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Results for “PULMONARY FIBROSIS”

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At least 19 recordsLinked to original sources
PubMed1999

Elevation of anti-cytokeratin 19 antibody in sera of the patients with idiopathic pulmonary fibrosis and pulmonary fibrosis associated with collagen vascular disorders.

It has been suggested that cytokeratin 19 is expressed in regenerated bronchoepithelial cells in patients with pulmonary fibrosis, and serum cytokeratin 19 fragment is elevated in patients with pulmonary fibrosis. We hypothesized that serum antibodies to cytokeratin 19 may be formed in patients with pulmonary fibrosis. To prove the existence of anti-cytokeratin 19 antibodies in patients' sera, human recombinant cytokeratin 19 was stained with patients' sera by a Western immunoblot. Then, we tried to establish an enzyme-linked immunosorbent assay to quantitate anti-cytokeratin 19 antibody in the sera of patients with idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis associated with collagen vascular disorders (PF-CVD). We demonstrated the anti-cytokeratin 19 antibody in patient' sera by a Western immunoblot. In patients with IPF and PF-CVD, significantly high anti-cytokeratin 19 antibody was demonstrated compared with normal volunteers, patients with chronic bronchitis, and patients with pneumonia. These results suggest that anti-cytokeratin 19 antibody may have played a role in the process of lung injury in pulmonary fibrosis.

Adult↗
PubMed1997

Idiopathic pulmonary fibrosis and pulmonary fibrosis in diffuse systemic sclerosis: two fibroses with different prognoses.

Idiopathic pulmonary fibrosis and diffuse cutaneous systemic sclerosis (dSSc) involve the lung by a fibrotic process. In recent years, there has been increasing awareness that the natural history of these two types of pulmonary fibrosis might be different. The purpose of this study was to compare lung involvement in these two diseases in a prospective fashion in order to address differences in their clinical course. Forty-three consecutive patients, 18 with lone interstitial pulmonary fibrosis (lone IPF) and 25 with dSSc-IPF were evaluated clinically, radiologically and physiologically at the entry into the study and the evolution of their disease was contrasted by survival analysis. Patients with lone IPF compared with dSSc-IPF were characterized by male predominance (p < 0.001), older age at disease onset (p < 0.001), shorter disease duration (p < 0.001), more frequent crackles on auscultation and clubbing (p < 0.001 and p < 0.0001, respectively), more severe dyspnea (p < 0.0001) and more advanced radiological involvement (p < 0.0001). Functional indices presented comparable values and did not reach statistically significant differences except for the values of single breath CO diffusing capacity (p < 0.0001) and the PaO2 (p < 0.01) which was worse in patients with lone IPF. Finally 12 of the 18 patients with lone IPF died in 2.66 +/- 1.18 years from the onset of respiratory symptoms, while none of the dSSc-IPF patients had died 5.6 +/- 4.25 years from the first ever appearance of respiratory involvement (p < 0.001). In conclusion, although the two groups of patients were not at an absolutely comparable stage of their disease, a worse prognosis for patients with lone IPF seems to emerge from this study.

Adolescent↗
PubMed2001

Role of osteopontin in the pathogenesis of bleomycin-induced pulmonary fibrosis.

Pulmonary fibrosis is initiated by migration, adhesion, and proliferation of fibroblasts. Osteopontin (OPN) is one of the cytokines produced by activated macrophages and mediates various functions, including cell attachment and migration, by interacting with alphav integrin. In this study, we have investigated the role of OPN in the pathogenesis of pulmonary fibrosis. We developed a mouse model for pulmonary fibrosis by intratracheal instillation of bleomycin (BLM). OPN was strongly expressed in alveolar macrophages accumulating in the fibrotic area of the lung. OPN messenger RNA (mRNA) in the lung was notably induced by BLM instillation, and the development of the fibrotic process was associated with an increase in the expression of OPN mRNA and protein. In vitro, recombinant OPN enhanced migration, adhesion, and platelet-derived growth factor (PDGF)-mediated DNA synthesis of murine fibroblast cell line NIH3T3. These effects of OPN on fibroblasts were significantly suppressed by addition of antimouse alphav integrin monoclonal antibody (RMV-7). Furthermore, treatment of mice with RMV-7 repressed the extent of pulmonary fibrosis in this model. Conclusively, these data suggest that OPN produced by alveolar macrophages functions as a fibrogenic cytokine that promotes migration, adhesion, and proliferation of fibroblasts in the development of BLM-induced pulmonary fibrosis.

Animals↗
PubMed2002

A pivotal role of cytosolic phospholipase A(2) in bleomycin-induced pulmonary fibrosis.

Pulmonary fibrosis is an interstitial disorder of the lung parenchyma whose mechanism is poorly understood. Potential mechanisms include the infiltration of inflammatory cells to the lungs and the generation of pro-inflammatory mediators. In particular, idiopathic pulmonary fibrosis is a progressive and fatal form of the disorder characterized by alveolar inflammation, fibroblast proliferation and collagen deposition. Here, we investigated the role of cytosolic phospholipase A(2) (cPLA(2)) in pulmonary fibrosis using cPLA(2)-null mutant mice, as cPLA(2) is a key enzyme in the generation of pro-inflammatory eicosanoids. Disruption of the gene encoding cPLA(2) (Pla2g4a) attenuated IPF and inflammation induced by bleomycin administration. Bleomycin-induced overproduction of thromboxanes and leukotrienes in lung was significantly reduced in cPLA(2)-null mice. Our data suggest that cPLA(2) has an important role in the pathogenesis of pulmonary fibrosis. The inhibition of cPLA(2)-initiated pathways might provide a novel therapeutic approach to pulmonary fibrosis, for which no pharmaceutical agents are currently available.

Animals↗
PubMed1991

The role of TGF-beta in pulmonary fibrosis.

Pulmonary fibrosis is an irreversible accumulation of connective tissue in the interstitium of the lung. The pathogenesis of pulmonary fibrosis is not well understood. Research on animal models and studies of human lung disease suggest the initiating events may be a combination of pulmonary injury and the recruitment of inflammatory cells, mainly macrophages. A number of well characterized cytokines, including TGF-beta, have been either found in the injured lung or produced by inflammatory cells removed from the lung. In an animal model of pulmonary fibrosis, TGF-beta production is increased prior to collagen synthesis and is mainly produced by alveolar macrophages. In advanced idiopathic pulmonary fibrosis, a human fibrotic lung disease, extensive TGF-beta deposition can be detected by immunohistochemical staining, primarily in epithelial cells in areas of lung regeneration and remodelling. This suggests that the pathogenesis of the progressive fibrosis characteristic of this lung disease may be an aberrant repair process.

Bleomycin↗
PubMed2002

Molecular mechanisms of pulmonary fibrosis.

Pulmonary fibrosis is the end-point of a numerous and heterogeneous group of disorders known as interstitial lung diseases (ILD). Lung fibrotic remodeling is characterized by fibroblast/myofibroblast activation, and excessive extracellular matrix accumulation leading to progressive organ dysfunction and usually terminal outcome. Treatment is largely ineffective primarily because few of the molecular mechanisms have been well defined to design appropriate targets for therapy. While the pathogenesis is incompletely understood, a growing body of evidence suggests two different pathogenic routes for developing pulmonary fibrosis. The inflammatory pathway, where a shift to the so-called T-helper 2 type cytokine networks is critical, and the epithelial pathway represented by idiopathic pulmonary fibrosis, by far the most aggressive ILD. In this pathway the inflammatory process is irrelevant, and the physiopathology seems to be dominated by epithelial cell injury and activation. Both routes may trigger a number of cytokines/growth factors inducing fibroblast migration/proliferation and phenotype change to myofibroblasts, with a consequent accumulation of extracellular matrix. An imbalance in matrix metalloproteinase/tissue inhibitors of metalloproteinases may contribute to alteration in extracellular matrix turnover and remodeling. This review will focus in some of the mechanisms involved in both prefibrotic pathways, as well as those involved in fibroblast activation and abnormal matrix deposition.

Animals↗
PubMed2002

Involvement of gelatinases (MMP-2 and MMP-9) in the development of airway inflammation and pulmonary fibrosis.

Pulmonary fibrosis has an aggressive course and is usually fatal an average of 3 to 6 years after the onset of symptoms. Pulmonary fibrosis is associated with deposition of extracellular matrix (ECM) components in the lung interstitium. Matrix metalloproteinases (MMPs) are a major group of proteinases known to regulate the ECM remodeling and so they are hypothesized to be important in the process of lung fibrosis. These led to the concept that modulation of airway remodeling including excessive proteolytic damage of the tissue may be of interest for future treatment. The excessive airway remodeling as a result of an imbalance in the equilibrium of the normal processes of synthesis and degradation of extracellular matrix components could argue in favor of antiprotease treatments. Moreover, these observations emphasize that effective therapies for these disorders must be given early in the natural history of the disease, prior to the development of expensive lung destruction and fibrosis.

Extracellular Matrix↗
PubMed1989

Early increases in pulmonary mRNA encoding procollagens and transforming growth factor-beta in mice sensitive to cyclophosphamide-induced pulmonary fibrosis.

Pulmonary fibrosis was induced 7 weeks after a single i.p. injection of cyclophosphamide (200 mg/kg b.wt.) in BALB/c mice; C57Bl/6 mice were unaffected. There was a corresponding strain variation in the effects of cyclophosphamide on levels of pulmonary mRNA encoding alpha 2I and alpha 1III procollagen, and transforming growth factor-beta. In BALB/c mice, the ratios of alpha 2I and alpha 1III procollagen mRNA to polyadenylated RNA were increased 1 week after cyclophosphamide injection. No increases in levels of either procollagen mRNA occurred in C57Bl/6 mice. The ratio of fibronectin mRNA to polyadenylated RNA was elevated to a similar extent in both murine strains during the 1st week after cyclophosphamide treatment. The pulmonary content of transforming growth factor-beta mRNA and its ratio to polyadenylated RNA increased 2-fold at 1 and 2 weeks in BALB/c but not C57Bl/6 mice. Thus, collagen accumulation in cyclophosphamide-sensitive mice is preceded by increased pulmonary alpha 2I and alpha 1III procollagen mRNA. The early strain selective elevation of transforming growth factor-beta mRNA in response to cyclophosphamide suggests a role, in vivo, for transforming growth factor-beta in drug-induced pulmonary fibrosis.

Animals↗
PubMed2002

Overview of pulmonary fibrosis.

Pulmonary fibrosis is a component of over 200 interstitial lung diseases. Some have known etiologies, however, for many diseases, the etiology remains unknown or obscure. This brief review examines the prevalence and classification of these diseases, the approach to be taken for the investigation of a patient suspected of having pulmonary fibrosis, the indications for the performance of lung biopsy, and current thoughts concerning the pathogenesis of the idiopathic forms of fibrotic lung disease. A brief review of established and emerging therapeutic strategies is included.

Humans↗
PubMed1996

Heparin attenuates bleomycin but not silica-induced pulmonary fibrosis in mice: possible relationship with involvement of myofibroblasts in bleomycin, and fibroblasts in silica-induced fibrosis.

Pulmonary fibrosis was elicited in mice or rats by the intratracheal instillation of bleomycin or silica. Daily injections of heparin significantly reduced the collagen deposition in bleomycin, but not in silica, injected mice, as evaluated by the lung hydroxyproline content on day 15 after instillation. Heparin also reduced the bleomycin-induced morbidity and mortality. Study of the broncho-alveolar lavage fluid (BAL) detected no significant change in the number of leucocytes or the amount of protein in heparin treated mice. Histologies of bleomycin instilled mice suggested that heparin did reduce the alveolar remodelling but not the alveolitis, evidenced by leucocytic infiltration. As detected by electron microscopy (EM), bleomycin increased the number of leucocytes and platelets within the alveolar capillaries but this was not significant ly reduced by heparin. The phenotype of the interstitial cell involved in these two types of pulmonary fibrosis was investigated by immunohistochemistry and EM. While in bleomycin injected animals the interstitial cells had the phenotype of an actin (alpha-actin in the rat) and lipid containing interstitial cell, with a poorly developed RE, in silica injected animals in contrast, the interstitial cells were without cytoplasmic actin or lipid but with a markedly developed endoplasmic reticulum (ER). Thus bleomycin and silica induced the growth of two different types of interstitial cells, the myofibroblast and the regular fibroblast, which might be a reason why heparin selectively inhibits bleomycin but not silica-induced fibrosis.

Animals↗
PubMedDate not supplied

Role of oxidative stress in pulmonary fibrosis.

Pulmonary fibrosis can be observed as an end state in a number of chronic inflammatory pulmonary diseases. Although the mechanisms by which lung fibrosis develops are not fully ascertained, recent findings suggest that oxidative stress may play an important role in the pathogenesis of tissue fibrosis affecting apoptosis of both structural and inflammatory cells and altering the cytokine microenvironment balance. Damage and alteration of alveolar epithelial cells is one of the hallmarks of interstitial lung fibrosis. Recently, it has been demonstrated that the presence of oxidative stress may lead to the damage, activation and/or apoptosis of alveolar epithelial cells either directly, through an imbalanced intracellular redox equilibrium, or indirectly, by activating redox-sensitive effector pathways, such as transcription factors and angiotensin converting enzyme, increasing the conversion of angiotensinogen into angiotensin II that can be considered a mediator of oxidative stress, capable of inducing apoptosis. Furthermore, it has been demonstrated that angiotensin II acts as a proinflammatory cytokine and is effective in activating fibroblasts through the release of transforming growth factor (TGF-beta). As well as activation, differentiation, proliferation and apoptosis of fibroblasts seem related to the oxidant/antioxidant balance, and the maintenance of a high intracellular level of reduced glutathione (GSH) is considered crucial in providing a reducing environment within the cell, able to protect against oxidative stress. In those conditions where oxidants, either inhaled or produced by inflammatory cell, increase, the ratio between GSH and oxidized glutathione (GSSH) may lower, influencing a variety of cellular redox-sensitive signaling processes such as the activation of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) that lead to a transcriptional up-regulation of a number of genes involved in inflammation and/or fibrogenesis, including cytokines [interleukin (IL)-1,, tumor necrosis factor (TNF-alpha), IL-6] chemokines (IL-8), adhesion molecules (VCAM-1, ICAM-1) and growth factors (GM-CSF). In addition, several studies have shown that oxidative stress may also affect the immune response by inducing an up-regulation of HLA-DR as well as the expression of two costimulatory molecules such as CD40 and CD86, determining a persistent state of immune activation, and affecting the Th1/Th2 balance, modulating the T-cell effector response towards the Th2 phenotype. It is clear that a better understanding of the precise sequence of events that make the difference between normal tissue repair and fibrosis, including the role played by oxidative stress, will certainly improve our therapeutic approach to pulmonary fibrosis.

Angiotensin II↗
PubMed2001

Differential mRNA expression of insulin-like growth factor-1 splice variants in patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis.

Insulin-like growth factor-1 (IGF-1) is a highly mitogenic polypeptide detectable in human lung. Using competitive reverse transcriptase/polymerase chain reaction (RT-PCR), expression of four IGF-1 transcripts was examined in bronchoalveolar lavage cells (BALC) from normal subjects, idiopathic pulmonary fibrosis (IPF), stage I/II (no fibrosis), and stage III/IV (confirmed fibrosis) pulmonary sarcoidosis patients, and fibroblast strains isolated from normal and IPF lungs. Transcripts studied were Class 1 and Class 2 (exons 1 or 2, respectively) with IGF-1Eb or IGF-1Ea (exons 5 or 6, respectively). Total IGF-1 expression was downregulated in BALC of both patients with IPF (p < 0.01) and patients with sarcoidosis (p < 0.04) compared with healthy subjects. In contrast, both constitutive (p < 0.003) and transforming growth factor-beta (TGF-beta)- induced (p < 0.02) IGF-1 expression was higher in fibrotic, compared with normal, fibroblasts. These changes were associated with differential expression of IGF-1 splice variants. Healthy subjects and sarcoidosis patients without fibrosis showed similar expression of Class 1/Class 2 and IGF-1Ea/IGF-1Eb. However, patients with fibrosis demonstrated discordant, increased relative abundance of Class 1 transcripts (p < 0.01). In parallel, all fibrosis patients failed to express Class 2, IGF-1Eb forms and sarcoidosis patients with fibrosis did not express the Class 1, IGF-1Eb variant either. Fibrotic fibroblasts expressed higher constitutive levels of Class 1, IGF-1Ea transcripts compared with normal fibroblasts. Class 2, IGF-1Eb forms were moderately expressed by fibroblasts only after stimulation with TGF-beta, which also further increased levels of Class 1, IGF-1Ea transcripts. Our findings suggest that transition from a healthy to a fibrotic phenotype occurs in association with a changing pattern of IGF-1 mRNA heterogeneity and leads us to hypothesize a potential role for specific IGF-1 variants in fibrogenesis.

Adult↗
PubMed1989

[Assessment of pulmonary hemodynamics in patients with idiopathic pulmonary fibrosis].

Pulmonary hemodynamics were assessed in 52 patients with idiopathic pulmonary fibrosis of which 25 were confirmed histopathologically. The study group consisted of 26 males and 26 females, of a mean age of 41 +/- 15 years. Pulmonary function studies revealed restrictive changes and increased elastic recoil. Mean vital capacity was 2.6 +/- 1.2 L, compliance - static 97 +/- 59 ml/cm H2O, dynamic 71 +/- 50 ml/cm H2O. Esophageal pressure was - 8.0 +/- 5.3 mm Hg. Mean pulmonary artery pressure was slightly elevated - 22.6 +/- 8.3 mm Hg. Transmural pulmonary pressure was 31.3 +/- 9.8 mm Hg, cardiac output was 7.6 +/- 3.8 L/min, pulmonary resistance 206 +/- 119 dyn sec cm-5. A mild hypoxemia was observed--PaO2 71.8 +/- 13.3 mm Hg. In part of the study group (27 subjects) the response to exercise was assessed. A mean increase of pulmonary artery pressure from 20.4 +/- 7.2 to 38.0 +/- 14.7 mm Hg and a decrease of PaO2 from 74.2 +/- 11.7 mm Hg to 62.5 +/- 15.3 mm Hg were found. Negative correlation was found between mean artery pulmonary pressure and arterial oxygen partial pressure, vital capacity and one-second forced expiratory volume, and a higher correlation between mean transmural pulmonary pressure and PaO2, VC, FEV1 and Cdyn.

Adolescent↗