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)

Pneumonia is a major complication of human immunodeficiency virus (HIV) pathogenesis but it develops only after prolonged infection. We used the macaque model to explore a hypothesis that the disease is a two-stage process, the first stage being establishment of the viral infection in the lung and the second being amplification of virus replication by host factors induced by chemical agents or opportunistic pathogens in the lung. Bleomycin, a chemical known to induce diffuse alveolar damage and pulmonary fibrosis with accumulation of macrophages and a rich T helper type 2 (Th2) cytokine environment, was inoculated intratracheally into five of eight SHIV 89.6P-infected macaques and into one uninfected macaque. Three additional simian HIV (SHIV)-infected macaques without bleomycin treatment served as untreated virus controls. Although none of the animals became clinically ill, bleomycin induced classical host responses in the lungs of all the treated, virus-infected macaques. There was enhanced production of the chemokine, monocyte chemotactic protein-1 (MCP-1), that had previously been shown to cause enhanced replication of the virus. Four of the five treated animals developed more productive SHIV infection in the lungs compared with the infected untreated animals. Enhanced virus replication was found primarily in infiltrating macrophages. Enhanced replication of the virus in the lungs was associated with host factors induced by the drug and supported the hypothesis for a two-stage process of pulmonary pathogenesis.
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PMID:Bleomycin treatment causes enhancement of virus replication in the lungs of SHIV-infected macaques. 1722 Mar 71

Angiogenesis is a feature of chronic lung diseases such as asthma and pulmonary fibrosis; however, the pathways controlling pathological angiogenesis during lung disease are not completely understood. Adenosine is a signaling molecule that has been implicated in the exacerbation of chronic lung disease and in the regulation of angiogenesis; however, the relationship between these factors has not been investigated. The current study utilized adenosine deaminase (ADA)-deficient mice to determine whether chronic elevations in adenosine in vivo result in pulmonary angiogenesis. Results demonstrate substantial angiogenesis in the tracheas of ADA-deficient mice in association with adenosine elevations. ADA replacement enzyme therapy resulted in a lowering of adenosine levels and reversal of tracheal angiogenesis, indicating that the increases in vessel number are dependent on adenosine elevations. Levels of the angiogenic chemokine CXCL1 (mouse functional homologue of human IL-8) were found to be elevated in an adenosine-dependent manner in the lungs of ADA-deficient mice. Neutralization of CXCL1 and its receptor, CXCR2, resulted in the inhibition of angiogenic activity, which suggests that CXCL1 signaling through the CXCR2 receptor mediated the observed increases in angiogenesis. Our findings suggest that adenosine plays an important role, via CXCL1, in the induction of pulmonary angiogenesis.
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PMID:Enhanced CXCL1 production and angiogenesis in adenosine-mediated lung disease. 1722 50

The chemokine receptor CXCR4, which binds the chemokine stromal cell-derived factor 1, has been reported to be involved in the chemotaxis of inflammatory cells. In addition, AMD3100, an antagonist of CXCR4, has been reported to be an attractive drug candidate for therapeutic intervention in several disorders in which CXCR4 is critically involved. However, little is known about the therapeutic value of AMD3100 in the treatment of pulmonary fibrosis. In this study, we examined the effects of AMD3100 on a murine bleomycin-induced pulmonary fibrosis model. Concurrent administration of AMD3100 and bleomycin apparently attenuated bleomycin-induced pulmonary inflammation. In this process, an inhibition of neutrophil recruitment at early stage followed by the decrease of other inflammatory cell recruitment in the lung were observed. In addition, it also inhibited the expression of cytokines, including MCP-1, MIP-2, MIP-1alpha, and TGF-beta. In contrast, when AMD3100 was administered following bleomycin treatment, the bleomycin-induced lung inflammation progressed and resulted in severe pulmonary fibrosis. In this process, an increase of inflammatory cell recruitment, an up-regulation of lung MCP-1 and TGF-beta, and a remarkable activation of p44/42 MAPK in neutrophils were observed. U0126, an inhibitor of p44/42 MAPK, significantly abolished these effects. Thus, AMD3100 has dual effect on bleomycin-induced pulmonary fibrosis. Difference of inflammatory cell recruitment and activation might be associated with the dual effect of AMD3100 on bleomycin-induced pulmonary fibrosis.
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PMID:Dual effect of AMD3100, a CXCR4 antagonist, on bleomycin-induced lung inflammation. 1894 Dec 58

Fibrocytes were first described over a decade ago as a population of cells in circulation with fibroblast-like properties, which were involved in tissue repair. Since that time, we have learned a significant amount about these bone marrow-derived cells, which contribute to wound healing and fibrosis. Fibrocytes express leukocyte markers such as CD34, CD45, and CD13 and also express mesenchymal markers such as pro-collagens I and III, vimentin, and fibronectin. In addition, they have been shown to express the chemokine receptors CXCR4 and CCR7, which appear to be important in cellular trafficking from the vascular to the extravascular compartment. Fibrocytes have been shown to contribute to a number of fibrotic disorders, and here, we review their involvement in lung diseases including pulmonary fibrosis, asthma, and vascular remodeling.
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PMID:Fibrocytes in lung disease. 1755 Sep 74

Pulmonary fibrosis is characterized by the accumulation of fibroblasts and myofibroblasts. These cells may accumulate from three potential sources: the expansion of resident lung fibroblasts, the process of epithelial-mesenchymal transition, or the recruitment and differentiation of circulating mesenchymal precursors known as fibrocytes. We have previously demonstrated that fibrocytes participate in lung fibrogenesis following administration of FITC to mice. We now demonstrate that leukotriene-deficient 5-LO(-/-) mice are protected from FITC-induced fibrosis. Both murine and human fibrocytes express both cysteinyl leukotriene receptor (CysLT) 1 and CysLT2. In addition, fibrocytes are capable of producing CysLTs and can be regulated via the autocrine or paracrine secretion of these lipid mediators. Exogenous administration of leukotriene (LT) D(4), but not LTC(4) induces proliferation of both murine and human fibrocytes in a dose-dependent manner. Consistent with this result, CysLT1 receptor antagonists are able to block the mitogenic effects of exogenous LTD(4) on fibrocytes. Endogenous production of CysLTs contributes to basal fibrocyte proliferation, but does not alter fibrocyte responses to basic fibroblast growth factor. Although CysLTs can induce the migration of fibrocytes in vitro, they do not appear to be essential for fibrocyte recruitment to the lung in vivo, possibly due to compensatory chemokine-mediated recruitment signals. However, CysLTs do appear to regulate the proliferation of fibrocytes once they are recruited to the lung. These data provide mechanistic insight into the therapeutic benefit of leukotriene synthesis inhibitors and CysLT1 receptor antagonists in animal models of fibrosis.
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PMID:Cysteinyl leukotrienes are autocrine and paracrine regulators of fibrocyte function. 1802 35

Scleroderma is a systemic, mixed connective tissue disease that can impact the lungs through pulmonary fibrosis, vascular remodeling, and the development of pulmonary hypertension and right heart failure. Currently, little is known about the molecular mechanisms that drive this condition, but we have recently identified a novel gene product that is up-regulated in a murine model of hypoxia-induced pulmonary hypertension. This molecule, known as hypoxia-induced mitogenic factor (HIMF), is a member of the newly described resistin gene family. We have demonstrated that HIMF has mitogenic, angiogenic, vasoconstrictive, inflammatory, and chemokine-like properties, all of which are associated with vascular remodeling in the lung. Here, we demonstrate that the human homolog of HIMF, resistin-like molecule (RELM)-beta, is expressed in the lung tissue of patients with scleroderma-associated pulmonary hypertension and is up-regulated compared with normal control subjects. Immunofluorescence colocalization revealed that RELM-beta is expressed in the endothelium and vascular smooth muscle of remodeled vessels, as well as in plexiform lesions, macrophages, T cells, and myofibroblast-like cells. We also show that addition of recombinant RELM-beta induces proliferation and activation of ERK1/2 in primary cultured human pulmonary endothelial and smooth muscle cells. These results suggest that RELM-beta may be involved in the development of scleroderma-associated pulmonary hypertension.
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PMID:Resistin-like molecule-beta in scleroderma-associated pulmonary hypertension. 1925 45

Fibrotic interstitial lung diseases are characterized by progressive decline in lung function and premature death from respiratory failure. Fibrocytes are circulating bone marrow-derived progenitor cells that traffic to the lungs and contribute to fibrosis and may represent novel therapeutic targets in these diseases. We have previously found the recruitment of fibrocytes to the lung to be dependent on the chemokine ligand CXCL12. Given that the expression of the CXCL12 receptor, CXCR4, can be modulated pharmacologically in other cell types, we tested the hypotheses that the regulation of CXCR4 expression on fibrocytes mediates their influx to the lung in the context of pulmonary fibrosis and that pharmacologic inhibition of this process results in attenuated disease severity. CXCR4 was the predominant chemokine receptor on human fibrocytes, and its expression on fibrocytes was enhanced by hypoxia and by growth factors including platelet-derived growth factor. Both hypoxia-induced and growth factor-induced CXCR4 expressions were attenuated by specific inhibition of PI3-kinase and mTOR. Finally, in the mouse model of bleomycin-induced pulmonary fibrosis, treatment with the mTOR inhibitor rapamycin resulted in reduced numbers of CXCR4-expressing fibrocytes in the peripheral blood and lung as well as reduced lung collagen deposition. Taken together, these experiments support the notion that pharmacologic inhibition of the CXCR4/CXCL12 biological axis is achievable in human fibrocytes and reduces the magnitude of pulmonary fibrosis in an animal model. This approach may hold promise in human fibrotic lung diseases.
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PMID:Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis. 1943 12

Pulmonary fibrosis is a progressive, dysregulated response to injury culminating in compromised lung function due to excess extracellular matrix production. The heparan sulfate proteoglycan syndecan-4 is important in mediating fibroblast-matrix interactions, but its role in pulmonary fibrosis has not been explored. To investigate this issue, we used intratracheal instillation of bleomycin as a model of acute lung injury and fibrosis. We found that bleomycin treatment increased syndecan-4 expression. Moreover, we observed a marked decrease in neutrophil recruitment and an increase in both myofibroblast recruitment and interstitial fibrosis in bleomycin-treated syndecan-4-null (Sdc4-/-) mice. Subsequently, we identified a direct interaction between CXCL10, an antifibrotic chemokine, and syndecan-4 that inhibited primary lung fibroblast migration during fibrosis; mutation of the heparin-binding domain, but not the CXCR3 domain, of CXCL10 diminished this effect. Similarly, migration of fibroblasts from patients with pulmonary fibrosis was inhibited in the presence of CXCL10 protein defective in CXCR3 binding. Furthermore, administration of recombinant CXCL10 protein inhibited fibrosis in WT mice, but not in Sdc4-/- mice. Collectively, these data suggest that the direct interaction of syndecan-4 and CXCL10 in the lung interstitial compartment serves to inhibit fibroblast recruitment and subsequent fibrosis. Thus, administration of CXCL10 protein defective in CXCR3 binding may represent a novel therapy for pulmonary fibrosis.
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PMID:Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4. 2048 22

The chemokine receptors CCR5 and CXCR4 are the two major coreceptors for HIV entry. Numerous efforts have been made to develop a new class of anti-HIV agents that target these coreceptors as an additional or alternative therapy to standard HAART. Among the CCR5 inhibitors developed so far, maraviroc is the first drug that has been approved by the US FDA for treating patients with R5 HIV-1. Although many CXCR4 inhibitors, some of which are highly active and orally bioavailable, have also been studied, they are still at preclinical stages or have been suspended during development. Importantly, the interaction between CXCR4 and its ligand SDF-1 is involved in various disease conditions, such as cancer cell metastasis, leukemia cell proliferation, rheumatoid arthritis and pulmonary fibrosis. Therefore, CXCR4 inhibitors have potential as novel therapeutics for the treatment of these diseases as well as HIV infection.
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PMID:Role of CXCR4 in HIV infection and its potential as a therapeutic target. 2063 3

Regulatory T cells (Treg) play a critical role in immune homeostasis and expansion of Treg is controlled by chemokine receptors. The chemokine CXCL12 and its G-protein-coupled receptor (CXCR4) are involved in the development of idiopathic pulmonary fibrosis (IPF), but the association of Treg with the CXCL12/CXCR4 axis has not been documented. The aim of this study is to determine the distribution and extent of CXCL12/CXCR4 expression in idiopathic type of pulmonary fibrosis, and the relation of Treg expansion in the interstitium of pulmonary fibrosis patients to CXCL12/CXCR4 expression. CXCL12 expression was examined by immunostaining and ELISA in tissue specimens from patients with usual interstitial pneumonia (UIP, n=15), patients with fibrotic non-specific interstitial pneumonia (f-NSIP, n=4), and controls (n=6). CXCR4 expression was examined by in situ hybridization and immunoblotting. Expression of CD45, CD3, CD20, transcription factor forkhead box P3 (FOXP3), and CD25 was assessed by immunostaining. Fibrosis was evaluated by determining the established fibrosis (EF) score. The CXCL12/CXCR4 axis was upregulated in UIP and f-NSIP, and CXCL12 derived from lung tissue attracted CXCR4(+) cells. CXCR4(+) cells showed a CD3(+) cell distribution pattern. The interstitial FOXP3(+)/CD3(+) and CD25(+)/CD3(+) cell ratios were lower in UIP than f-NSIP, but the CXCR4(+)/CD3(+) cell ratio was not different. The FOXP3(+)/CD3(+) cell ratio and EF score were inversely correlated. These findings suggest that the CXCL12/CXCR4 axis contributes to inflammation in UIP and f-NSIP by promoting the accumulation CXCR4(+) lymphocytes, and a decrease of Treg is correlated with the severity of fibrosis in UIP.
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PMID:Decreased interstitial FOXP3(+) lymphocytes in usual interstitial pneumonia with discrepancy of CXCL12/CXCR4 axis. 2064 40


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