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PubMed2003

[Idiopathic pulmonary fibrosis and lung cancer].

It is widely known that patients with idiopathic pulmonary fibrosis (IPF) are frequently associated with lung cancer. Although a complication with lung cancer is an important prognostic factor for IPF, standard treatments for lung cancer cannot be given because of IPF. Especially, the administration of many anticancer agents is limited by a complication with IPF, which is recognized as a risk factor for the development of fatal lung injury in cancer chemotherapy. Epidemiological studies reveal that cigarette smoking and occupational and environmental exposure to toxic substances are common risk factors for both IPF and lung cancer. It has been assumed that metaplasia in fibrous lesions is pathologically a precancerous lesion, but it is necessary to prove several genetic abnormalities in the process of carcinogenesis in order to clarify that. Currently, several genetic abnormalities in IPF, including in p53, K-ras, FHIT and transforming growth factor (TGF)-beta 1 type II receptor, have been reported.

Acid Anhydride Hydrolases↗
PubMed2001

Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality.

It is hypothesized that the extent and severity of fibrosis and cellularity found on lung biopsy determine the prognosis and response to therapy in idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine which histopathologic features predict survival in IPF. We prospectively studied 87 patients with usual interstitial pneumonia (UIP) confirmed by surgical lung biopsy. Four pathologists independently graded the extent and severity of specific histopathologic features. We used Cox proportional-hazards models to assess the effect of histopathologic patterns on patients' survival. The effects of age, sex, and smoking were also included in the analysis. Sixty-three patients died during the 17-yr study period. Survival was longer in subjects with lesser degrees of granulation/connective tissue deposition (fibroblastic foci). The degree of alveolar space cellularity, alveolar wall fibrosis, and cellularity did not affect survival. A history of cigarette smoking, the level of dyspnea, and the degree of lung stiffness at presentation were also shown to be independent factors predicting survival. The extent of fibroblastic foci present on lung biopsy predicts survival in IPF. These findings support the hypothesis that the critical pathway to end-stage fibrosis is not "alveolitis" but rather the ongoing epithelial damage and repair process associated with persistent fibroblastic proliferation. Controlling these processes, rather than stopping inflammation, appears most important in preventing progressive disease and the fatal outcome common in IPF.

Adult↗
PubMed2002

Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice.

Transforming growth factor-beta (TGF-beta) signaling plays an important regulatory role during lung fibrogenesis. Smad3 was identified in the pathway for transducing TGF-beta signals from the cell membrane to the nucleus. Using mice without Smad3 gene expression, we investigated whether Smad3 could regulate bleomycin-induced pulmonary fibrosis in vivo. Mice deficient in Smad3 demonstrated suppressed type I procollagen mRNA expression and reduced hydroxyproline content in the lungs compared with wild-type mice treated with bleomycin. Furthermore, loss of Smad3 greatly attenuated morphological fibrotic responses to bleomycin in the mouse lungs, suggesting that Smad3 is implicated in the pathogenesis of pulmonary fibrosis. These results show that Smad3 contributes to bleomycin-induced lung injury and that Smad3 may serve as a novel target for potential therapeutic treatment of lung fibrosis.

Animals↗
PubMed1981

Bleomycin-induced pulmonary fibrosis. Effects of steroid on lung collagen metabolism.

Using bleomycin-induced pulmonary fibrosis as a model, we have set out to study collagen metabolism in the fibrotic process. As was previously shown, intratracheal administration of bleomycin in the rat caused increased deposition and net synthesis of collagen in the lung. This was accompanied by marked increases in the tissue-free proline pool size and less dramatic increases in the pool's radioactivity when lung mince was pulsed with radioactive proline to measure the net collagen synthesis. Using a technique based on the quantitation of the rate of release of hydroxyproline-containing peptides when lung homogenates were incubated in calcium-containing buffer, lung collagenolytic activity was markedly diminished as a result of bleomycin treatment. Concomitant treatment with the steroid methylprednisolone did not affect significantly this decrease in lung collagenolytic activity. Such steroid treatment, however, prevented the increase in bleomycin-induced lung collagen deposition and partially suppressed total lung collagen synthesis, without affecting the net rate of lung collagen synthesis expressed per mg of DNA. Steroid treatment also inhibited the marked increase in tissue-free proline pool size and radioactivity caused by bleomycin. The mechanism of amelioration of the fibrotic response by the steroid is discussed.

Animals↗
PubMed2005

Interferon-gamma1b therapy in idiopathic pulmonary fibrosis: a metaanalysis.

CONTEXT: Despite the investigation of multiple therapeutic options, idiopathic pulmonary fibrosis (IPF) remains a devastating, progressively fatal disease. Much interest has focused on the use of interferon (IFN)-gamma1b therapy, but the efficacy of this treatment has not been proven. OBJECTIVE: To determine whether IFN treatment reduces mortality in patients with IPF. DESIGN: A meta-analysis of randomized controlled trials evaluating the use of IFN-gamma1b as treatment for IPF. MAIN OUTCOME MEASURE: Mortality in patients treated with IFN-gamma1b was compared to mortality in patients treated with control therapies. RESULTS: A total of three studies involving 390 patients was included in the analysis. IFN-gamma1b therapy was associated with reduced mortality (hazard ratio [HR], 0.418; 95% confidence interval [CI], 0.253 to 0.690; p = 0.0003). A comparison of mortality at different time points revealed that IFN-gamma1b therapy was associated with significantly reduced mortality at 1 year (0.0861; 95% CI, 0.0244 to 0.1478; p = 0.0063), 18 months (0.1682; 95% CI, 0.1065 to 0.2299; p < 0.0001), 650 days (0.1939; 95% CI, 0.1386 to 0.2492; p < 0.0001), and 2 years (0.2652; 95% CI, 0.1652 to 0.3652; p < 0.0001). CONCLUSION: When the results of multiple studies are combined in a meta-analysis, IFN-gamma1b therapy is associated with reduced mortality.

Humans↗
PubMed1996

TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study.

Although it is recognized that three isoforms of transforming growth factor-beta (TGF-beta) exist in mammals, their expression, distribution, and function in injury and repair are not well characterized. Using immunohistochemistry and antibodies to synthetic peptides of TGF-beta 1, TGF-beta 2, and TGF-beta 3, we determined the distribution of TGF-beta isoforms in lung sections with acute and chronic lesions of idiopathic pulmonary fibrosis (IPF), chronic asbestosis and hypersensitivity pneumonitis, as well as non-specific pneumonitis. In lung sections with advanced pulmonary fibrosis and honeycombing, irrespective of the diagnosis, TGF-beta 1 was prominently expressed in epithelial cells and macrophages and was found to be associated with the extracellular matrix. In lungs with early lesions of IPF and only inflammatory changes, TGF-beta 1 was present in alveolar macrophages but TGF-beta 1 was not present in epithelial cells. Small amounts of matrix-associated TGF-beta 1 were present subepithelially in areas of lung sections from patients with IPF with minimal inflammation and no fibrosis. In normal lungs with no evidence of inflammation or fibrosis TGF-beta 1 was not seen in alveolar macrophages, epithelial cells, or extracellularly. TGF-beta 2 and TGF-beta 3 were expressed in alveolar macrophages, epithelial cells, and smooth muscle cells of vessels and bronchi of normal lungs and lungs with both inflammatory and fibrotic changes. Our findings suggest that while TGF-beta 2 and TGF-beta 3 are ubiquitously expressed in the lung, TGF-beta 1 is expressed in epithelial cells of fibrotic lungs where the presence of TGF-beta 1 is not disease-specific but an indication of the chronicity of the injury.

Adult↗
PubMed1989

Widespread pulmonary fibrosis as a major clinical manifestation of chronic graft-versus-host disease.

A 20-year-old Chinese male given an HLA-identical sibling bone marrow transplant for severe aplastic anemia, who had previously had chronic graft-versus-host disease (GVHD) of the mouth, developed myasthenia gravis and widespread pulmonary infiltrates with cough and exertional dyspnea at day 820 post-transplant. There was nothing to suggest aspiration pneumonia. Lung histology at day 940 showed some areas of dense pulmonary fibrosis, some areas of normal parenchyma, and some areas of widening of the interstitium and a mild lymphocytic infiltrate. Evidence of infection was not found. Treatment with cyclosporin and prednisone resulted in slow partial resolution of the infiltrates over 5 months. The myasthenia gravis was controlled with pyridostigmine. In view of the association with myasthenia gravis, of the absence of infectious agents and the response to immunosuppression, we conclude that widespread pulmonary fibrosis can be a major clinical manifestation of chronic GVHD. Examination of lung tissue to distinguish this from infective interstitial pneumonitis is essential.

Adult↗
PubMed1987

Bleomycin-associated pulmonary fibrosis: rapidly fatal progression without chest radiotherapy.

Two patients with carcinoma of the tonsil were treated with bleomycin (396 and 224 units, respectively) but not with radiotherapy. Respiratory insufficiency led to death 45 and 52 days, respectively, after onset of therapy. Chest radiographs before bleomycin therapy revealed no evidence for lung disease. Postmortem examinations showed severe interstitial and intraalveolar pulmonary fibrosis. Comparably rapid progression from radiographically normal pulmonary parenchyma to fatal fibrosis has been documented previously only in patients with thoracic neoplasia as well as, in all but one instance, either prior or concurrent chest radiotherapy. These two cases indicate that chest radiotherapy is not a necessary cofactor for the development of rapidly progressive, fatal, diffuse interstitial pulmonary fibrosis after bleomycin therapy.

Aged↗
PubMed1985

Biochemical pathways leading to collagen deposition in pulmonary fibrosis.

Fibrosis in the lung is well described histologically. There is destruction of the normal architecture with the appearance of inflammatory cells and connective tissue components, particularly collagen. Biochemical evidence for an increased deposition of collagen in man has been demonstrated in patients with both acute and chronic forms of pulmonary fibrosis. Studies of collagen metabolism in man are equivocal but there is convincing evidence for an increased synthesis rate in animal models of pulmonary fibrosis. Collagen degradation has been little studied but may be important, given the recent evidence indicating quite rapid turnover of lung collagen and a decreased degradation of collagen in experimental disease. The distribution of collagen types has been studied in man, where there is some evidence for the production of type III collagen in the early active phase of disease with a preponderance of type I collagen in the late stages. The cellular mechanisms leading to these changes are uncertain but the alveolar macrophage may play a central role, since it is capable of releasing factors which expand the fibroblast population as well as attracting new fibroblasts to the site of injury. These pathways are described for what is essentially the normal physiological response of scar formation, which has pathological consequences in the lung, a tissue requiring thin membranes at its epithelial and endothelial surfaces, in order to perform its main function of gas exchange.

Cell Communication↗
PubMed2001

Prognosis of patients with advanced idiopathic pulmonary fibrosis requiring mechanical ventilation for acute respiratory failure.

STUDY OBJECTIVE: To evaluate the beneficial effect of mechanical ventilation (MV) in patients with idiopathic pulmonary fibrosis (IPF) who develop acute respiratory failure (ARF), with special emphasis on prognosis. DESIGN: Retrospective study. SETTING: Ten-bed respiratory ICU that is a part of a respiratory department actively involved in lung transplantation (LTx). PATIENTS: From 1991 to 1999, 23 patients (mean age, 52.9 years; range, 21 to 82 years) with IPF required MV for ARF. At admission to the ICU, 16 patients were potential candidates for LTx, with 5 patients already on the waiting list. MEASUREMENTS AND RESULTS: Survival and gas exchange under MV were assessed. The precipitating cause of ARF was also analyzed. With the exception of 1 patient who successfully received a single-lung transplant 6 h after initiation of MV, all the remaining 22 patients died while receiving MV (median survival, 3 days; range, 1 h to 60 days). The duration of MV correlated positively with baseline vital capacity (percent predicted) (R = 0.54; p = 0.01) and baseline total lung capacity (percent predicted) (R = 0.71; p < 0.001), and correlated negatively with baseline PaCO(2) (R = - 0.47; p = 0.03) and the duration of evolution of IPF (R = -0.50; p = 0.01). Duration of MV did not correlate with the duration of immunosuppressive therapy (R = - 0.24; p = 0.27) or duration of oxygen therapy (R = - 0.32; p = 0.14) prior to admission. The precipitating cause of ARF was most often not identified. CONCLUSIONS: Our data support the general belief that MV does not benefit IPF patients presenting with ARF. Initiation of MV in IPF patients is thus questionable and should, in our opinion, be restricted to patients in whom LTx can be performed within a few days after initiation of MV.

Acute Disease↗
PubMed1991

Scanning electron microscopic study of capillary change in bleomycin-induced pulmonary fibrosis.

The architectural changes which occur in the capillaries are difficult to illustrate without a three-dimensional tool, such as scanning electron microscopy. Therefore, a scanning electron microscopic study was occasionally undertaken to show the capillary changes of lung fibrosis. Fibrosis was induced in twenty rats by an intratracheal injection of bleomycin. After 30 days the rats were sacrificed, and light microscopy and scanning electron microscopy were performed. The vascular trees of both lungs were cast with methacrylate. Light microscopically, the pulmonary fibrosis was patchy and inflammatory cell infiltration was rather sparse. Scanning electron microscopically, the intercapillary spaces became wider; and some capillaries revealed large irregular dilatation. The pleural and alveolar capillaries were variably dilated. The pleural capillary diameter was increased (P = 0.06), and the capillary plexus diameter was decreased (P = 0.00). Distance between the capillary branches of the pleural surface was increased (P = 0.06). The appearance of irregularly shaped capillaries, an increase in diameter with variable dilatation of alveolar capillary rings and a decrease in branching between the capillaries, resulting in a loss of surface area are the main scanning electron microscopic findings of the remodeling which occurs pulmonary capillaries in bleomycin-induced pulmonary fibrosis.

Animals↗
PubMed1989

Coordinate regulation of transforming growth factor beta gene expression and cell proliferation in hamster lungs undergoing bleomycin-induced pulmonary fibrosis.

The number of mesenchymal cells, as well as their ability to synthesize extracellular matrix (ECM) components, greatly increase in the interstitium of fibrotic lungs. We have previously shown that the transcription of type I procollagen and fibronectin genes in the lungs is preferentially elevated during the early stages of bleomycin-induced pulmonary fibrosis (Raghow, R., S. Lurie, J. M. Seyer, and A. H. Kang. 1985, J. Clin. Invest. 76:1734-1739. Since a cytokine-like transforming growth factor beta (TGF beta) that is capable of enhancing mesenchymal cell proliferation and ECM synthesis could be potentially involved in this process, we investigated the temporal relationship between the regulation of TGF beta gene transcription and cellular proliferation in the bleomycin-treated hamster lungs. We observed a transient 5-7-fold increase in the accumulation of TGF beta transcripts, a concomitant 3-4-fold elevation in the cellular proliferation, and 8-10-fold stimulation of DNA synthesis in these lungs; all three parameters peaked around day 10 after bleomycin administration. Based on these results, we conclude that regulation of TGF beta gene expression may contribute significantly to the early events that lead to bleomycin-induced pulmonary fibrosis.

Actins↗
PubMed1994

Antihistone antibodies in systemic sclerosis. Association with pulmonary fibrosis.

OBJECTIVE: To determine the prevalence and clinical significance of antihistone antibodies (AHA) in systemic sclerosis (SSc). METHODS: Serum samples from patients with limited cutaneous SSc (n = 44), diffuse cutaneous SSc (dcSSc; n = 48), and other SSc-related disorders (n = 22) were examined by enzyme-linked immunosorbent assay and immunoblotting for AHA. RESULTS: AHA were demonstrated in 29% of the 92 SSc patients and in 44% of those with dcSSc. The presence of AHA correlated with severe pulmonary fibrosis in those with dcSSc. Immunoblotting revealed that the predominant antigen was histone H1. CONCLUSION: AHA might be a serologic indicator of the severity of pulmonary fibrosis in SSc.

Adult↗
PubMed1989

Fluorescent antibodies in polymyositis using cultured human skin fibroblasts: granular perinuclear cytoplasmic staining pattern by sera from patients with polymyositis and pulmonary fibrosis.

Immunofluorescent antibodies were studied in sera from 48 patients with polymyositis (PM) and 149 control subjects using cultured human skin fibroblasts as substrate. Forty-six (95.8%) of PM sera showed a positive reaction. Among them, a characteristic granular perinuclear cytoplasmic staining was seen in 8 sera, including 4 with anti-Jo-1. Four of these 8 sera showed positive staining on HEp-2 cells with the same pattern. All patients showing this pattern of staining had pulmonary fibrosis which was not seen in control patients. Consequently, this staining pattern might be a specific marker for a subset of patients with PM with pulmonary fibrosis.

Adult↗