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Results for “PULMONARY FIBROSIS”

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PubMed1983

The effects of the nude (nu/nu) mutation on bleomycin-induced pulmonary fibrosis. A biochemical evaluation.

Previous reports have suggested that the immune system is involved in the lung fibrogenic response to certain agents or treatments. In the present study, we have evaluated the impact of the athymic (nude) mutation on the development of pulmonary fibrosis in mice induced by a single intratracheal instillation of bleomycin (0.75 units/animal). Histologic examination revealed that cellular infiltration, fibroblast proliferation, and connective tissue accumulation were diminished in the nude mice when compared with euthymic (het) control mice. In contrast to control animals treated with saline, total lung hydroxyproline in the nude mouse was not significantly increased at 14 and 30 days after bleomycin treatment. Net collagen synthesis, as assessed by measuring the rate of incorporation of tritiated proline in an organ culture system, was increased above control values in both nude and euthymic mice at 14 days after bleomycin treatment, although these values returned to normal at 30 days. However, lung collagen synthetic rates, normalized to dry lung weights, were significantly higher at 14 days in euthymic bleomycin-treated control mice than in the nude bleomycin-treated animals. The data indicate that the nude athymic mutation protects, at least partially, against bleomycin-induced pulmonary fibrosis, thus suggesting a role for the cellular immune system in regulating the fibrogenic response to this drug.

Animals↗

PubMed1995

Expression of a tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis. A mouse model of progressive pulmonary fibrosis.

The murine TNF-alpha gene was expressed under the control of the human surfactant protein SP-C promoter in transgenic mice. A number of the SP-C TNF-alpha mice died at birth or after a few weeks with very severe lung lesions. Surviving mice transmitted a pulmonary disease to their offspring, the severity and evolution of which was related to the level of TNF-alpha mRNA in the lung; TNF-alpha RNA was detected in alveolar epithelium, presumably in type II epithelial cells. In a longitudinal study of two independent mouse lines, pulmonary pathology, at 1-2 mo of age, consisted of a leukocytic alveolitis with a predominance of T lymphocytes. Leukocyte infiltration was associated with endothelial changes and increased levels of mRNA for the endothelial adhesion molecule VCAM-1. In the following months, alveolar spaces enlarged in association with thickening of the alveolar walls due to an accumulation of desmin-containing fibroblasts, collagen fibers, and lymphocytes. Alveolar surfaces were lined by regenerating type II epithelial cells, and alveolar spaces contained desquamating epithelial cells in places. Platelet trapping in the damaged alveolar capillaries was observed. Pulmonary pathology in the SP-C TNF-alpha mice bears a striking resemblance to human idiopathic pulmonary fibrosis, in which increased expression of TNF-alpha in type II epithelial cells has also been noted. These mice provide a valuable animal model for understanding the pathogenesis of pulmonary fibrosis and exploring possible therapeutic approaches.

Animals↗

PubMed1995

Priming of alveolar macrophages for interleukin-8 production in patients with idiopathic pulmonary fibrosis.

We evaluated the contribution of interleukin-8 (IL-8) to the pathogenesis of idiopathic pulmonary fibrosis (IPF) by studying bronchoalveolar lavage fluid (BALF) in eight patients with IPF in the chronically progressive phase, five patients with IPF in the subacutely progressive phase, eight patients with sarcoidosis (SAR), and eight control (CTL) subjects. IL-8 levels were not increased in the BALF of the patients with IPF in the chronic phase (11.3 +/- 8.8 pg/ml), nor in that of the SAR patients (13.8 +/- 7.8 pg/ml), whereas they were increased in the BALF of patients with IPF in the subacutely progressive phase (1.93 +/- 1.10 ng/ml). We then investigated extracellular and cell-associated IL-8 in lipopolysaccharide (LPS)-stimulated BALF cells to determine the IL-8-producing potential of alveolar macrophages (AM). Following LPS stimulation of BALF cells from patients with IPF in the chronic phase, both the extracellular IL-8 in culture fluid and the cell-associated IL-8 in AM were increased as compared with those for the CTL subjects (p < 0.05 and p < 0.05, respectively). These results suggest that AM of patients with IPF are primed for IL-8 production. We conclude that IL-8 may play a role in neutrophilic alveolitis, especially during the subacute phase of IPF.

Acute Disease↗

PubMed2005

Insulin-like growth factor binding proteins 3 and 5 are overexpressed in idiopathic pulmonary fibrosis and contribute to extracellular matrix deposition.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease of unknown etiology that results in significant morbidity and mortality. The pathogenesis of IPF is not completely understood. Because recent studies have implicated insulin-like growth factor-I (IGF-I) in the pathogenesis of fibrosis, we examined the expression and function of insulin-like growth factor binding proteins (IGFBP)-3 and -5 in IPF. IGFBP-3 and -5 levels were increased in vivo in IPF lung tissues and in vitro in fibroblasts cultured from IPF lung. The IGFBPs secreted by IPF fibroblasts are functionally active and can bind IGF-I, and IGFBPs secreted by primary fibroblasts bind extracellular matrix components. Our results also suggest that IGFBPs may be involved in the initiation and/or perpetuation of fibrosis by virtue of their ability to induce the production of extracellular matrix components such as collagen type I and fibronectin in normal primary adult lung fibroblasts. Although transforming growth factor-beta increased IGFBP-3 production by primary fibroblasts in a time-dependent manner, IGFBP-5 levels were not increased by transforming growth factor-beta. Taken together, our results suggest that IGFBPs play an important role in the development of fibrosis in IPF.

Adenoviridae↗

PubMed1992

Serum and bronchoalveolar lavage of N-terminal type III procollagen peptides in idiopathic pulmonary fibrosis.

Collagen deposition is a prime determinant of clinical course in idiopathic pulmonary fibrosis (IPF). Identification of a marker of connective tissue metabolism would significantly enhance the ability to stage the disease and monitor the course of these patients. Prior studies of IPF have indicated that N-terminal Type III procollagen peptide (N-PIIIP) levels in blood and bronchoalveolar lavage BAL fluid are elevated. We hypothesized that elevated levels of procollagen peptides are a marker of enhanced collagen deposition, which is associated with interstitial fibrosis characterizing active disease. The purpose of the present study was to explore the relationship between N-PIIIP recovery and physiologic parameters of lung function. N-PIIIP levels in sera and bronchoalveolar lavage (BAL) from 24 patients with IPF and 29 volunteers were measured by radioimmunoassay. The extent of disease in IPF was assessed by clinical history, physical examination, chest radiograph, pulmonary physiology evaluation, and confirmatory open-lung biopsy. The severity of disease was graded using a previously described clinical, radiologic, and physiologic (CRP) scoring system. N-PIIIP normalized to albumin was higher in BAL than in serum for both volunteers (1.6-fold; p less than 0.05) and IPF patients (24-fold; p less than 0.05), consistent with local pulmonary production. BAL N-PIIIP was significantly elevated in IPF patients, whether expressed as concentration (healthy volunteer 0.11 +/- 0.06 ng/ml; IPF, 5.0 +/- 14.4; mean +/- SD; p less than 0.05) or normalized to albumin (healthy volunteer, 2.8 +/- 1.2; IPF, 73 +/- 106; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2005

Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations.

Adenosine, a signaling nucleoside, exhibits tissue-protective and tissue-destructive effects. Adenosine levels in tissues are controlled in part by the enzyme adenosine deaminase (ADA). ADA-deficient mice accumulate adenosine levels in multiple tissues, including the lung, where adenosine contributes to the development of pulmonary inflammation and chronic airway remodeling. The present study describes the development of pulmonary fibrosis in mice that have been genetically engineered to possess partial ADA enzyme activity and, thus, accumulate adenosine over a prolonged period of time. These partially ADA-deficient mice live for up to 5 mo and die from apparent respiratory distress. Detailed investigations of the lung histopathology of partially ADA-deficient mice revealed progressive pulmonary fibrosis marked by an increase in the number of pulmonary myofibroblasts and an increase in collagen deposition. In addition, in regions of the distal airways that did not exhibit fibrosis, an increase in the number of large foamy macrophages and a substantial enlargement of the alveolar air spaces suggest emphysemic changes. Furthermore, important proinflammatory and profibrotic signaling pathways, including IL-13 and transforming growth factor-beta1, were activated. Increases in tissue fibrosis were also seen in the liver and kidneys of these mice. These changes occurred in association with pronounced elevations of lung adenosine concentrations and alterations in lung adenosine receptor levels, supporting the hypothesis that elevation of endogenous adenosine is a proinflammatory and profibrotic signal in this model.

Adenosine↗

PubMed1988

Clinical, functional and pathological correspondence in early stage idiopathic pulmonary fibrosis: evidence for small airway obstruction 1-2.

We describe the clinical, physiological and pathological features of 23 subjects with early stage idiopathic pulmonary fibrosis. Thirteen subjects who had no symptoms had been fortuitously recruited by a routine chest radiograph, whereas the 10 other subjects complained of dyspnea. Twenty-one subjects showed only light to moderate extent of abnormalities on the chest radiograph. Fourteen subjects had a reduced vital capacity whereas 16 and 17 showed a reduced pulmonary compliance and an increase in lung elastic recoil, respectively. Transfer factor was significantly reduced in 18 subjects. Evidence for significant airway obstruction, mainly located at the peripheral level, was demonstrated by a reduced specific lung conductance and upstream conductance in 13 subjects. Airway obstruction was not associated with smoking habits. Bronchial hyperresponsiveness was noted in 50% of the 18 subjects studied. Although fibrosis was mild to moderate in 15 instances, it was only focal, i.e. at least one zone of normal parenchyma in the lung specimen in 17 subjects. Peribronchial fibrosis was established in 8/11 satisfactory biopsy specimens. Significant correlations were observed between rales, the radiological score, some functional indices and the characteristics of fibrosis. We conclude that small airway obstruction documented by physiological and pathological means is frequent in early stage idiopathic pulmonary fibrosis.

Adult↗

PubMed1983

Protein metabolism during bleomycin-induced pulmonary fibrosis in rabbits. In vivo evidence for collagen accumulation because of increased synthesis and decreased degradation of the newly synthesized collagen.

In vivo rates of synthesis and degradation of collagen and noncollagen protein were measured in normal lung and during the first 14 days of bleomycin-induced pulmonary fibrosis in rabbits. Protein synthesis rates were obtained by measuring the incorporation of labeled proline into tissue proteins after the injection of 3H-proline with a large amount of unlabeled proline. Degradation rates were assessed by several independent methods, including measurement of hydroxy-3H-proline in the tissue-free pool as an index of the degradation of newly synthesized collagen. In normal lung, collagen was synthesized and degraded at a rate of 9.5 +/- 1.5%/day compared with a rate of 34.6 +/- 1.9%/day for noncollagen proteins. About one third of the newly synthesized collagen was degraded rapidly after its production. Six days after bleomycin administration the collagen synthesis rate almost doubled and the synthesis rate of noncollagen protein increased by about 35%. At this time the degradation rate of newly synthesized collagen had decreased by about 30%. From this study we conclude: (1) that the lung is an active tissue in terms of protein metabolism with rapid turnover for both collagen and noncollagen proteins, and (2) that an increased rate of synthesis and a decreased rate of degradation contribute to rapid accumulation of collagen in the early stages of pulmonary fibrosis.

Animals↗

PubMedDate not supplied

Interferon gamma-1b as therapy for idiopathic pulmonary fibrosis. An intrapatient analysis.

BACKGROUND: The only proven therapeutic option for idiopathic pulmonary fibrosis (IPF) is lung transplantation. It is biologically plausible that interferon gamma-1b (G-IFN) may halt or even reverse the disease process and therefore prove to be an effective medical therapy. We report our results using this medication in a cohort of patients with a wide range of severity of IPF. OBJECTIVES: To determine the impact of G-IFN therapy on the progression of disease in patients with IPF. METHODS: We performed a retrospective analysis of patients' pulmonary function tests (PFTs), specifically the forced vital capacity (FVC) and the single breath diffusing capacity for carbon dioxide (DLCO). Comparisons of these parameters prior to and after the implementation of therapy were made by generating regression slopes by least-squares equations. RESULTS: Twenty-two patients qualified for the analysis. For the FVC, comparison of pre- and post-therapy best-fit regression lines demonstrated a significant difference in favor of G-IFN (p<0.015). For the DLCO, a significant difference in favor of gamma interferon therapy was detected in the advanced group (p<0.03). Seventy percent of the patients showed either stabilization or regression of disease in both their FVCs and their DLCO. CONCLUSION: G-IFN appears to be an effective new therapy for patients with IPF. Salutary effects on the rate of change in the FVC and DLCO were most apparent in patients with advanced disease. With slowing or reversal in loss of lung function, G-IFN may improve longevity and may have utility as a bridge to lung transplantation in those patients who are appropriate candidates.

Cohort Studies↗

PubMed1988

[Post-actinic pulmonary fibrosis. Longitudinal study of 279 cases].

The incidence and extent of postactinic pulmonary fibrosis was investigated in relation to the different types of radiation therapy. For this purpose, 131 patients treated with fast electron (for breast cancer) and 148 patients treated with TCT (for breast cancer and cancer of other nature) observed in the period 1976-1987 were followed up (from 13 months to 7 years). The frequency of postactinic fibrosis was much less in the first group of patients than the second (6.61% vs 18.99%); further, the functional damage in these patients proved less and developed in a less unfavourable way.

Breast Neoplasms↗

PubMed1990

Pulmonary fibrosis as the initial manifestation of scleroderma.

We report a patient who developed pulmonary fibrosis before the appearance of cutaneous scleroderma. This unusual clinical presentation has been infrequently reported in the English literature. Recognition that pulmonary disease may occur before extensive skin changes in scleroderma is important to ensure proper management.

Biopsy↗

PubMed2006

COX-2-derived prostacyclin protects against bleomycin-induced pulmonary fibrosis.

Prostacyclin is one of a number of lipid mediators elaborated from the metabolism of arachidonic acid by the cyclooxygenase (COX) enzymes. This prostanoid is a potent inhibitor of platelet aggregation, and its production by endothelial cells and protective role in the vasculature are well established. In contrast, much less is known regarding the function of this prostanoid in other disease processes. We show here that COX-2-dependent production of prostacyclin plays an important role in the development of fibrotic lung disease, limiting both the development of fibrosis and the consequential alterations in lung mechanics. In stark contrast, loss of prostaglandin E(2) synthesis and signaling through the G(s)-coupled EP2 and EP4 receptors had no effect on the development of disease. These findings suggest that prostacyclin analogs will protect against bleomycin-induced pulmonary fibrosis in COX-2(-/-) mice. If such protection is observed, investigation of these agents as a novel therapeutic approach to pulmonary fibrosis in humans may be warranted.

Animals↗

PubMed2002

The effect of melatonin on bleomycin-induced pulmonary fibrosis in rats.

The present investigation was designed to determine the protective effects of melatonin against bleomycin (BLM)-induced oxidant lung toxicity. Wistar-albino rats were divided into four groups: saline (SA, 0.4 mL/animal), 1% ethanol-saline (ALC, 0.4 mL/animal), bleomycin sulphate (BLM, 10 mg/kg), or bleomycin sulphate + melatonin (BLM, 10 mg/kg + MLT, 10 mg/kg). All injections were given intraperitoneally (i.p.), twice weekly for a period of 3 wk (a total of seven injections for each group). Twenty-five days after BLM treatment, pulmonary fibrosis was assessed as hydroxyproline content in lung homogenates. Findings show that BLM-induced pulmonary injury resulted in increases in bronchoalveolar lavage fluid (BALF) biomarkers including total protein, lactate dehydrogenase (LDH), glutathione-peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT). Additionally, the levels of thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation (LPO), were also increased in BALF. Conversely, the level of glutathione (GSH) was reduced in BALF of BLM-treated rats. Melatonin provided protection against BLM-induced pulmonary fibrosis by suppressing oxidative stress. It abolished BLM-stimulated LPO and reversed the imbalance between oxidants and antioxidants in the BALFs. Results thus indicate that melatonin inhibits BLM-induced lung toxicity associated with oxidative damage.

Animals↗

PubMed2003

Impairments and prognostic factors for survival in patients with idiopathic pulmonary fibrosis.

The aim of the present study was to evaluate exercise limiting factors using cardiopulmonary exercise testing (CPET) in patients with idiopathic pulmonary fibrosis (IPF), and to investigate whether these parameters are related to survival after CPET. We evaluated 41 patients with IPF (mean 68.2 years, 27 male) who performed CPET. The exercise capacity in patients with IPF was limited more strongly by gas exchange and/or ventilatory impairments, compared with cardiac impairment. Using univariate analysis, the severity of exercise-induced hypoxemia (EIH) evaluated by deltaPaO2/deltaVO2 (PaO2-slope), oxygen uptake at maximum exercise, oxygen pulse at maximum exercise, ventilatory equivalent for carbon dioxide at maximum exercise and age were significantly related to the survival rate. Interestingly, the PaO2-slope was most closely correlated with the survival rate using multiple analysis with a stepwise evaluation. Nevertheless, PaO2 at rest and at maximum exercise were not factors influencing survival. In patients with IPF, CPET can simultaneously evaluate the ability of both the cardiovascular and respiratory systems, and should be available so that parameters can be derived to make the necessary prognostic estimations, with the most useful parameter being the degree of EIH as represented by the PaO2-slope.

Aged↗

PubMed1997

Lung interleukin-5 expression in murine bleomycin-induced pulmonary fibrosis.

Eosinophils are primary sources of fibrogenic cytokines in lung fibrosis, and interleukin (IL)-5 is important in their differentiation, proliferation, recruitment and activation. To investigate the potential role of this cytokine, lung IL-5 expression was examined in a murine model of bleomycin-induced pulmonary fibrosis. Analysis of lung RNA showed significant increases in lung IL-5 mRNA content between days 3 and 14 after induction of lung injury, which decreased toward control levels after day 21. In situ hybridization revealed essentially no detectable IL-5 mRNA expression before day 3, but showed elevated expression in mononuclear cells and eosinophils between days 3 and 14, localized within areas of active fibrosis. After 21 days, the intensity and number of IL-5-expressing cells significantly declined. Immunostaining with anti-IL-5 antibodies confirmed the predominant IL-5 expression by mononuclear cells and eosinophils in areas of active fibrosis. The kinetics of increase in the number of cells expressing significant IL-5 mRNA in lung sections paralleled that for IL-5 mRNA expression in whole-lung homogenates. These results demonstrate for the first time that IL-5 is upregulated in this murine model and suggest a novel role for this cytokine in pulmonary fibrosis via its ability to recruit and activate eosinophils.

Animals↗

PubMed1999

Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis.

The Fas ligand is predominantly expressed in activated T lymphocytes and is one of the major effector molecules of cytotoxic T lymphocytes and natural killer cells. Previously, we found excessive apoptosis of epithelial cells and infiltrating lymphocytes expressing Fas ligand mRNA in the lung tissue of bleomycin-induced pulmonary fibrosis in mice. Here we demonstrated that the administration of a soluble form of Fas antigen or anti-Fas ligand antibody prevented the development of this model and that lpr and gld mice were resistant against the induction of pneumopathy. These results suggest that the Fas-Fas ligand pathway plays an essential role in the development of pulmonary fibrosis and that preventing this pathway could have therapeutic value in lung injury and fibrosis.

Animals↗

PubMed2005

CCR5 expression and CC chemokine levels in idiopathic pulmonary fibrosis.

CC chemokines play an important role in the pathogenetic mechanisms of interstitial lung disease, while a downregulation of CC chemokine receptor (CCR)5 in the fibrotic stages of sarcoidosis has been observed. To evaluate the involvement of CC chemokines and the expression of CCR5 in idiopathic pulmonary fibrosis (IPF) and, more specifically, in usual interstitial pneumonia, 35 subjects were studied. CC chemokine ligand (CCL)2, CCL3 and CCL4 levels were measured in the bronchoalveolar lavage fluid (BALF) of 18 nonsmoker control subjects and 17 patients affected by IPF. CCR5 expression was evaluated in alveolar macrophages and lymphocytes. The BALF levels of all chemokines were significantly increased in IPF: median (range) CCL3 1.6 (1.0-11.1) versus 1.2 (0.0-3.8) pg x mL(-1); CCL4 6.2 (1.3-96.0) versus 3.4 (0.3-6.8) pg x mL(-1); and CCL2 60.1 (16.7-251.3) versus 4.6 (0.5-119.4) pg x mL(-1). CCL2 levels correlated negatively with the carbon monoxide diffusing capacity of the lung (D(L,CO)) and arterial oxygen tension. CCR5 expression was significantly reduced in lymphocytes from IPF compared with controls. The CC chemokines investigated are involved in the inflammatory mechanisms of idiopathic pulmonary fibrosis, and the results are in agreement with the hypothesis of a downregulation of the T-helper 1 immunological response in this disease.

Bronchoalveolar Lavage Fluid↗

PubMed2001

Selective induction of tissue inhibitor of metalloproteinase-1 in bleomycin-induced pulmonary fibrosis.

Tissue inhibitors of metalloproteinases (TIMPs) are multifunctional proteins that have the capacity to modify cellular activities and to modulate matrix turnover. We demonstrate that TIMP-1 messenger RNA (mRNA) and protein expression are selectively and markedly increased in a murine model of bleomycin-induced pulmonary fibrosis. Northern analysis showed that lung steady-state TIMP-1 mRNA levels increased 14-fold after bleomycin administration compared with control mice. Expression of the genes for TIMP-2, TIMP-3, and interstitial collagenase (matrix metalloproteinase-13) was unaltered in the injured lung. In situ hybridization demonstrated that TIMP-1 gene induction was spatially restricted to areas of lung injury. Metalloproteinase inhibitory activity of relative molecular mass of ~ 21 to 28 kD, corresponding to the molecular weights for TIMP-1 and TIMP-2, was identified in lung extracts of bleomycin-injured mice by reverse zymography. Western analysis demonstrated that TIMP-1 protein levels in bronchoalveolar lavage fluid (BALF) of bleomycin-treated mice increased 220- and 151-fold at Days 4 and 28, respectively, compared with control mice. TIMP-2 immunoreactive protein in the BALF increased 20- and 103-fold relative to controls at Days 4 and 28, respectively. These results demonstrate that TIMP-1 gene expression is selectively increased, and that the expression of TIMP-1 and TIMP-2 is differentially regulated in bleomycin-induced pulmonary fibrosis. The profound and durable increase in TIMP-1 and TIMP-2 proteins suggests an important regulatory role for these antiproteases in the inflammatory and fibrotic responses to bleomycin-induced lung injury.

Animals↗