inflammation, mucus production, and lung remodeling in the chronic phase. Together, these studies reveal partially redundant roles for TSLP, IL-25, and IL-33 in the maintenance of type 2 pathology and suggest that in some settings, early combined targeting of these mediators is necessary to ameliorate progressive type 2-driven disease.
Total knee arthroplasty (TKA) is one of the most successful orthopaedic procedures that alleviates pain and restores function in patients with degenerative knee joint diseases. Arthrofibrosis, ...abnormal scarring in which dense fibrous tissue prevents normal range of motion, develops in ~3-10% of TKA patients. No prophylactic intervention is available and treatment is restricted to aggressive physiotherapy or revision surgery. Tissue was collected from patients undergoing primary (n = 30) or revision (n = 27) TKA. Revision patients were stratified as non-arthrofibrotic and arthrofibrotic. Tissue was macroscopically and histologically compared to improve our understanding of the pathophysiology of arthrofibrosis. Macroscopically, tissue from primary TKA presents as homogenous, fatty tissue whereas tissue from revision TKA presents as dense, pigmented tissue. Histologically, there was dramatic tissue remodelling, increased collagen deposition and increased (myo)fibroblast staining in tissue from revision TKA. Significantly, tissue architecture was similar between revision patients regardless of clinically diagnosis. There are significant differences in architecture and composition of tissue from revision TKA over primary TKA. Surprisingly, whether revision TKA were clinically diagnosed as arthrofibrotic or non-arthrofibrotic there were still significant differences in fibrotic markers compared to primary TKA suggesting an ongoing fibrotic process in all revision knees.
Mice expressing a Cre recombinase from the lysozyme M-encoding locus (Lyz2) have been widely used to dissect gene function in macrophages and neutrophils. Here, we show that while naïve resident ...tissue macrophages from IL-4Rαf(lox/delta)LysM(Cre) mice almost completely lose IL-4Rα function, a large fraction of macrophages elicited by sterile inflammatory stimuli, Schistosoma mansoni eggs, or S. mansoni infection, fail to excise Il4rα. These F4/80(hi)CD11b(hi) macrophages, in contrast to resident tissue macrophages, express lower levels of Lyz2 explaining why this population resists LysM(Cre)-mediated deletion. We show that in response to IL-4 and IL-13, Lyz2(lo)IL-4Rα(+) macrophages differentiate into an arginase 1-expressing alternatively-activated macrophage (AAM) population, which slows the development of lethal fibrosis in schistosomiasis. In contrast, we identified Lyz2(hi)IL-4Rα(+) macrophages as the key subset of AAMs mediating the downmodulation of granulomatous inflammation in chronic schistosomiasis. Our observations reveal a limitation on using a LysMCre mouse model to study gene function in inflammatory settings, but we utilize this limitation as a means to demonstrate that distinct populations of alternatively activated macrophages control inflammation and fibrosis in chronic schistosomiasis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Th2-driven lung inflammation increases Arginase 1 (Arg1) expression in alternatively-activated macrophages (AAMs). AAMs modulate T cell and wound healing responses and Arg1 might contribute to asthma ...pathogenesis by inhibiting nitric oxide production, regulating fibrosis, modulating arginine metabolism and restricting T cell proliferation. We used mice lacking Arg1 in myeloid cells to investigate the contribution of Arg1 to lung inflammation and pathophysiology. In six model systems encompassing acute and chronic Th2-mediated lung inflammation we observed neither a pathogenic nor protective role for myeloid-expressed Arg1. The number and composition of inflammatory cells in the airways and lungs, mucus secretion, collagen deposition, airway hyper-responsiveness, and T cell cytokine production were not altered if AAMs were deficient in Arg1 or simultaneously in both Arg1 and NOS2. Our results argue that Arg1 is a general feature of alternative activation but only selectively regulates Th2 responses. Therefore, attempts to experimentally or therapeutically inhibit arginase activity in the lung should be examined with caution.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Extended criteria donor lungs deemed unsuitable for immediate transplantation can be reconditioned using ex vivo lung perfusion (EVLP). Objective identification of which donor lungs can be ...successfully reconditioned and will function well post-operatively has not been established. This study assessed the predictive value of markers of inflammation and tissue injury in donor lungs undergoing EVLP as part of the DEVELOP-UK study.
Longitudinal samples of perfusate, bronchoalveolar lavage, and tissue from 42 human donor lungs undergoing clinical EVLP assessments were analyzed for markers of inflammation and tissue injury. Levels were compared according to EVLP success and post-transplant outcomes. Neutrophil adhesion to human pulmonary microvascular endothelial cells (HPMECs) conditioned with perfusates from EVLP assessments was investigated on a microfluidic platform.
The most effective markers to differentiate between in-hospital survival and non-survival post-transplant were perfusate interleukin (IL)-1β (area under the curve = 1.00, p = 0.002) and tumor necrosis factor-α (area under the curve = 0.95, p = 0.006) after 30 minutes of EVLP. IL-1β levels in perfusate correlated with upregulation of intracellular adhesion molecule-1 in donor lung vasculature (R2 = 0.68, p < 0.001) and to a lesser degree upregulation of intracellular adhesion molecule-1 (R2 = 0.30, p = 0.001) and E-selectin (R2 = 0.29, p = 0.001) in conditioned HPMECs and neutrophil adhesion to conditioned HPMECs (R2 = 0.33, p < 0.001). Neutralization of IL-1β in perfusate effectively inhibited neutrophil adhesion to conditioned HPMECs (91% reduction, p = 0.002).
Donor lungs develop a detectable and discriminatory pro-inflammatory signature in perfusate during EVLP. Blocking the IL-1β pathway during EVLP may reduce endothelial activation and subsequent neutrophil adhesion on reperfusion; this requires further investigation in vivo.
Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the ...number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103(+) dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.
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