The etiology of idiopathic pulmonary fibrosis (IPF) is unknown. Because viral pathogenesis IPF has been suggested, we have established a murine model progressive by infecting IFN-gammaR-deficient mice (IFN-gammaR(-/-)) with the gamma-herpesvirus 68. alveolar macrophages in humans implicated driving profibrotic response, studied their role our model. Chronic herpesvirus infection lung was associated recruitment to areas epithelial hyperplasia and infected lungs. Using immunohistochemistry,...

The mechanisms by which tobacco promotes lung cancer remain incompletely understood. Herein, we report that nicotine, a major component of tobacco, the proliferation cultured non-small cell carcinoma (NSCLC) cells; this effect was most noticeable at 5 days. However, nicotine had no on apoptosis NSCLC cells. In experiments designed to unveil for effect, found also stimulated mRNA and protein expression fibronectin. Fibronectin is matrix glycoprotein regulates important cellular processes...

A transforming growth factor-beta (TGF-beta) activating element (TAE), with a nuclear factor-1 (NF-1)-like sequence, was previously located 1.6 kilobases upstream from the transcription start site in alpha 1(I) collagen promoter (Ritzenthaler, J. D., Goldstein, R. H., Fine, A., Lichtler, Rowe, D. W., and Smith, B. (1991) Biochem. 280, 157-162). Double-stranded TAE, but not NF-1 consensus sequences, abrogated TGF-beta stimulation of co-transfected promoter-chloramphenicol acetyltransferase...

Tobacco-related lung diseases are associated with alterations in tissue remodeling and characterized by increased matrix deposition. Among the molecules found to be highly expressed tobacco-related is fibronectin, a cell adhesive glycoprotein implicated injury repair. We hypothesize that nicotine, component of tobacco, stimulates expression fibronectin fibroblasts via activation intracellular signals lead gene transcription. In support this, we nicotine stimulated its stimulatory effect was...

Abstract Although it is well recognized that alcohol abuse impairs alveolar macrophage immune function and renders patients susceptible to pneumonia, the mechanisms are incompletely understood. Alveolar maturation requires priming by GM-CSF, which produced secreted into space epithelium. In this study, we determined although chronic ethanol ingestion (6 wk) in rats had no effect on GM-CSF expression within space, significantly decreased membrane of receptor macrophages. parallel, cellular...

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disorder of unknown cause. Several studies suggest an association between Epstein-Barr virus infection and the development IPF.Objectives: To determine whether reduction γ-herpesvirus reactivation from latency would alter fibrogenesis in animal model virus-induced fibrosis.Methods: IFN-γ receptor–deficient (IFN-γR−/−) mice infected intranasally with murine 68 (MHV68) develop that progresses for up to at...

Cyclooxygenase-2-derived prostaglandin E(2) (PGE(2)) stimulates tumor cell growth and progression. However, the mechanisms by which PGE(2) increases remain incompletely understood. In studies performed in non-small lung carcinoma (NSCLC) cells, we found that expression of integrin-linked kinase (ILK). ILK small interfering RNA (siRNA) inhibited mitogenic effects PGE(2). view its perceived importance, turned our attention to involved PGE(2)-induced this effect was blocked an antagonist...

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We have shown that Smad3, an intracellular signal transducer for transforming growth factor-beta1 (TGF-beta1), is required to elicit the full histological manifestations of obliterative airway disease in a tracheal transplant model. This suggests chronic allograft rejection results TGF-beta1-induced Smad3 activation leads obliteration through fibroproliferation and increased matrix deposition. In other systems, these latter events are causally related transdifferentiation fibroblasts into...

Recent studies suggest that activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) promotes cancer cell survival. We previously demonstrated a selective PPARbeta/delta agonist, GW501516, stimulated human non-small lung carcinoma (NSCLC) growth. Here, we explore the mechanisms responsible for this effect. show GW501516 decreased phosphate and tensin homolog deleted on chromosome 10 (PTEN), tumor suppressor known to decrease growth induce apoptosis. Activation...

Increased senescence and expression of profibrotic genes in old lung fibroblasts contribute to disrepair responses. We reported that primary from mice have lower activity the cystine transporter Slc7a11/xCT than cells young mice, resulting changes both intracellular extracellular redox environments. This study examines hypothesis low Slc7a11 promotes gene expression. The levels mRNA protein Slc7a11, markers, were measured lungs (24 mo) (3 mice. In addition, effects genetic pharmacological...

Ethanol renders the lung susceptible to acute injury in setting of insults such as sepsis. The mechanisms mediating this effect are unknown, but activation tissue remodeling is considered key process. We found that chronic ethanol ingestion rats increased expression fibronectin, a matrix glycoprotein implicated injury. In cultured NIH/3T3 cells and primary rat mouse fibroblasts, induced fibronectin mRNA protein dose- time-dependent fashion. was prevented by inhibitors kinase C...

Lung carcinoma often occurs in patients with chronic lung disease such as tobacco-related emphysema and asbestos-related pulmonary fibrosis. These diseases are characterized by dramatic alterations the content composition of extracellular matrix, we believe this “altered” matrix has ability to promote cell growth. One molecule shown be altered these is fibronectin (Fn). We previously reported increased growth survival non-small (NSCLC) cells exposed Fn. Thus Fn may serve a mitogen/survival...

We have previously demonstrated that fibronectin (Fn) stimulates the proliferation of non-small cell lung carcinoma (NSCLC) growth through induction cyclooxygenase-2 (COX-2) and prostaglandin E2 secretion. Here, we demonstrate NSCLC cells express mRNA protein for receptor EP4 Fn enhances its stimulatory effect by inducing expression EP4, but not EP1, EP2, EP3 subtypes. The on was inhibited an antibody against alpha5beta1 integrin inhibitors phosphoinositide 3-kinase (wortmannin)...

Adenosine is an extracellular nucleoside that elevated in tissues during hypoxia and ischemia reperfusion has been implicated asthma other lung disorders. There, adenosine considered important modulator of physiological functions inflammation, but its effects on matrix expression turnover tissue remodeling are unknown. We examined the epithelial cells with particular attention to fibronectin, a glycoprotein highly expressed injured wound healing. In A549 cells, we found induced fibronectin...

Rationale: The incidence and severity of the acute respiratory distress syndrome (ARDS) is increased in individuals who abuse alcohol. One possible mechanism by which alcohol increases susceptibility to lung injury through alterations alveolar macrophage function induction tissue remodeling activity. Our objective was determine whether abuse, independent other comorbidities, alters fibronectin metalloproteinase gene expression macrophages epithelial lining fluid (ELF) lung. Methods:...

Chronic alcohol exposure is a clinically important risk factor for the development of acute respiratory distress syndrome, most severe form lung injury (ALI). However, mechanisms by which sensitizes to this disease are poorly understood. We determined role antifibrinolytic protein plasminogen activator inhibitor-1 (PAI-1) in enhancement experimental endotoxin-induced ALI. Wild-type, PAI-1-/-, and integrin β3-/- mice were fed ethanol-containing Lieber-DeCarli liquid or control diet 6 weeks,...

We previously demonstrated that a selective agonist of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta), GW501516, stimulated human non-small cell lung carcinoma (NSCLC) growth, partly through inhibition phosphatase and tensin homolog deleted on chromosome 10 expression. Here, we show GW501516 also decreases the phosphorylation AMP-activated protein kinase alpha (AMPKalpha), major regulator energy metabolism. This was mediated specific activation PPARbeta/delta, as...

Background: Using an experimental model of airway fibrosis following lung transplantation, we recently showed that chronic alcohol ingestion by donor rats amplifies in the recipient. Associated with alcohol‐mediated amplification is increased transforming growth factor β‐1(TGFβ 1 ) and α‐smooth muscle actin expression. Other studies have shown interleukin‐13 (IL‐13) modulates TGFβ signaling during experimentally‐induced fibrosis. Therefore, hypothesized IL‐13 a component pro‐fibrotic...