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PubMed1992

Interstitial pulmonary fibrosis with and without associated collagen vascular disease: results of a two year follow up.

BACKGROUND: Interstitial pulmonary fibrosis is a disease with a highly variable clinical course. To ascertain if an inadequate selection of patients might explain part of this variability, two different groups of patients with interstitial pulmonary fibrosis, those with the "lone" form of the disease (LIPF) and those with associated collagen vascular disorders (AIPF), were studied separately. METHODS: Twenty consecutive patients (nine with LIPF and 11 with AIPF) were included. Their clinical and radiographic findings and results of pulmonary function tests, gallium-67 lung scanning, and cellular analysis of bronchoalveolar lavage fluid were compared at diagnosis. Moreover, the evolution of LIPF and AIPF was contrasted after a follow up of two years, both groups having received a similar treatment regimen of corticosteroids. RESULTS: At enrollment, patients with LIPF and AIPF were of similar age, and had similar symptoms and derangement of lung function, but patients with LIPF presented with finger clubbing, more obvious radiographic abnormalities, and a greater percentage of eosinophils in bronchoalveolar lavage fluid. Two years later, patients with LIPF had significantly decreased FVC, FEV1, TLC, TLCO, and PaO2. By contrast, lung function remained unaltered in patients with AIPF. Similarly, when the percentage change from entry to the study was compared, patients with LIPF showed a significant decrease in FVC, FEV1, and PaO2. CONCLUSIONS: Unlike the patients with AIPF, those with LIPF showed a deterioration in lung function and developed further restrictive impairment and poorer gas exchange. This has implications in their clinical management.

Adult↗

PubMed2001

Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-beta in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice.

Prostaglandin E(2) (PGE(2)) inhibits fibroblast proliferation and collagen production. Its synthesis by fibroblasts is induced by profibrotic mediators including transforming growth factor (TGF)-beta(1). However, in patients with pulmonary fibrosis, PGE(2) levels are decreased. In this study we examined the effect of TGF-beta(1) on PGE(2) synthesis, proliferation, collagen production, and cyclooxygenase (COX) mRNA levels in fibroblasts derived from fibrotic and nonfibrotic human lung. In addition, we examined the effect of bleomycin-induced pulmonary fibrosis in COX-2-deficient mice. We demonstrate that basal and TGF-beta(1)-induced PGE(2) synthesis is limited in fibroblasts from fibrotic lung. Functionally, this correlates with a loss of the anti-proliferative response to TGF-beta(1). This failure to induce PGE(2) synthesis is because of an inability to up-regulate COX-2 mRNA levels in these fibroblasts. Furthermore, mice deficient in COX-2 exhibit an enhanced response to bleomycin. We conclude that a decreased capacity to up-regulate COX-2 expression and COX-2-derived PGE(2) synthesis in the presence of increasing levels of profibrotic mediators such as TGF-beta(1) may lead to unopposed fibroblast proliferation and collagen synthesis and contribute to the pathogenesis of pulmonary fibrosis.

Bleomycin↗

PubMed2005

Pediatric lung disease: from proteinases to pulmonary fibrosis.

One distinctive outcome of interstitial lung diseases in childhood is the abnormal accumulation of pulmonary extracellular matrix. The clinical consequence of such excessive connective tissue accumulation is known as pulmonary fibrosis. While numerous aspects of its pathogenesis have become familiar, many key events involved in its inception and progression still remain unclear. There is now compelling evidence that lung damage due to uncontrolled proteolysis may help drive critical processes that regulate fibrotic matrix remodeling. In this regard, a number of proteinases have been implicated in promoting both the initial lung injury and the fibroproliferative repair that follows. This review summarizes the knowledge of how different matrix-targeting enzymes may act to influence the development of pediatric pulmonary fibrosis. Understanding the scientific basis of this complex process may highlight opportunities to limit unwanted proteolysis and the intensity of its fibrotic sequelae.

Child↗

PubMed2005

Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis.

OBJECTIVE: To clarify the clinical significance of serum levels of pulmonary and activation-regulated chemokine (PARC) in the diagnosis and monitoring of pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc) and to compare PARC levels with KL-6 antigen or surfactant protein D (SP-D) levels. METHODS: Serum PARC levels were determined by enzyme-linked immunosorbent assay in 123 SSc patients. In a retrospective longitudinal study, correlation of serum PARC levels with the activity of PF was assessed in 21 SSc patients with active PF. RESULTS: PARC levels at the first visit were higher in patients with SSc than in patients with systemic lupus erythematosus (SLE) or healthy controls. Increased serum PARC levels were associated with involvement of PF, decreased diffusing capacity for carbon monoxide, and decreased vital capacity in SSc patients. In the longitudinal study, serum PARC levels were significantly decreased in SSc patients with inactive PF compared with those with active PF. CONCLUSION: Elevated serum PARC levels correlated with PF and more sensitively reflected the PF activity than did serum KL-6 or SP-D levels in SSc. Serum PARC levels may be a useful new serum marker for active PF in SSc.

Antigens↗

PubMed1991

Idiopathic pulmonary fibrosis. Abnormalities in the bronchoalveolar lavage content of surfactant protein A.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung characterized by an inflammatory infiltrate, alveolar type II cell hypertrophy and hyperplasia, and ultimate parenchymal scarring. The phospholipid composition of the surface-active material recovered by bronchoalveolar lavage (BAL) is abnormal in this disease. In the present study we have extended the analysis of surfactant components in IPF to include the major surfactant-associated protein, surfactant protein A (SP-A). SP-A has been reported to be essential for the formation of tubular myelin, to facilitate the adsorption of phospholipid to the air/liquid interface, and to stimulate uptake and inhibit secretion of surfactant in vitro. The BAL of 25 normal volunteers and 42 patients with interstitial lung disease (ILD) was analyzed for surfactant protein A content by ELISA and for phospholipids. The changes in BAL components were correlated to histopathologic markers at open-lung biopsy, clinical status, and survival. The total phospholipid (PL) recovered at lavage was reduced in patients with IPF relative to normal volunteers (p less than 0.0005). In addition, the percentage of phosphatidyl-glycerol (% PG) was decreased in patients with IPF (p less than 0.0001), whereas the percentage of phosphatidylcholine that was saturated was not altered. The content of surfactant protein A in lavage was reduced, even when normalized for the total amount of surface-active material recovered (SP-A/PL) (p less than 0.007). The reduction in SP-A was not specific to IPF but also occurred in other interstitial lung diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchoalveolar Lavage Fluid↗

PubMed1988

Adverse impact of interstitial pulmonary fibrosis on prognosis in polymyositis and dermatomyositis.

Interstitial pulmonary fibrosis occurs in approximately 9% of patients with PM/DM, yet its effect on the course of PM/DM has been scarcely noted. In this report, two patients with PM/DM and IPF were presented to highlight the fact that pulmonary disease can overshadow the primary muscle disorder and progress despite therapy with corticosteroids and nonsteroidal immunosuppression. Our patients were added to previously reported cases and an overview of PM/DM and IPF was presented. Sixty-seven patients with the diagnosis of PM/DM and IPF, with a mean age of 60 +/- 18 years, were identified. Pulmonary complaints were present in 64 cases. Fever was present in 18, arthritis or arthralgias in 11, and Raynaud's phenomenon in 9. Forty percent died after followup of 31 +/- 32 months. This mortality was significantly higher (P less than .05) than that in 745 historical controls with PM/DM without IPF. Progressive IPF was the immediate cause of death in 58% of those who died. A subgroup of 29 patients who had histologic documentation of both myositis and IPF had a mortality of 62% after 22 +/- 25 months. In this latter group, six patients had RP; five of these died. Patients who were not treated with corticosteroids also appeared to fare worse but, given the small number of patients involved, definite conclusions cannot be drawn. We conclude that patients with PM/DM can be adversely affected by the presence of IPF and that this negative impact may be exaggerated by RP and perhaps by lack of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗

PubMed1975

Experimental pulmonary fibrosis induced by soluble immune complex and 60% oxygen atmosphere.

In our previous papers we reported characteristic morphological changes of the capillary endothelium in the lung and of the arterial endothelium. These changes were induced by administration of various soluble immune complexes. In this paper we have induced pulmonary fibrosis in guinea pigs under allergic procedures. Administration of soluble immune complexes alone produces interstitial pneumonia. However, these changes would not normally result in diffuse pulmonary fibrosis. The administration of soluble immune complexes to guinea pigs plus exposure to a 60% oxygen-rich atmosphere yielded diffuse pulmonary fibrosis.

Animals↗

PubMed1997

Antiinflammatory and antifibrotic properties of colchicine: implications for idiopathic pulmonary fibrosis.

The ancient drug colchicine has repeatedly been proposed as a novel drug for therapy of pulmonary fibrosis. The present study was undertaken to add to the knowledge on colchicine's antiinflammatory and antifibrotic properties and thus help determine its actual rank in the treatment of pulmonary fibrosis. In vitro cell culture experiments with stimulated and unstimulated normal donor peripheral blood mononuclear cells (PMNC) and a human lung fibroblast cell line (WI-38) were used to determine the effects of colchicine on PMNC cytokine release (interleukin-6 and tumor necrosis factor-alpha) as well as on fibroblast proliferation and collagen synthesis rates. Reverse transcriptase polymerase chain amplifications of alpha 1 (III) collagen were done to detect collagen messenger ribonucleic acid (mRNA) expression. Colchicine did not significantly modulate tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) release of PMNC. Colchicine inhibited fibroblast proliferation and total collagen synthesis significantly at concentrations obtainable in serum in vivo. Transcription of the alpha 1 (III) collagen gene into mRNA continued under colchicine. We conclude that colchicine is a potent in vitro inhibitor of fibroblast functions in terms of proliferation and collagen synthesis. The mechanism of collagen inhibition is more likely an inhibition of cellular collagen secretion than a switch off of collagen mRNA transcription. On the other hand, although colchicine is known to inhibit many leukocyte functions, it is a poor inhibitor of cytokines known to be important for fibrogenesis (e.g. IL-6, TNF-alpha, IL-1, platelet-derived growth factor, and transforming growth factor-beta). This makes colchicine, at least from a theoretical standpoint and as concluded from in vitro studies, a preferable candidate for a combined therapeutic strategy.

Cells, Cultured↗

PubMed2006

[Feature changes of MMP-2/9 activities and TIMP-1/2 protein expressions during the progression of pulmonary fibrosis in rats].

OBJECTIVE: To investigate the dynamic trends of activities of matrix metalloproteinase (MMP)-2/9 and protein expressions of their inhibitors-tissue inhibitor of matrix metalloproteinase (TIMP)-1/2 during the progression of pulmonary fibrosis in rats so as to get insight of the roles played by MMP-2/9 in lung injury and fibrogenesis. METHODS: Forty-eight SD rats were randomly divided into normal control group (n=18) and bleomycin (BLM)-treated group (n=30). The pulmonary fibrosis was induced by intratracheal injection of BLM once. At the consecutive time of 1 day, 3 days, 1 week, 2, 3, and 4 weeks after intoxication, the lung-to-body weight ratio was calculated and the inflammation and collagen deposition in lung tissue were checked by HE and Masson stainings respectively. Meanwhile, the content of hypdroxyproline (Hyp) in lung tissue was assayed with Jamall's method, the protein expressions of MMP-2/9, TIMP-1/2 were examined by Western blotting, and the activities of MMP-2/9 were detected by gelatin zymography. RESULTS: The histopathological changes in lung tissue in the BLM-treated group from 1 day to 2 weeks after intoxication presented local lesions, broadened alveolar wall and septum, infiltration with lots of inflammatory cells and few of fibroblasts inside alveolar space and septum. At this early stage in the BLM-treated group, the lung-to-body weight ratio was increased significantly, the protein expressions and activities of MMP-2/9 were obviously increased especially for activity of active MMP-2, and the protein expressions of TIMP-1/2 were also increased gradually, as compared with those in the normal control group. From 3 to 4 weeks after intoxication in the BLM-treated group, the alveolar structure was damaged, parts of the alveolar space collapsed and replaced by collagens and fibroblasts, and the alveolar wall and septum obviously widened with remarkable fibrotic characteristics, as compared with those in the normal control group. Meanwhile, the lung-to-body weight ratio and the activities of MMP-2/9 were decreased in the BLM-treated group as compared with those in the same group at 2 weeks after intoxication, but the content of Hyp and the protein expressions of TIMP-1/2 were both increased dramatically, especially at 4 weeks after intoxication. CONCLUSIONS: During the lung fibrogenesis induced by BLM in rats, the alveolar inflammation is the most important alteration with enhanced MMP-2/9 activities in the early stage. While in the late stage, the main change is displayed as pulmonary fibrosis, characterized by increased TIMP-1/2 and declined MMP-2/9 activities.

Animals↗

PubMed1999

[The expression of integrin alpha5beta1 and transforming growth factor-beta in pulmonary fibrosis of rat].

OBJECTIVE: To study the roles of integrin alpha(5)beta(1) played in rat pulmonary fibrosis. METHODS: The dynamic changes of fibronectin (FN), FN receptor alpha(5)beta(1), and TGF-beta were analysed in bleomycin-induced rat pulmonary fibrosis by using immunohistochemical technique. Northern blot analysis and immunocytochemistry techniques were performed in order to detect the expression of alpha(5)beta(1), FN mRNA and their relevant proteins in cultured rat pulmonary fibroblasts (PFbs) after administration of TGF-beta1. RESULTS: (1) A strong positive reaction with anti-integrin alpha(5)beta(1) was seen in the pneumocytes, endothelial cells and proliferated mesenchymal cells on the 1st to 3rd day after bleomycin. The positive signals for integrin alpha(5)beta(1) were apparent mainly in those proliferated interstitial cells with fibroblast and myofibroblast differentiation 7 days after bleomycin treatment. Changes in FN were similar to that of the integrin alpha(5)beta(1). (2) Expression of alpha(5)beta(1), FN mRNAs and their relevant proteins was increased in rat PFbs after TGF-beta1 administration. CONCLUSIONS: Integrin alpha(5)beta(1) played a key role in inducing the activation, proliferation and differentiation of PFbs, causing an increase of extra-cellular matrix synthesis during pulmonary fibrogenesis.

Animals↗

PubMed1987

Pulmonary fibrosis following pneumonia due to acute Legionnaires' disease. Clinical, ultrastructural, and immunofluorescent study.

During a recent nosocomial outbreak, 20 critically ill patients with acute Legionnaires' disease were admitted to the intensive care unit of Hopital Bichat, Paris. Pulmonary specimens were obtained at surgery or immediately after death in 12 patients and were examined by light, immunofluorescent, and electron microscopy. Five of these 12 patients showed evidence of pulmonary fibrosis. In all of these five patients, infection with Legionella pneumophila was evidenced by bacteriologic methods, and other diseases known to cause fibrosis were excluded. The condition of four patients deteriorated rapidly with respiratory failure, and they died with pulmonary fibrosis. Only one patient finally recovered but was left with pulmonary sequelae. Two distinctive morphologic patterns were observed, one in which interstitial fibrosis was predominant and one in which intra-alveolar organization and fibrosis were also present. The alveolar epithelial lining and the basement membranes were disrupted in all patients, as evidenced by ultrastructural observations and by immunofluorescent studies showing gaps in the distribution of type 4 collagen and laminin. Types 1 and 3 collagen accumulated in areas corresponding to thickened interstitium and intra-alveolar fibrosis. Thus, some patients who survive the acute pneumonia of Legionnaires' disease may develop pulmonary fibrosis, and this process may lead to functional impairment or death despite prompt and appropriate treatment.

Adult↗

PubMed2001

Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder.

Idiopathic pulmonary fibrosis is a chronic and usually progressive lung disorder of unknown etiology. A growing body of evidence suggests that, in contrast to other interstitial lung diseases, IPF is a distinct entity in which inflammation is a secondary and non-relevant pathogenic partner. Evidence includes the presence of similar mild/moderate inflammation either in early or late disease, and the lack of response to potent anti-inflammatory therapy. Additionally, it is clear from experimental models and some human diseases that it is possible to have fibrosis without inflammation. An evolving hypothesis proposes that IPF may result from epithelial micro-injuries and abnormal wound healing.

Animals↗

PubMed1984

Amiodarone-induced pulmonary fibrosis in hamsters.

Amiodarone, a cardiac antiarrhythmic agent, has been associated with the development of interstitial pulmonary fibrosis in patients receiving prolonged therapy with the drug. To further assess the toxic effects of amiodarone on lung tissue, Syrian hamsters were given a single intratracheal insufflation of the agent and evaluated for histologic evidence of lung injury. Control animals received intratracheal insufflations of the vehicle in which amiodarone was dissolved. After an initial, transient alveolitis in both experimental and control animals, the amiodarone-treated lungs developed increased interstitial thickening due to fibrinous exudates, alveolar epithelial hyperplasia, inflammatory cell infiltrates, and marked deposition of collagen manifested on trichrome staining. Controls, in contrast, showed nearly complete resolution of the initial alveolitis. An unusual feature of the amiodarone-induced lung injury was reemergence of the alveolitis between 5 and 14 days, which included a marked influx of eosinophils into the lung. Although the precise mechanism of the lung injury is not known, the persistence of the acute inflammatory cells as well as the presence of eosinophils suggests a hypersensitivity-type reaction. Furthermore, the progression of lung injury to fibrosis after a single insult with the drug suggests that mere discontinuation of amiodarone therapy in humans may not reverse the disease process, but that corticosteroid therapy may also be required. Amiodarone appears to be a useful agent to induce diffuse fibrotic reactions in the lung that morphologically resemble idiopathic pulmonary fibrosis in humans.

Amiodarone↗

PubMed1992

[Idiopathic interstitial pulmonary fibrosis. Clinical picture, diagnosis, treatment and prognosis].

Idiopathic pulmonary fibrosis (IPF) was found to have a higher incidence than previously assumed and the population involved was younger. These findings were made in a retrospective investigation during the period 1986-1990. The condition should be suspected on the basis of the radiographic characteristics, reduced lung volume (TLC), decreased DLco during testing of pulmonary function, hypoxemia at rest and also the symptoms revealed in the medical history. It is of importance for planning of treatment that the diagnosis of IPF is confirmed early by excision biopsy of pulmonary tissue. Patients with IPF were treated successfully by intravenous administration of a solution of 500 mg methylprednisolone in 500 ml isotonic glucose. This regime is administered for three consecutive days and supplemented by azathioprine as required. In order to prevent further progression of this chronic disease, patients with IPF should be followed-up at frequent intervals.

Adult↗

PubMed1987

Role of alveolar phospholipids in bleomycin-induced pulmonary fibrosis in the rat.

The events leading to the onset of the experimental bleomycin-induced pulmonary fibrosis are so far unknown, though recent observations emphasize the crucial role played by lung phospholipids and by alveolar macrophages. In an attempt to verify this point, a series of studies were undertaken by treating rats (CD-COBS) with intratracheal instillation of a single dose of bleomycin (1.5 U). At the same time a group of animals was pretreated with ambroxol (which is known to be a powerful inducer of surfactant production both in fetal and adult type II pneumocytes), 4 mg/kg body weight/day per os, 5 days before the treatment with bleomycin and up to the sacrifice of the animals at the 1st, 3rd, 7th, 14th or 28th day from the instillation. In our experimental model, the 14th day from the treatment with bleomycin seems to be a crucial time since it histologically corresponds to the proliferation of type II pneumocytes; furthermore, an increase of total lecithins in the alveolar spaces was observed, together with an increase of macrophage membrane fluidity. In the ambroxol-pretreated group a partial reduction of the rate of interstitial fibrosis was observed. At the 14th day from treatment the alteration of phospholipid levels was much less pronounced and the microviscosity of alveolar macrophages was similar to that of control animals. These data suggest that the onset of bleomycin-induced pulmonary fibrosis in the rat is characterized by an increase of alveolar lecithins and that this fact could modify the physico-chemical peculiarities of alveolar macrophages. Ambroxol shows a partially protective effect, perhaps by modulating the activity of type II pneumocytes.

Ambroxol↗

PubMedDate not supplied

Pathogenesis of idiopathic interstitial pulmonary fibrosis.

The histopathology and ultrastructure of idiopathic interstitial pulmonary fibrosis is described and illustrated. There is evidence that proliferating type II pneumocytes in regenerating alveolar epithelium are implicated in the pathogenesis of this disorder.

Basement Membrane↗

PubMed1991

Bleomycin-induced pulmonary fibrosis in genetically mast cell-deficient WBB6F1-W/Wv mice and mechanism of the suppressive effect of tranilast, an antiallergic drug inhibiting mediator release from mast cells, on fibrosis.

It has been well known that the number of mast cells increases during the development of fibrosis in various tissues including the lung. However, the role of mast cells in fibrosis still remains obscure. In the present paper, we evidenced that pulmonary fibrosis could be induced in genetically mast cell-deficient WBB6F1-W/Wv mice as well as WBB6F1-(+/+) mice having mast cells normally by the treatment with bleomycin (BLM, 5 mg/kg, i.v., 10 days), and there was not much difference in the histological changes of lungs between the two strains. An increase in the hydroxyproline content of the lung of WBB6F1-W/Wv mice was rather higher than that of WBB6F1-(+/+) mice. Previously, we reported that tranilast, an antiallergic drug inhibiting chemical mediator release from mast cells, suppressed the development of BLM-induced pulmonary fibrosis in ICR mice, suggesting the possibility that mast cells play certain roles in fibrosis. However, it was evidenced in the present report that tranilast suppressed BLM-induced fibrosis in WBB6F1-W/Wv mice. Tranilast neither suppressed the cytotoxic activity of BLM against KB cells and L-929 cells in vitro, nor inhibited the antitumor activity of BLM against Sarcoma-180 transplanted subcutaneously into ICR mice. Tranilast may act through suppressing BLM-induced activation of lymphoid cells including macrophage and neutrophil. These results indicate an inconsequential role of mast cells in the development of fibrosis. Increases in the number of mast cells and in histamine content of the lung, which were widely reported in the lungs of BLM-treated mice, may be the result of fibrosis.

Analysis of Variance↗

PubMed2001

[Idiopathic pulmonary fibrosis. A case report].

A case of idiopathic pulmonary fibrosis is presented. The difficulty of a differential diagnosis with other interstitial lung diseases and the necessity of a right and complete diagnostic pathway are underlined.

Aged↗