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Results for “PULMONARY FIBROSIS”

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PubMed2001

[mRNA expression of matrix metalloproteinase-2 and membrane type matrix metalloproteinase in pulmonary fibroblasts and macrophages of rat pulmonary fibrosis model].

OBJECTIVE: To study the changes and significance of MMP-2 and MT1-MMP mRNA expressions in fibroblasts and macrophages of rat pulmonary fibrosis model. METHODS: Fifty pathogen-free Sprague-Dawley rats were randomly divided into ten groups. Five groups were instillated with bleomycin A5 (BLM A5) intratracheally, while 5 control groups with normal saline instead. Pulmonary interstitial fibroblasts and alveolar macrophages were isolated at day 1,3,7,14,28th after BLM exposure. The mRNA expression of MMP-2 and MT1-MMP was evaluated by RT-PCR quantitative analysis. RESULTS: (1) The MMP-2 gene expression of fibroblasts increased 2.05 times(t = 10.667, P < 0.01) higher than that of control in 24 hours after bleomycin instillation and remained at the high level until the 28th day after exposure. It was only slightly increased in macrophages at the first day (t = 3.27, P < 0.05) and dropped down to the level of control during pulmonary fibrosis. (2) The mRNA expressions of MT1-MMP were enhanced both in fibroblasts and macrophages of fibrosis groups. They were 2.1 times(t = 4.823, P < 0.01) higher than that of control at the 14th day and 1.8 times(t = 4.016, P < 0.01) at the 28th day, respectively, in fibroblasts, while it was 2.4 times(t = 5.851, P < 0.01) higher than that of control at the 28th day in macrophages. CONCLUSIONS: (1) Fibroblasts not only were the target cells but also involved in the damage of the pulmonary basement membrane and in the initiation of pulmonary fibrosis mediated by up-regulation of the mRNA expression of MMP-2. (2) The highly expressed MT1-MMP of fibroblasts and macrophages in the late stage of pulmonary fibrosis participated in the activation of pro-MMP-2 to promote the progression of pulmonary fibrosis.

Animals↗

PubMed2005

Thoracic high-resolution computed tomographic findings in dogs with canine idiopathic pulmonary fibrosis.

OBJECTIVES: To identify features of canine idiopathic pulmonary fibrosis (CIPF) using high-resolution computed tomography (HRCT), and to correlate these features with clinical stages of the disease. METHODS: Ten dogs with signalment, history and clinical signs highly suggestive of CIPF were investigated. Thoracic radiography, haematology and biochemistry profiles, bronchoscopy and bronchoalveolar lavage and HRCT were performed in each case. The dogs were classified as having mild, moderate or severe stages of the disease based on their clinical presentation and radiographic signs. Features identified by HRCT were correlated with these disease stages. RESULTS: HRCT showed a spectrum of pulmonary changes and it was possible to match some of these to the stage of CIPF. CLINICAL SIGNIFICANCE: HRCT is used extensively in humans in the diagnosis and treatment planning of idiopathic pulmonary fibrosis. This preliminary study identifies the high-resolution computed tomographic features of CIPF in a small group of dogs. With further work it may be possible to use HRCT as a non-invasive tool for diagnosing, staging and therapeutically monitoring CIPF.

Animals↗

PubMed2005

Losartan attenuates bleomycin-induced pulmonary fibrosis in rats.

BACKGROUND: In addition to regulating blood pressure and body fluid homeostasis, the renin-angiotensin system is also involved in lung fibrogenesis. OBJECTIVE: To study the effect of losartan, an angiotensin II antagonist, on bleomycin-induced pulmonary fibrosis in rats and its possible mechanism. METHODS: Pulmonary fibrosis was induced in SD rats by intratracheal instillation of bleomycin (5 mg x kg(-1)). Subsequently, the rats received daily losartan (3, 9 and 27 mg x kg(-1)) or prednisone (20 mg x kg(-1)) orally. Six rats in each group were sacrificed 14 and 21 days after intratracheal instillation. Hydroxyproline, superoxide dismutase (SOD), and malondialdehyde (MDA) levels in lung tissues were determined by spectroscopy. The levels of TGF-beta1 in serum were measured by ELISA. Histological changes in the lungs were evaluated by hematoxylin-eosin stain, and scored. RESULTS: Rat body weight evidently decreased while the indices of lung and hydroxyproline contents in lung tissue were significantly increased 14 and 21 days after intratracheal bleomycin instillation. Inflammatory cell infiltration and fibrotic scores were more prominent in the model group compared to the sham group. Losartan (3, 9 and 27 mg.kg(-1), i.g.) apparently attenuated the degree of pulmonary fibrosis. Further study showed that losartan significantly increased SOD levels while it decreased MDA contents in lung homogenates. Serum TGF-beta1 levels of pulmonary fibrosis rats were also decreased by losartan. CONCLUSIONS: Losartan had an inhibitory effect on bleomycin-induced pulmonary fibrosis, and its effect may be associated with its anti-free radicals and the reduction in TGF-beta1.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2001

Inhibition of bleomycin-induced pulmonary fibrosis in mice by the matrix metalloproteinase inhibitor batimastat.

Bleomycin-induced pulmonary fibrosis is known to be associated with the increased activity of two gelatinases, matrix metalloproteinase (MMP)-2 and MMP-9, in bronchoalveolar lavage (BAL). This study has investigated the effect of a synthetic inhibitor of MMP, batimastat, on the development of pulmonary fibrosis induced by bleomycin administration in mice. Animals were intranasally instilled with saline or bleomycin (0.5 mg in 100 microl per mouse). Batimastat (30 mg/kg) or vehicle alone was administered by intraperitoneal injection 24 h and 1 h before saline or bleomycin instillation, and then daily at the same dosage until the end of the study. Fifteen days after bleomycin administration, BAL was performed and the lung was removed. Treatment of mice with batimastat significantly reduced bleomycin-induced lung fibrosis, as shown in the lung by histopathological examination and by a decrease in hydroxyproline levels. Batimastat also prevented the increase in BAL macrophage and lymphocyte numbers, whereas it did not show any effect on the increased expression of active transforming growth factor-beta (TGF-beta) in BAL. Batimastat treatment was effective in reducing MMP-2 and MMP-9 activity as well as the tissue inhibitor of metalloproteinase-1 (TIMP-1) level in BAL. These results suggest that administration of the MMP inhibitor batimastat is useful in preventing experimental pulmonary fibrosis induced by bleomycin and raises the possibility of a therapeutic approach to human pulmonary fibrotic disease.

Animals↗

PubMed1988

An investigation of possible models for the production of progressive pulmonary fibrosis in the rat. The effects of repeated intratracheal instillation of bleomycin.

Pulmonary fibrosis is a common later sequel to damage to the lung caused by a wide variety of agents. Bleomycin is an antineoplastic drug used in the treatment of squamous cell carcinomas and lymphomas. It is known to cause pulmonary fibrosis is both man and experimental animals. Bleomycin, dissolved in saline, was given by intratracheal instillation (dose = 0.5 U/animal; dose vol. = 0.5 ml/animal) to groups of at least 5 rats. Groups received either a single dose or 2, 3 or 4 doses each given a week apart. They were then sacrificed at periods of up to 90 days after the last dose. Subsequent histology revealed varying degrees of alveolitis, type II pneumocyte hyperplasia, alterations to alveolar structure including obliteration, degeneration, collapse and enlargement with significant interstitial fibrosis. The lesion appeared to be diffusely distributed throughout the lung. After a single dose or 2 doses regression of the lesion was observed with time following dosing whereas with 3 or 4 doses of bleomycin the changes increased progressively in extent and severity. Three or more doses of intratracheal instilled bleomycin appear to be a good model of progressive pulmonary fibrosis in the rat.

Animals↗

PubMedDate not supplied

Establishment of an animal model for pulmonary fibrosis in mice using monocrotaline.

A preliminary attempt at experimental induction of pulmonary fibrosis in which male ICR mice received 15 weekly sc injections of 200 or 100 mg/kg monocrotaline (MC) revealed that most animals treated with the larger dose died of severe interstitial pneumonia, whereas those given 100 mg/kg exhibited only relatively slight lung injury. Based on these results, male mice were administered sc injections of 200 and 100 mg/kg MC once a week for 9 and 18 times, respectively, and then maintained without any further treatment until week 28 after the start. Mice treated with 200 mg/kg MC showed severe pulmonary damage and died by week 25. Mortalities also occurred in the 100-mg group from week 16, with 11 of 40 animals surviving at the termination of the experiment. Histologically, both dose groups demonstrated severe interstitial pneumonia and/or pulmonary fibrosis. Ultrastructurally, inflammatory edema possibly attributable to injuries of alveolar capillary endothelial cells was observed in the high-dose group at week 8, and there was a remarkable increase in collagen fibers in alveolar septa in this group thereafter. The present study results suggest that lung injuries induced by MC treatment progress to irreversible lung fibrosis and that this animal model may have advantage for studying the pathogenesis of lung cancers in patients with pulmonary fibrosis.

Animals↗

PubMed2006

High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis.

The aim of this prospective study was to determine the prevalence and characteristics of acid gastro-oesophageal reflux (GER) in patients with idiopathic pulmonary fibrosis (IPF). Sixty-five consecutive patients with well-defined IPF were subjected to 24-h pH monitoring and oesophageal manometry. A total of 133 consecutive patients with intractable asthma and symptoms of GER were used as comparisons. The prevalence of abnormal acid GER in IPF patients was 87%, with 76% and 63% demonstrating abnormal distal and proximal oesophageal acid exposures, respectively. Abnormal acid GER was significantly more common in IPF patients than asthma patients. Only 47% of IPF patients experienced classic GER symptoms. Despite treatment with standard doses of proton pump inhibitors (PPIs), 12 out of 19 patients receiving PPIs during the 24-h pH monitoring had abnormal oesophageal acid exposures by pH probe. There was no correlation between IPF severity and acid GER severity. In conclusion, abnormal acid gastro-oesophageal reflux is highly prevalent, but often clinically occult in patients with idiopathic pulmonary fibrosis. Standard doses of proton pump inhibitors may not suppress the acid gastro-oesophageal reflux in this population. Therefore, further studies are needed to determine if acid abnormal gastro-oesophageal reflux represents an important risk factor for idiopathic pulmonary fibrosis development or progression, and if optimal suppression of acid gastro-oesophageal reflux slows the progression of idiopathic pulmonary fibrosis and/or decreases episodic exacerbations of idiopathic pulmonary fibrosis.

Adult↗

PubMed1995

[Gamma delta T cells in peripheral blood and in bronchoalveolar lavage fluid from patients with sarcoidosis and idiopathic pulmonary fibrosis].

We measured levels of gamma delta T cells in peripheral blood and in bronchoalveolar lavage fluid from patients with sarcoidosis, from patients with pulmonary fibrosis, and from normal subjects. In blood from both groups of patients, the percentage of lymphocytes was significantly greater than normal. The number of CD3+ cells per cubic millimeter was significantly lower than normal in patients with sarcoidosis, and tendency to be lower than normal in patients with pulmonary fibrosis. The percentage of CD3+ cells tended to be low, but there was no significant difference. The percentage and number of gamma delta T cells in patients with sarcoidosis, and the number of gamma delta T cells in patients with pulmonary fibrosis tended to be high. In bronchoalveolar lavage fluid, the percentage of lymphocyte was significantly higher than normal, and the numbers of CD3+ cells and gamma delta T cells per cubic millimeter tended to be high. In both groups of patients, cell counts of lymphocytes were significantly higher than normal. Numbers of CD3+ cells and of gamma delta T cells were significantly higher than normal in patients with sarcoidosis, and tended to be higher than normal in those with pulmonary fibrosis. These findings indicate local activation of gamma delta T cell function, recruitment of these cells into the bronchoalveolar system, and augmentation of gamma delta T cell supply in the whole body, especially in patients with sarcoidosis. In patients with pulmonary fibrosis the results were inconclusive; they were not as striking as were the results in patients with sarcoidosis.

Adult↗

PubMed1986

[Severe pulmonary fibrosis disclosing primary Gougerot-Sjögren syndrome. Apropos of 5 cases, 2 of which were fatal].

Five cases (four women and one man) with primary Gougerot-Sjögren syndromes presenting as interstitial pulmonary fibrosis are reported. The main point of interest was the severity of the pulmonary changes: effort dyspnoea from the outset, radiological interstitial pneumonitis, restrictive syndrome with a CO diffusing capacity less than 50 p. 100 of theoretical values in 4 cases. Broncho-alveolar lavage was performed in all patients: it showed a high polynuclear neutrophil and particularly high eosinophil counts. Lung biopsy showed severe fibrotic changes. The pulmonary changes dominated the clinical presentation in all patients and the Gougerot-Sjögren syndrome was only diagnosed after systematic examination completed by biopsy of the accessory salivary glands. In the absence of an associated connective tissue disease, these cases of the Gougerot-Sjögren syndrome were considered to be primary. Four patients were given steroid therapy but this did not prevent a fatal outcome in two cases after 6 and 14 months respectively. The clinical states of the other patients were unaffected by treatment. Twenty-one other, but less severe cases, have been previously reported. They confirm that interstitial pulmonary fibrosis observed during the Gougerot-Sjögren syndrome does not differ from idiopathic pulmonary fibrosis and that observed in other connective tissue diseases. Nevertheless, analysis of our cases showed that biopsy of the accessory salivary glands should be part of the routine investigation of apparently idiopathic pulmonary fibrosis. These pulmonary changes may be life-threatening when associated with a primary Gougerot-Sjögren syndrome.

Adult↗

PubMed1997

Clinical, laboratory and radiological findings in pulmonary fibrosis with and without connective tissue disease.

Uncertainty exists over whether to consider "lone" idiopathic pulmonary fibrosis (LIPF) and pulmonary fibrosis associated with connective tissue disorders (PFCTD) as significantly different entities. We retrospectively analysed data collected at the time of first diagnosis in 17 patients with LIPF and in 14 patients with PFCTD and compared survival in the two groups. At first evaluation, the time from onset of respiratory symptoms, spirometric volumes and the diffusing capacity for carbon monoxide were not significantly different between the two groups. However, arterial oxygen tension was significantly lower in LIPF than in PFCTD (63 +/- 3 vs 88 +/- 3 mmHg, p < 0.001). The radiological profusion scores relative to the upper and middle lung fields were significantly higher in LIPF than in PFCTD (upper regions: 6.9 +/- 0.6 vs 3.4 +/- 0.6, p < 0.005 - middle regions: 7.1 +/- 0.5 vs 4.8 +/- 0.7, p < 0.025), whereas the scores relative to the lower fields were similar (7.4 +/- 0.4 in LIPF and 8.4 +/- 0.6 in PFCTD). Survival since onset of respiratory symptoms was significantly better in the PFCTD than in LIPF patients, with a hazard ratio of 4.16 (95% CI 1.12-15.58, p=0.034). Thus, in our series of patients, those with LIPF had a more severe disease than those with PFCTD as shown by the higher frequency of hypoxaemia, the more diffuse pulmonary involvement demonstrated by the chest X-ray and the decreased survival.

Antibodies, Antinuclear↗

PubMed1999

Elevated serum and BAL cytokeratin 19 fragment in pulmonary fibrosis and acute interstitial pneumonia.

Cytokeratin 19 fragment (CK19) levels in serum have already been documented as a useful tumour marker for lung cancer. In the present study, it was hypothesized that CK19 may be increased in the serum and epithelial lining fluid of the respiratory tract from patients with pulmonary fibrosis. CK19 was measured in the serum and bronchoalveolar lavage fluid (BALF) of patients with pulmonary fibrosis and the correlation between CK19 levels and clinical parameters evaluated. Nineteen patients diagnosed with idiopathic pulmonary fibrosis (IPF), eight with pulmonary fibrosis associated with a collagen vascular disorder (PF-CVD), seven patients with acute interstitial pneumonia (AIP), and 10 normal smokers as a control group were studied. CK19 levels in sera of patients with IPF and patients with PF-CVD were significantly increased compared to those of normal smokers. CK19 levels in sera of patients with AIP were significantly increased compared to those of other groups. CK19 values in the BALF of patients with pulmonary fibrosis were significantly elevated compared to those of normal smokers. CK19 values in sera charged according to the progression or improvement of the acute lung injury. Immunohistochemical study using pulmonary tissues obtained from patients with AIP demonstrated that the hyaline membrane and proliferating type II pneumocytes were stained by anti-human cytokeratin 19 antibody. These data demonstrated that the measurement of cytokeratin 19 fragment is a useful parameter to evaluate the activity of lung epithelial cell damage and repair.

Acute Disease↗

PubMed2000

Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice.

The pulmonary endothelin (ET) system has been implicated in the pathogenesis of chronic lung diseases such as pulmonary hypertension, asthma, chronic obstructive lung disease, idiopathic pulmonary fibrosis, and bronchiolitis obliterans. However, the etiologic role of ET-1 in these diseases has not yet been established. We recently demonstrated that ET-1 transgenic mice, generated using the human prepro-ET-1 expression cassette including the cis-acting transcriptional regulatory elements, had predominant transgene expression in lung, brain, and kidney. We used these mice in the present study to analyze the pathophysiologic consequences of long-term pulmonary overexpression of ET-1. We found that ET-1 overexpression in the lungs did not result in significant pulmonary hypertension, but did result in development of a progressive pulmonary fibrosis and recruitment of inflammatory cells (predominantly CD4-positive cells). Our study provides evidence that a long-term activated pulmonary ET system, without any other stimuli, produces chronic lymphocytic inflammation and lung fibrosis. This suggests that overexpression of ET-1 may be a central event in the pathogenesis of lung diseases associated with fibrosis and chronic inflammation, such as pulmonary fibrosis and bronchiolitis.

Animals↗

PubMed2006

Diffuse alveolar damage after a single dose of topotecan in a patient with pulmonary fibrosis and small cell lung cancer.

Drug-induced pulmonary toxicities of anticancer agents have been well described, but the pathophysiology of agents typically used in advanced disease has not been well studied. Symptoms of pulmonary drug toxicity in advanced lung cancer patients may frequently be attributed to disease progression, pulmonary embolism, or infection. In patients with pre-existing interstitial pulmonary fibrosis even less is known. This report describes an unfortunate patient with pre-existing pulmonary fibrosis and progressive extensive stage small cell lung cancer. After receiving a single intravenous dose of topotecan, the patient developed sub-acute respiratory failure, and died 15 days later with pathology findings of organizing, reparative phase, diffuse alveolar damage. To our knowledge this is the first pathology confirmation of diffuse alveolar damage in a patient developing dyspnea following topotecan therapy. The frequency with which camptothecin-related dyspnea is associated with diffuse alveolar damage might be underestimated and is of special concern in patients with limited pulmonary reserve.

Antineoplastic Agents↗

PubMed2001

Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosis.

Dramatic activation of the coagulation cascade has been extensively documented for pulmonary fibrosis associated with acute and chronic lung injury. In addition to its role in hemostasis, thrombin exerts profibrotic effects via activation of the major thrombin receptor, protease-activated receptor-1. In this study, we examined the effect of the direct thrombin inhibitor, UK-156406 on fibroblast responses in vitro and on bleomycin-induced pulmonary fibrosis in rats. UK-156406 significantly inhibited thrombin-induced fibroblast proliferation, procollagen production, and connective tissue growth factor (CTGF) mRNA levels when used at equimolar concentration to the protease. Thrombin levels in bronchoalveolar lavage fluid and expression of thrombin and protease-activated receptor-1 in lung tissue were increased after intratracheal instillation of bleomycin. The characteristic doubling in lung collagen in bleomycin-treated animals (38.4 +/- 2.0 mg versus 17.1 +/- 1.4 mg, P < 0.01) was preceded by significant elevations in alpha1(I) procollagen and CTGF mRNA levels (3.0 +/- 0.4-fold and 6.3 +/- 0.4-fold respectively, (P < 0.01), and total inflammatory cell number. UK-156406, administered at an anticoagulant dose, attenuated lung collagen accumulation in response to bleomycin by 35 +/- 12% (P < 0.05), inhibited alpha1(I) procollagen and CTGF mRNA levels by 50% and 35%, respectively (P < 0.05), but had no effect on inflammatory cell recruitment. This is the first report showing that direct thrombin inhibition abrogates lung collagen accumulation in bleomycin-induced pulmonary fibrosis.

Animals↗

PubMed1978

[Bronchial arteries in interstitial pulmonary fibrosis (author's transl)].

6 autopsy lungs with interstitial pulmonary fibrosis were subjected to comparative angiographical and morphological investigations of bronchial arteries. During the final stage of interstitial pulmonary fibrosis, bronchial arteries were increased in number, and so were their anastomoses with pulmonary arteries. Extensive formation of broncho-pulmoary anastomosis as well as proliferation and formation of new bronchial arteries, is associated with interstitial chronic inflammation and fibrosis in the lung. The findings explain functional interconnections between the vessels of the systemic and the pulmonary circulations by direct artery-to-artery anastomoses, with a negative influence on pulmonary hypertension.

Autopsy↗

PubMed1999

[Diffuse interstitial pulmonary fibrosis and bronchial cancer].

Mortality due to lung cancer was 25% (7/28) in this study of patients with diffuse interstitial pulmonary fibrosis. Opacities on the chest x-ray suggestive of lung cancer were observed in 5 of the 7 cases. All 7 had squamous cell carcinoma. The percentage of smokers was significantly higher in patients with pulmonary fibrosis who developed lung cancer than in those with fibrosis who did not develop lung cancer (p = 0.016). These 7 cases of lung cancer with pulmonary fibrosis were compared with 174 cases of lung cancer without associated fibrosis. Peripheral localizations and lower lobe involvement were higher in cases of lung cancer with pulmonary fibrosis.

Aged↗

PubMed1988

Effects of vitamin E deficiency on bleomycin-induced pulmonary fibrosis in the hamster.

The effects of vitamin E deficiency on bleomycin (BLM)-induced pulmonary fibrosis have been studied by analyses of pressure volume (PV) curves and morphological examinations. Golden hamsters were divided into groups on a control diet (group C), vitamin E-deficient diet (E), control diet with BLM treatment (CB), and vitamin E-deficient diet with BLM treatment (EB). Group EB showed PV curves shifted downward and to the right soon after BLM administration (10 days) and gradually shifted upward and to the left compared to group CB in the later period (30 and 60 days after BLM treatment). Histologically group EB was characterized by relatively severe interstitial pneumonitis in the early stages. In later stages, emphysematous changes were induced in combination with a lesser degree of fibrosis in group EB. Mean thickness of the alveolar wall of group CB was larger than group C while that of group EB was smaller at 30 days after BLM treatment. These results indicate that, with BLM treatment, vitamin E-deficient hamsters show increased distensibility on the PV curve and emphysematous changes mixed with focal fibrosis on morphological examination. This means that by adding other modulating factors, such as vitamin E deficiency, BLM, an agent known to produce pulmonary fibrosis, acts to induce an emphysematous lesion in the lung. Although pulmonary fibrosis and emphysema have been considered to be final and different forms of parenchymal injury, each may proceed to the other under the influence of some modulating factors.

Animals↗

PubMed2005

Lung infection with gamma-herpesvirus induces progressive pulmonary fibrosis in Th2-biased mice.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease of unknown etiology. A viral pathogenesis in IPF has been suggested since >95% of IPF patients have evidence of chronic pulmonary infection with one or more herpesviruses. To determine whether pulmonary infection with herpesvirus can cause lung fibrosis, we infected mice with the murine gamma-herpesvirus 68 (MHV68). Because IPF patients have a T helper type 2 (Th2) pulmonary phenotype, we used IFN-gammaR-/-, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of IFN-gammaR-/- mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in IPF, increased transforming growth factor-beta expression, myofibroblast transformation, production of Th2 cytokines, hyperplasia of type II cells, and increased expression of matrix metalloproteinase-7, were also present in chronically infected IFN-gammaR-/- mice. There also was altered synthesis of surfactant proteins, which is seen in some patients with familial IPF. MHV68 viral protein was found in type II alveolar epithelial cells, especially in lung areas with extensive alveolar remodeling. In summary, chronic herpesvirus pulmonary infection in IFN-gammaR-/- mice causes progressive pulmonary fibrosis and many of the pathological features seen in IPF.

Animals↗