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PubMed1991

Modifying effects of preexisting pulmonary fibrosis on biological responses of rats to inhaled 239PuO2.

We investigated the modifying effects of preexisting, bleomycin-induced pulmonary fibrosis on the deposition, retention, and biological effects of inhaled 239PuO2 in the rat. Among rats exposed to similar airborne concentrations of 239PuO2, initial lung burdens of 239Pu per kilogram body mass were similar whether or not pulmonary fibrosis was present. However, clearance of 239Pu from the lungs was significantly decreased in the rats with preexisting pulmonary fibrosis. The incidence of lung lesions (epithelial hyperplasia, diffuse macrophage increases and aggregation, and loose and dense connective tissue) was significantly greater among rats with preexisting pulmonary fibrosis than among the exposed controls. Rats with preexisting fibrosis had shorter life spans than 239PuO2-exposed control rats. When groups of rats with similar alpha doses to the lungs were compared, the incidences of neoplastic lesions in the lung, the times to death of rats with lung neoplasms, and the risk of lung tumors per unit of alpha dose to the lungs in rats with or without pulmonary fibrosis were similar. The results of this study suggest that humans with uncomplicated pulmonary fibrosis may not be more sensitive to the carcinogenic effects of inhaled 239PuO2 than are individuals with normal lungs, assuming that the total alpha doses to the lungs are similar.

Administration, Inhalation↗
PubMed2003

Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis.

OBJECTIVE: Although lung transplantation is viewed as an acceptable option for patients with end-stage idiopathic pulmonary fibrosis, the survival benefit of this approach is still debated. This study examined whether there was a survival benefit of lung transplantation in a cohort of patients referred to our transplant center with a diagnosis of idiopathic pulmonary fibrosis according to American Thoracic Society criteria. METHODS: Forty-six patients accepted for lung transplantation during a 12-year period with a diagnosis of idiopathic pulmonary fibrosis form the basis of this study. Survival benefit offered by lung transplantation was assessed using Cox proportional-hazards modeling, with patients on a waiting list as the control group. RESULTS: Twenty-eight patients underwent lung transplantation (27 single and 1 double), 16 patients died while waiting, and 2 patients remained on the active waiting list. Diagnosis of idiopathic pulmonary fibrosis was made on histologic examination of the explanted lung or lung biopsy before lung transplantation. There was a pattern of usual interstitial pneumonia in 31 cases (67%). The 15 remaining patients fulfilled all American Thoracic Society criteria for idiopathic pulmonary fibrosis. The median waiting time for organs was 51 days. Survival after lung transplantation was 79.4% at 1 year, 63.5% at 2 years, and 39% at 5 years. The multivariable analysis showed that lung transplantation reduced the risk of death by 75% (95% confidence interval, 8%-86%; P =.03) after adjustment on potential confounding variables. CONCLUSIONS: Lung transplantation is effective in improving the survival of selected patients affected by idiopathic pulmonary fibrosis.

Adult↗
PubMed1978

Distribution of HLA antigens in idiopathic pulmonary fibrosis.

Divergent observations suggest that genetic factors contribute to the susceptibility to or clinical course of idiopathic pulmonary fibrosis. To determine whether there is an association between the major histocompatibility (HLA) system and idiopathic pulmonary fibrosis, the distribution of 35 antigens of HLA loci A and B was determined among 33 white patients with idiopathic pulmonary fibrosis and 329 healthy white control subjects. Although certain antigens tended to be more prevalent among patients with idiopathic pulmonary fibrosis compared with control subjects, there were no significant differences in the phenotype frequencies of the HLA-A and HLA-B antigens between these 2 groups. Thus, although subtle associations may exist between the HLA loci and idiopathic pulmonary fibrosis, these results indicate that antigens of the HLA-A and HLA-B loci are not linked with major risk factors in this disease.

Adult↗
PubMed1997

The pathogenesis of pulmonary fibrosis: is there a fibrosis gene?

Interstitial fibrosis is seen in the lung in response to a variety of insults, and often appears stereotypical in terms of its clinical and pathological features. However, exposure to a known aetiological factor does not always lead to fibrosis. For example in bleomycin-induced pulmonary fibrosis, a wide variation in response is seen both in humans and in animal models, which is not completely accounted for by known risk factors. These observations and the existence of a number of familial forms of lung fibrosis suggest a genetic predisposition. Current hypotheses concerning the pathogenesis of pulmonary fibrosis propose an initial stage involving the influx of inflammatory cells into the interstitium. These cells, together with activated resident cells are then thought to release polypeptide mediators that stimulate the fibroblast proliferation and matrix protein synthesis typical of these disorders. Genetic influences could have an important role in regulating a number of these events, altering the immunological response to injury or modulating collagen metabolism in the lung. However, despite recent advances in molecular genetic techniques, there have been few human studies to date. Most have concentrated on genetic loci with a high degree of polymorphism such as the human leucocyte antigen (HLA) system and yield conflicting results. Others offer tantalising but as yet, incomplete insights into the mechanisms involved. Defining the genetic abnormalities underlying both the familial forms of pulmonary fibrosis and the variations seen in response to lung injury should enhance our understanding of the pathogenic processes and help to focus research in this area.

Animals↗
PubMed2003

Acute respiratory failure after interferon-gamma therapy of end-stage pulmonary fibrosis.

Interferon (IFN)-gamma was recently proposed as a treatment for idiopathic pulmonary fibrosis. We report on four patients who developed acute respiratory failure with new alveolar opacities after 2 (two patients), 6, and 35 injections of IFN-gamma-1b. All four patients had advanced idiopathic pulmonary fibrosis (total lung capacity less than 45% predicted or carbon monoxide diffusion capacity less than 30% predicted), and two patients had familial pulmonary fibrosis. No other cause of deterioration was found. Refractory hypoxemia led to death in three cases and to lung transplantation in one case. Pathologic studies in two patients showed diffuse alveolar damage lesions with preexisting usual interstitial pneumonia. These cases suggest that IFN-gamma therapy can induce an acute respiratory failure in patients with end-stage idiopathic pulmonary fibrosis.

Acute Disease↗
PubMed1996

Administration of truncated secretory leukoprotease inhibitor ameliorates bleomycin-induced pulmonary fibrosis in hamsters.

The purposes of this study were to investigate the effect of our recently developed truncated secretory leukoprotease inhibitor (SLPI) on bleomycin (BLM)-induced lung injury and fibrosis in hamsters, which is widely used as a model of interstitial pulmonary fibrosis, and to assess the possible involvement of neutrophil elastase in the pathogenesis of pulmonary fibrosis. The fibrosis model was prepared by administration of BLM (10 mg/kg) intratracheally to hamsters. The truncated SLPI was administered at a dose 5 or 15 mg/kg intraperitoneally twice a day only for 10 d starting from the time of BLM administration. BLM administration resulted in decreases in body weight and survival rate. Elastase activity in the supernatant of bronchoalveolar lavage (BAL) fluids was increased at 3 and 7 d after BLM administration in parallel with the increase in the number of neutrophils in the fluids. Histopathologically, at 14 and 28 d after BLM administration, diffuse thickening and fibrosis of alveolar walls with marked cell infiltration and severe distortion of alveolar structure, including honeycomb lung, were observed to have occurred. In this model, the decreases in body weight and survival rate and the increase in elastase activity were inhibited by the truncated SLPI dose-dependently, and pulmonary fibrosis was significantly ameliorated by the administration of this shortened form of SLPI. These results suggest that neutrophil elastase may be implicated in the pathogenesis of BLM-induced pulmonary fibrosis and that the truncated SLPI might be a promising therapeutic in the treatment of interstitial pulmonary fibrosis.

Animals↗
PubMed2003

Relationship between the eosinophilia of bronchoalveolar lavage fluid (BALF) and the severity of pulmonary fibrosis induced by bleomycin in rats.

A large number of studies have demonstrated that the presence of eosinophils in the lungs of patients with pulmonary fibrosis correlates with poor prognosis or resistance to therapy. However, direct evidence of the relationship between the influx of eosinophil and pulmonary fibrosis has not yet been described experimentally. In this article, pulmonary fibrosis was induced by different doses of bleomycin (BLM) and using different aged rats. On selected days afterwards, the lungs were lavaged and harvested for analyzing fibrosis, eosinophil influx and cytokine expression. There was a significant relationship between eosinophilia and the pulmonary fibrosis (r=0.98, p<0.01). In spite of the fact that there was no significant increase in hydroxyproline of the lung, eosinophil influxes of bronchoalveolar lavage fluid (BALF) was maximal 7 d after BLM administration. Moreover, there were similar patterns among transforming growth factor beta (TGF)-beta(1), hepatocyte growth factor (HGF) and eosinophil influx of BALF in that they were dependent on dose of BLM and age. These findings, taken together, have suggested the causal correlation of eosinophilia during the early stage with subsequent pulmonary fibrosis. The possible role of eosinophils in the pathogenesis of pulmonary fibrosis might contribute to not only TGF-beta(1) but also HGF production.

Age Factors↗
PubMed1985

A new model of diffuse interstitial pulmonary fibrosis in the rat.

We have produced experimental diffuse interstitial pulmonary fibrosis in rats with a combination of low and repeated doses of paraquat plus continuous exposure to normobaric 74% O2 in the breathing air for several weeks. Pulmonary fibrosis was evaluated histologically and biochemically, through the determination of total collagen content in the lung. Our procedure is characterized by low initial mortality, the development of extensive distortion of the pulmonary architecture, and the presence of severe and diffuse interstitial fibrosis. The model was compared with bleomycin-induced pulmonary fibrosis in the same rat strain, in which the process is focal and leaves most of the lung unaffected. We conclude that lung damage produced by the combination of low doses of paraquat plus normobaric 74% O2 concentration in the breathing air is an adequate experimental model of diffuse interstitial pulmonary fibrosis as it occurs in many of the human cases of this condition.

Animals↗
PubMed1998

Neutrophil elastase: alpha-1-proteinase inhibitor complex in serum and bronchoalveolar lavage fluid in patients with pulmonary fibrosis.

It was hypothesized that neutrophil elastase released from activated neutrophils may play an important role in the pathogenesis of pulmonary fibrosis. In the present study, we measured the neutrophil elastase:alpha-1-proteinase inhibitor complex (E-PI) in serum and bronchoalveolar lavage fluid (BALF) in 26 patients with pulmonary fibrosis and evaluated the correlation between E-PI levels and several parameters. E-PI levels in serum of patients with pulmonary fibrosis (635.8+/-112.0 ng.mL(-1)) were significantly elevated compared to normal nonsmokers (122.0+/-4.0 ng.mL(-1)) as well as normal smokers (132.8+/-8.4 ng.mL(-1)) (p<0.01). E-PI levels in serum significantly correlated with hepatocyte growth factor (HGF) levels in serum, C-reactive protein (CRP), and negatively correlated with arterial oxygen tension (Pa,O2), and arterial carbon dioxide tension (Pa,CO2). E-PI/albumin levels in BALF significantly correlated with HGF/albumin levels in BALF, lactate dehydrogenase (LDH)/albumin in BALF, total number of inflammatory cells (alveolar macrophages and neutrophils) in BALF, and several markers derived from epithelial cells in BALF. Our data demonstrated: 1) neutrophil elastase:alpha-1-proteinase inhibitor complex in serum increased in patients with pulmonary fibrosis; and 2) neutrophil elastase:alpha-1-proteinase inhibitor complex in serum and bronchoalveolar lavage fluid correlated with clinical parameters in pulmonary fibrosis. These results suggest that neutrophil elastase may play a significant role in the process of lung injury in pulmonary fibrosis.

Adult↗
PubMed1981

Biochemical and histological changes in pulmonary fibrosis induced in rabbits with intratracheal bleomycin.

Pulmonary fibrosis was induced in rabbits by an intratracheal instillation of bleomycin. Histologically, at 2 weeks there was inflammation but only limited evidence of increased collagen deposition; at 8 weeks the inflammatory response had subsided and increased collagen deposition, characteristic of early interstitial fibrosis, was observed. Biochemical analyses showed bleomycin treatment caused marked increases in the total amounts of RNA, DNA, mixed protein, collagen and elastin when compared to controls (P less than 0.001 in all cases). Furthermore the increases were essentially complete by 2 weeks where the contents had increased by 110 +/- 13%, 60 +/- 11%, 148 +/- 12%, 94 +/- 15% and 89 +/- 11% respectively (P less than 0.001 in all cases). When collagen and elastin were expressed as concentrations with respect to wet weight, total protein or DNA content, the changes were not statistically significant. No changes were observed in the relative amounts of type I and type III collagen. It is concluded that: (1) compared to biochemical analysis, histology is relatively insensitive in detecting the early increases in connective tissue proteins; (2) measurements of lung collagen and elastin should be expressed as total lung contents wherever possible; the concentration of these proteins may remain unchanged, especially in the early stages of fibrosis, due to concomitant increases in other lung constituents; (3) changes in the relative amounts to types I and III collagens do not play a major role in the pathology of this form of pulmonary fibrosis.

Animals↗
PubMed1998

Increased endothelin-1 and its localization during the development of bleomycin-induced pulmonary fibrosis in rats.

Endothelin-1 (Et-1) has been implicated in the pathogenesis of pulmonary fibrosis with increased levels in the lung tissue of patients with pulmonary fibrosis and profibrotic effects in vitro. In this study we have investigated the temporal changes in lung Et-1 levels and immunohistochemical localization in relation to collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats. Lung Et-1 content doubled by 3 d following the intratracheal instillation of bleomycin, and continued to increase up to 7 d when values were about threefold greater than controls. Thereafter, the values for bleomycin-treated animals remained constant up to 21 d. There was no change in collagen content at 3 d but after 7 d there was a 25% increase and by 21 d levels were almost double those of the controls. In normal lung, Et-1 was predominantly associated with epithelial cells of conducting and nonconducting airways. Following bleomycin administration, intense staining of macrophages and conducting airway and alveolar epithelial cells was observed with marked staining of perivascular, peribronchiolar, and alveolar septal connective tissue, as well as the venular and arterial intima and media. These results demonstrate elevation of Et-1 levels prior to an increase in collagen content which, along with its localization within developing fibrotic lesions, provides further evidence of a profibrotic role for Et-1 in the pathogenesis of pulmonary fibrosis.

Animals↗
PubMed2006

A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma.

OBJECTIVE: The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc. METHODS: Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed. RESULTS: At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P = 0.08). No improvements in DLCO or secondary outcome measures were identified. CONCLUSION: This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events.

Administration, Oral↗
PubMed1991

Mechanisms of gas-exchange impairment in idiopathic pulmonary fibrosis.

To investigate the mechanisms of pulmonary gas-exchange impairment in idiopathic pulmonary fibrosis (IPF) and to evaluate their potential relationship to the CO diffusing capacity (DLCO), we studied 15 patients with IPF (mean DLCO, 52% of predicted) at rest (breathing room air and pure O2) and during exercise. We measured pulmonary hemodynamics and respiratory gas-exchange variables, and we separated the ventilation-perfusion (VAQ) mismatching and O2 diffusion limitation components of arterial hypoxemia using the multiple inert gas elimination technique. At rest VA/Q mismatching was moderate (2 to 4% of cardiac output perfusing poorly or unventilated lung units), and 19% of AaPO2 was due to O2 diffusion limitation. During exercise VA/Q mismatch did not worsen but the diffusion component of arterial hypoxemia increased markedly (40% AaPO2, p less than 0.005). We observed that those patients with higher pulmonary vascular tone (more release of hypoxic pulmonary vasoconstriction) showed less pulmonary hypertension during exercise (p less than 0.05), less VA/Q mismatching [at rest (p less than 0.005) and during exercise (p less than 0.0025)], and higher arterial PO2 during exercise (p = 0.01). We also found that DLCO corrected for alveolar volume (KCO) correlated with the mechanisms of hypoxemia during exercise [VA/Q mismatching (p less than 0.025) and O2 diffusion limitation (p less than 0.05)] and with the increase in pulmonary vascular resistance elicited by exercise (p less than 0.005). In conclusion, we showed that the abnormalities of the pulmonary vasculature are key to modulate gas exchange in IPF, especially during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

Elevation of antibodies to cytomegalovirus and other herpes viruses in pulmonary fibrosis.

The aim of this study was to determine whether latent viral infection is associated with idiopathic pulmonary fibrosis (IPF), an interstitial lung disease whose aetiology remains to be elucidated. Cytomegalovirus (CMV) immunoglobulin G (IgG) and complement fixation (CF), Epstein-Barr (EB) viral capsid antigen (VCA) IgG, herpes simplex virus (HSV) IgG, adenovirus CF, and parainfluenza 3 virus haemagglutinin inhibition (HI) titres were measured in the serum from patients with pulmonary diseases. The study included five subject groups: 35 normal controls (aged (mean +/- SD) 38 +/- 17 yrs); 43 IPF (63 +/- 10 yrs), seven collagen vascular disease-related interstitial pneumonitis (CVD-IP) (62 +/- 12 yrs); 22 sarcoidosis (36 +/- 14 yrs); and 17 emphysema (66 +/- 11 yrs). Levels of CMV IgG in IPF (87.6 +/- 51.7) and CVD-IP (101.2 +/- 69.9) were significantly elevated compared to those in the control (30.9 +/- 24.1), sarcoidosis (34.4 +/- 38.3) and emphysema groups (40.3 +/- 24.6), whereas CMV immunoglobulin M (IgM) was generally below the limit of detection. Similarly, CMV CF titres in IPF and CVD-IP were elevated compared to those in other diseases. EB VCA IgG titres in IPF, CVD-IP and emphysema and HSV IgG in IPF were also elevated. In contrast, adenovirus CF and parainfluenza 3 HI titres demonstrated no significant difference among all of the groups investigated. Increases in cytomegalovirus immunoglobulin G and complement fixation titres with negative cytomegalovirus immunoglobulin M suggest that latent cytomegalovirus infection may be more prominent in idiopathic pulmonary fibrosis or collagen vascular disease-related interstitial pneumonitis. Together with the elevation of Epstein-Barr virus viral capsid antigen and herpes simplex virus immunoglobulin G in idiopathic pulmonary fibrosis and/or collagen vascular disease-related interstitial pneumonitis, it is rational to assume that these viruses may be implicated in the development of pulmonary fibrosis. Further study is necessary to investigate the relationship between latent viral infection and pulmonary fibrosis.

Adenoviruses, Human↗
PubMed1990

Pulmonary fibrosis associated with low-dose adjuvant methyl-CCNU.

Pulmonary fibrosis is a serious side effect of nitrosourea therapy, occurring most frequently in patients treated with BCNU. Pulmonary fibrosis developed in a 63 year-old male patient while being treated with adjuvant methyl-CCNU for rectal carcinoma. This toxicity is rare with methyl-CCNU, having only been reported once previously. The case of methyl-CCNU-induced pulmonary fibrosis reported here occurred at a much lower total dose than the first reported case (604 mg/m2 vs. 2,733 mg/m2). Details of the case history, including radiographic and pathologic findings, are presented.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Immunologic alterations in bleomycin-treated mice: role of pulmonary fibrosis in the modulation of immune responses.

Among the side effects of bleomycin (BLM), a drug frequently used in the treatment of lymphomas and squamous-cell carcinomas, is pneumonitis with pulmonary fibrosis. The most prominent biochemical lesion associated with pulmonary fibrosis, a chronic debilitating and sometimes fatal disease, is an increase in the levels of collagen in the lung parenchyma. The mechanisms involved in the induction of this disease are still unclear, although results have suggested that the development of fibrosis may be immunologically mediated. There have, however, been no reports in the literature on the frequency and function of lymphocytes in the regional and systemic lymphoid tissues in BLM-induced pulmonary fibrosis. We therefore conducted a study, in which we inoculated C57Bl/6 mice intratracheally with BLM or saline, and tested the animals' lymphoid cells for various cell-mediated and humoral immune responses. The results indicated an increase in the number of lymphocytes in the lung-associated hilar lymph nodes, whereas the number of splenic lymphocytes was reduced as compared with control mice. Moreover, there was a significant inhibition of the antibody response to sheep erythrocytes in both the spleen and hilar lymph nodes of BLM-treated mice. Inhibition of the immune system appeared to be associated with the development of pulmonary fibrosis, and not to result from BLM toxicity, since the immune response of mice was not inhibited when they were injected with an identical dose of BLM under conditions that did not cause pulmonary fibrosis. Moreover, inhibition of splenic antibody responses was also observed in a hapten-induced model of pulmonary fibrosis, providing additional evidence that the induction of fibrosis and not the chemical toxicity of BLM was responsible for the modulation of immune responses.

Animals↗
PubMed2004

C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases.

Macrophage infiltration is implicated in various types of pulmonary fibrosis. One important pathogenetic process associated with pulmonary fibrosis is injury to basement membranes by matrix metalloproteinases (MMPs) that are produced mainly by macrophages. In this study, C-C chemokine receptor 2-deficient (CCR2-/-) mice were used to explore the relationship between macrophage infiltration and MMP activity in the pathogenesis of pulmonary fibrosis, using the bleomycin-induced model of this disease process. CCR2 is the main (if not only) receptor for monocyte chemoattractant protein-1/C-C chemokine ligand 2 (MCP-1/CCL2), which is a critical mediator of macrophage trafficking, and CCR2 -/- mice demonstrate defective macrophage migration. Pulmonary fibrosis was induced in CCR2-/- and wild-type (CCR2+/+) mice by intratracheal instillation of bleomycin. No significant differences in the total protein concentration in bronchoalveolar lavage (BAL) fluid, or in the degree of histological lung inflammation, were observed in the two groups until day 7. Between days 3 and 21, however, BAL fluid from CCR2-/- mice contained fewer macrophages than BAL fluid from CCR2+/+ mice. Gelatin zymography of BAL fluid and in situ zymography revealed reduced gelatinolytic activity in CCR2-/- mice. Immunocytochemical staining showed weaker expression of MMP-2 and MMP-9 in macrophages in BAL fluid from CCR2-/- mice at day 3. Gelatin zymography of protein extracted from alveolar macrophages showed reduced gelatinolytic activity of MMP-2 and MMP-9 in CCR2-/- mice. At days 14 and 21, lung remodelling and the hydroxyproline content of lung tissues were significantly reduced in CCR2-/- mice. These results suggest that the CCL2/CCR2 functional pathway is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis and that CCR2 deficiency may improve the outcome of this disease by regulating macrophage infiltration and macrophage-derived MMP-2 and MMP-9 production.

Animals↗