Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human interleukin 13 (IL-13) is a cytokine that has a profound effect on primary immune cells by inducing immunoglobulin production, proliferation of B cells, and the differentiation of cells of the monocytic lineage. IL-13 can inhibit the production of inflammatory cytokines by both macrophages and monocytes. Previously, IL-13 expression has been reported only in cells of the T-cell lineage and the mast cell line HMC-1. We now report the presence of IL-13 mRNA and protein in human alveolar macrophages (AMs) analyzed by the reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunoabsorbent assay (ELISA), respectively, and IL-13 protein in bronchoalveolar lavage fluid (BALF) of subjects with pulmonary fibrosis. We have investigated 13 patients from 49 to 75 yr of age with forms of pulmonary fibrosis, and eight healthy volunteers from 24 to 61 yr of age. Their AMs were obtained by bronchoalveolar lavage (BAL) and purified by adherence. The proportion of BAL purified AMs expressing IL-13 mRNA was increased in those subjects with fibrotic lung disease, in comparison with those from control subjects (11 of 13 versus 2 of 8, P < 0.01). IL-13 protein was detectable in the BALF of 8 of 13 patients with pulmonary fibrosis, but in none of the control subjects. AMs of four subjects with systemic sclerosis were cultured and IL-13 protein was increased in the culture supernatants when compared to the control subjects, although this did not reach significance. These findings show that IL-13 mRNA is not only a product of T cells, but is also expressed in both normal AMs and those from subjects with pulmonary fibrosis, and that at least some of the IL-13 mRNA is translated into protein and secreted in subjects with pulmonary fibrosis. We hypothesize that IL-13 may be expressed by normal human AMs as part of the homeostatic control process but its production may be increased in the presence of inflammatory lung disease.
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PMID:Production of interleukin 13 by alveolar macrophages from normal and fibrotic lung. 944 46

Anaphylaxis represents an extreme form of allergic reaction. This acute-phase component of allergy and asthma is triggered by allergen-induced degranulation of mast cells following the cross-linking of cell surface-bound, allergen-specific IgE, resulting in the liberation of inflammatory mediators and the development of bronchoconstriction. We used IL-13 transgenic mice to investigate the role of this Th2 cell-derived cytokine in the onset of allergic disease. Strikingly, IL-13-transgenic mice were highly predisposed to fatal anaphylaxis following Ag sensitization. This response correlated with substantially elevated levels of circulating Ag-specific IgE, mast cell degranulation, and histamine release. Furthermore, allergen exposure also induced phenotypic changes typical of asthma, including pulmonary fibrosis, goblet cell hyperplasia, elevated Th2 cytokines, eosinophilia, and airways occluded by mucus and Charcot-Leyden crystals. Expression of IL-4 was not required for the induction of IgE-mediated responses. These data represent the first characterization of a functional role for IL-13-induced IgE in the generation of immediate hypersensitivity reactions and highlight the importance of IL-13 in the development of the symptoms of atopy. The systemic regulation of this response makes these mice an important resource for studying atopic responses.
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PMID:IL-13 overexpression predisposes to anaphylaxis following antigen sensitization. 1116 Mar 36

Various growth factors and cytokines have been suggested to play a central role in initiating and developing fibrosis in systemic sclerosis (SSc). To determine which serum levels of soluble mediators are the most relevant to the degree of skin sclerosis in SSc, serum levels of various soluble mediators were examined by ELISA and correlated with skin thickening that was measured using modified Rodnan total skin thickness scoring (TSS) system. Serum levels of IL-4, IL-12, IL-13, tumor necrosis factor-alpha, connective tissue growth factor (CTGF), vascular endothelial growth factor, monocyte chemotactic protein-1, macrophage inflammatory protein-1beta, soluble IL-6 receptor, and soluble L-selectin were higher in SSc patients than normal controls. Levels of IL-6, IL-10, and CTGF in patients with diffuse cutaneous SSc were higher than patients with limited cutaneous SSc and controls. Serum levels of IL-6 and IL-10 positively correlated with TSS in patients with SSc (r=0.625, P<0.0001 and r=0.663, P<0.0001, respectively). In addition, IL-10 levels significantly correlated with pulmonary fibrosis. Thus, serum levels of IL-6 and IL-10 most strongly reflect the extent of skin thickening in SSc, suggesting that levels of IL-6 and IL-10 are useful serological indicators for skin fibrosis in SSc.
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PMID:Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. 1153 78

Interleukin (IL)-13 is a key mediator of tissue fibrosis caused by T helper cell type 2 inflammation. We hypothesized that the fibrogenic effects of IL-13 are mediated by transforming growth factor (TGF)-beta. To test this hypothesis we compared the regulation of TGF-beta in lungs from wild-type mice and CC10-IL-13 mice in which IL-13 overexpression causes pulmonary fibrosis. IL-13 selectively stimulated TGF-beta(1) production in transgenic animals and macrophages were the major site of TGF-beta(1) production and deposition in these tissues. IL-13 also activated TGF-beta(1) in vivo. This activation was associated with decreased levels of mRNA encoding latent TGF-beta-binding protein-1 and increased mRNA encoding urinary plasminogen activator, matrix metalloproteinase (MMP)-9, and CD44. TGF-beta(1) activation was abrogated by the plasmin/serine protease antagonist aprotinin. It was also decreased in progeny of crosses of CC10-IL-13 mice and MMP-9 null mice but was not altered in crosses with CD44 null animals. IL-13-induced fibrosis was also significantly ameliorated by treatment with the TGF-beta antagonist soluble TGFbetaR-Fc (sTGFbetaR-Fc). These studies demonstrate that IL-13 is a potent stimulator and activator of TGF-beta(1) in vivo. They also demonstrate that this activation is mediated by a plasmin/serine protease- and MMP-9-dependent and CD44-independent mechanism(s) and that the fibrogenic effects of IL-13 are mediated, in great extent, by this TGF-beta pathway.
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PMID:Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). 1156 Sep 96

The initial stimulus for inflammatory cell recruitment and the mechanisms responsible for the perpetuation and evolution of chronic inflammation, granulation tissue formation, and fibrosis have not been fully elucidated. Although interleukin (IL)-13, a Th2 cytokine, has been shown to have direct effects on fibroblasts that support fibroproliferation, it is also a potent inducer of a novel CC chemokine, C10, which is chemotactic for mononuclear phagocytes. The macrophage/mononuclear phagocyte has been shown to have a role in the pathogenesis of pulmonary fibrosis, serving as an important source of growth factors that regulate extracellular matrix synthesis. In this study we demonstrate that IL-13 and C10 are elevated in the pathogenesis of bleomycin-induced pulmonary fibrosis. Neutralization of IL-13, but not IL-4, attenuated bleomycin-induced pulmonary fibrosis and levels of C10, suggesting that IL-13 has an important role in the development of pulmonary fibrosis. IL-13 is a potent inducer of C10 in vivo, and neutralization of C10 attenuated bleomycin-induced pulmonary fibrosis and intrapulmonary macrophage numbers. This suggests that IL-13 has a role in the development of pulmonary fibrosis that is independent of its direct effect on fibroblasts and is evidence for an interaction between Th2 cytokines and specific CC chemokines.
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PMID:Interaction of IL-13 and C10 in the pathogenesis of bleomycin-induced pulmonary fibrosis. 1235 75

Interleukin-13 (IL-13) has emerged as a major cytokine mediator of fibroblast activation and pulmonary fibrosis. Normal (from noninflamed lung), Th1-type (induced by the pulmonary embolization of purified peptide derivative-coated beads in mice sensitized to purified peptide derivative), and Th2-type (induced by the pulmonary embolization of Schistosoma mansoni egg antigen-coated beads in mice sensitized with S. mansoni eggs) primary fibroblast cell lines all exhibited constitutive gene expression of two receptor chains that bind and signal IL-13-mediated cellular events: IL-4Ralpha and IL-13Ralpha1. However, all three fibroblast cell lines exhibited divergent synthetic and proliferative responses to the exogenous addition of either recombinant IL-13 or a chimeric protein comprised of IL-13 and a truncated version of Pseudomonas exotoxin (IL13-PE), which targets and kills IL-13 receptor overexpressing cells. The exogenous addition of IL-13 to Th1-type and Th2-type fibroblast cultures significantly increased the cellular expression of IL-13Ralpha2, which may function as an IL-13 decoy receptor. After a 24-hour exposure to IL-13, the total collagen generation and cellular proliferation by Th2-type fibroblasts were significantly higher than that observed in similar numbers of normal and Th1-type fibroblasts. In addition IL13-PE, which binds with highest affinity to IL-13Ralpha2, exhibited down-regulatory effects on proliferation and matrix generation expression by Th1- and Th2-type, but not normal, fibroblasts. Thus, these data demonstrate that fibroblasts derived from murine pulmonary granulomas exhibit divergent expression of functional IL-13 receptor and this expression dictates the responsiveness and susceptibility to recombinant IL-13 and IL-13 immunotoxin, respectively.
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PMID:Impact of interleukin-13 responsiveness on the synthetic and proliferative properties of Th1- and Th2-type pulmonary granuloma fibroblasts. 1270 30

Severe forms of idiopathic interstitial pneumonia (IIP), such as usual interstitial pneumonia, can be impervious to modern steroid and immunosuppressive treatment regimens, thereby emphasizing the need for novel effective therapies. Consequently, research attention has been directed toward understanding the cytokine networks that may affect fibroblast activation and, hence, the progression of certain IIPs. This led us to investigate whether the specific targeting of resident lung cells responsive to IL-4 and IL-13 exerted a therapeutic effect in an experimental model of IIP, namely the bleomycin-induced model of pulmonary fibrosis. IL-4, IL-13, and their corresponding receptor subunits, IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2, were maximally expressed at the mRNA and protein levels in whole lung samples on day 21 or 28 after an intratracheal bleomycin challenge. The intranasal administration of an IL-13 immunotoxin chimeric molecule (IL13-PE) from days 21-28, but not for 1-wk periods at earlier times, after bleomycin challenge had a significant therapeutic effect on histological and biochemical parameters of bleomycin-induced pulmonary fibrosis compared with the control group. The intranasal IL13-PE therapy significantly reduced the numbers of IL-4 and IL-13 receptor-positive mononuclear cells and macrophages and the levels of profibrotic cytokine and chemokine in the lungs of bleomycin-challenged mice on day 28. Thus, this study demonstrates that IL-4- and/or IL-13-binding cells are required for the maintenance of pulmonary fibrosis induced by bleomycin and highlights the importance of further investigation of antifibrotic therapeutics that target these cells during pulmonary fibrosis.
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PMID:Therapeutic attenuation of pulmonary fibrosis via targeting of IL-4- and IL-13-responsive cells. 1292 22

Macrophage-derived insulin-like growth factor-I (IGF-I) has long been implicated in the pathogenesis of the interstitial lung disease, idiopathic pulmonary fibrosis, in part, by its ability to 1) stimulate the proliferation and survival of fibroblasts and myofibroblasts and 2) promote collagen matrix synthesis by these cells. However, little is known about the mechanisms that stimulate the expression of IGF-I by macrophages. Previous studies have shown that the development of pulmonary fibrosis is accompanied by enhanced expression of Th2-profile cytokines, especially IL-4, and diminished expression of Th1 cytokines, including IFN-gamma. In addition, in vitro studies have shown that IFN-gamma down-regulates the expression of IGF-I. Thus, the paucity of IFN-gamma in the fibrotic lung may favor increased growth factor production by allowing Th2 cytokines to predominate. In view of these findings, we investigated the hypothesis that Th2 cytokines stimulate the expression of IGF-I by macrophages. Incubation with IL-4 or IL-13 led to concentration- and time-dependent increases in the expression of IGF-I mRNA and the secretion of IGF-I protein by mouse macrophages as a consequence of increased transcription of IGF-I pre-mRNA. Exposure of macrophages to IL-4 in the presence of IFN-gamma inhibited the increase in the expression of IGF-I. Studies using STAT6-deficient macrophages indicated that the increase in IGF-I expression was dependent on STAT6. In addition, the down-regulation of IGF-I expression by IFN-gamma was absent in STAT1-deficient macrophages. Collectively, these findings define a homeostatic mechanism in which Th2 cytokines promote, and Th1 cytokines inhibit, the expression of IGF-I by macrophages.
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PMID:Induction of macrophage insulin-like growth factor-I expression by the Th2 cytokines IL-4 and IL-13. 1450 Jun 51

Leukocyte infiltration is characteristic of lung injury and fibrosis, and its role during tissue repair and fibrosis is incompletely understood. We found that overexpression of IL-5 in transgenic mice (IL-5(TG)) or by adenoviral gene transfer increased bleomycin (blm)-induced lung injury, fibrosis, and eosinophilia. Surprisingly, blm-treated IL-5-deficient (IL-5(-/-)) mice also developed pronounced pulmonary fibrosis but characterized by marked T lymphocyte infiltration and absence of eosinophilia. In both murine strains however, induction of lung TGF-beta expression was evident. Purified lung eosinophils from blm-treated IL-5(TG) mice stimulated alpha-smooth muscle actin and collagen expression in mouse lung fibroblasts, without affecting proliferation. Furthermore instillation of purified eosinophils into murine lungs resulted in extension of blm-induced lung fibrosis, thus confirming a role for eosinophils. However, lung T lymphocytes from blm-treated IL-5(-/-) mice were able to stimulate fibroblast proliferation but not alpha-smooth muscle actin or collagen expression. Blocking T cell influx by anti-CD3 Abs abrogated lung fibrosis, thus also implicating T lymphocytes as a key participant in fibrosis. Pulmonary fibrosis in IL-5(TG) mice was preferentially associated with type 2 cytokines (IL-4 and IL-13), whereas fibrotic lesions in IL-5(-/-) animals were accompanied by proinflammatory cytokine (TNF-alpha, IL-1beta, and IFN-gamma) expression. We suggest that eosinophils and T cells contribute distinctly to the development of blm-induced lung fibrosis potentially via their production of different cytokine components, which ultimately induce TGF-beta expression that is intimately involved with the fibrosis.
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PMID:Eosinophils and T lymphocytes possess distinct roles in bleomycin-induced lung injury and fibrosis. 1460 53

The development of idiopathic pulmonary fibrosis (IPF) is associated with myofibroblast accumulation and collagen deposition in the lung parenchyma. Recent studies have suggested that the fibroproliferative response is associated with immune deviation toward a T helper cell type 2 (Th2) cytokine profile. In addition, myofibroblast accumulation may be the result of resistance to physiologic apoptosis. If and how these events are linked remain largely unknown. Insulin-like growth factor-I (IGF-I) is a fibroblast growth and survival factor that has long been implicated in the pathogenesis of IPF. We have previously shown that interstitial macrophage-derived IGF-I correlates with disease severity in IPF, and the Th2 cytokines interleukin (IL)-4 and IL-13 stimulate the expression and secretion of IGF-I by macrophages. In the present study, we tested the hypothesis that IL-4-induced, macrophage-derived IGF-I protects myofibroblasts from apoptosis. Using a growth factor withdrawal model of apoptosis in the myofibroblast cell line, CCL39, we demonstrate that conditioned media from IL-4-stimulated macrophages protect myofibroblasts from apoptosis. The survival effect is lost when IGF-I is immunodepleted from macrophage-conditioned media with IGF-I-specific antibodies. We also show that the protection of myofibroblasts by macrophage-derived IGF-I correlates with and is dependent on the activation of the prosurvival kinases Akt and extracellular signal-regulated kinase. These findings support the view that IL-4-stimulated, macrophage-derived IGF-I may contribute to the persistence of myofibroblasts in pulmonary fibrosis in the Th2-deviated environment of the fibrotic lung.
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PMID:IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal. 1531 31


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