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Results for “PULMONARY FIBROSIS”

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PubMedDate not supplied

Absence of pulmonary fibrosis in patients with psoriatic arthritis treated with weekly low-dose methotrexate.

OBJECTIVES: To analyse pulmonary toxicity in psoriatic arthritis patients treated with weekly low-dose methotrexate. METHODS: A transversal study was carried out to analyse the findings on chest x-rays and high resolution computed tomography, and the results of pulmonary function tests in 27 Caucasian psoriatic arthritis patients treated with weekly low-dose methotrexate. None of them had previous recognized interstitial lung disease. RESULTS: The median age of the patient cohort was 50 years (range 24-70 years) and the sex ratio was 20M/7F. 17 patients had previously used other disease-modifying antirheumatic drugs. The mean weekly dose of methotrexate was 8.46 mg (range 5-15 mg), the average treatment period was 52 months (range 3-240 months), and the median cumulative dose was 2241 mg (range 300-6520 mg). High resolution computed tomography failed to show alveolar or interstitial involvement in any patient. Diffusing lung capacity for carbon monoxide was mildly altered only in 2 cases. Pulmonary function tests did not show differences between patients with and without recognized risk factors for developing methotrexate-associated lung toxicity identified in rheumatoid arthritis patients (old age, diabetes, hypoalbuminemia, previous use of disease modifying antirheumatic drugs). CONCLUSION: In this cohort of 27 psoriatic arthritis patients methotrexate was not associated with pulmonary fibrosis evaluated by means of sensitive imaging findings and pulmonary function tests.

Adult↗

PubMed1997

Elevated serum tumor necrosis factor-alpha levels in patients with systemic sclerosis: association with pulmonary fibrosis.

OBJECTIVE: To determine whether serum tumor necrosis factor-alpha (TNF-alpha) levels are elevated, and whether they correlate with clinical features in patients with systemic sclerosis (SSc). METHODS: Serum samples from patients with limited cutaneous SSc (ISSc) (n = 51), diffuse cutaneous SSc (dSSc) (n = 30), and control subjects (n = 30) were examined by ELISA. RESULTS: Serum TNF-alpha levels were elevated in patients with ISSc and dSSc and correlated with the presence of pulmonary fibrosis and with the decreased vital capacity of the patients. CONCLUSION: Serum TNF-alpha may be one of the cytokines that contribute to the disease process, especially to pulmonary fibrosis in patients with SSc.

Adolescent↗

PubMed1999

Radioimmunotherapy using vascular targeted 213Bi: the role of tumor necrosis factor alpha in the development of pulmonary fibrosis.

A monoclonal antibody (201B) specific to murine thrombomodulin, covalently linked to cyclohexyl diethylenetriaminepentaacetic acid, successfully delivers chelated 213Bi, an alpha-particle emitter, (213Bi-201B) rapidly to lung vascular endothelium. When injected at doses of 1 MBq/mouse, 213Bi-201B destroyed most of the 100 colonies of EMT-6 mammary carcinomas growing as lung tumors of up to 2000 cells/colony. Some mice were cured of lung tumors, and others had extended life spans compared to untreated control animals but eventually succumbed to tumor recurrence. At injected doses of 4-6 MBq/mouse, 100% of lung tumor colonies were eliminated; however, 3-4 months later, these mice developed pulmonary fibrosis and died. The mechanisms leading to the fibrotic response in other pulmonary irradiation models strongly implicate tumor necrosis factor alpha (TNF-alpha), released from damaged tissues, as the pivotal inflammatory cytokine in a cascade of events that culminate in fibrosis. Attempts to prevent the development of pulmonary fibrosis, by using antibodies or soluble receptor (rhuTNFR:Fc) as inhibitors of TNF-alpha, were unsuccessful. Additionally, mice genetically deficient for TNF-alpha production developed pulmonary fibrosis following 213Bi-201B treatment. Interestingly, non-tumor-bearing BALB/c mice receiving rhuTNFR:Fc or mice genetically deficient in TNF-alpha production and treated with 213Bi-201B, had significantly reduced life spans compared to mice receiving no treatment or 213Bi-201B alone. We speculate that in normal mice, although TNF-alpha may induce an inflammatory response following alpha-particle radiation mediated tumor clearance and pulmonary damage, its effects in the post-tumor clearance time period may actually retard the development of fibrosis.

Animals↗

PubMed1995

Differences in correlation of mRNA gene expression in mice sensitive and resistant to radiation-induced pulmonary fibrosis.

Fibrosis, characterized by the accumulation of collagen, is a late result of thoracic irradiation. The purpose of this study was to determine if extracellular matrix protein and transforming growth factor beta mRNA expression are altered late in the course of pulmonary fibrosis after irradiation, and then to determine if these changes differ between two strains of mice which vary in their sensitivity to radiation. Radiation-sensitive (C57BL/6) and radiation-resistant (C3H/HeJ) mice were irradiated with a single dose of 5 or 12.5 Gy to the thorax. Total lung RNA was prepared and immobilized by Northern and slot blotting and hybridized with radiolabeled cDNA probes for collagens I, III and IV, fibronectin, and transforming growth factor beta 1 and beta 3. Autoradiographic data were quantified by video densitometry and results normalized to a control probe encoding for glyceraldehyde-3-phosphate dehydrogenase. Alterations in mRNA abundance were observed in the sensitive mice at all times, while levels in the resistant mice were unaffected until 26 weeks after irradiation. The relationship between extracellular matrix protein per se and increased mRNA abundance suggests that late matrix protein accumulation may be a function of gene expression. Differences in levels of transforming growth factor beta mRNA may lead to strain-dependent variation in fibrotic response and may also contribute to the radiation-induced component of pulmonary fibrosis.

Animals↗

PubMed2004

Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis.

OBJECTIVE: To clarify the clinical significance of surfactant protein-D (SP-D) and KL-6 in the diagnosis and monitoring of pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc), and to evaluate the differences between SP-D and KL-6. METHODS: Serum SP-D and KL-6 concentrations were determined by ELISA in 42 SSc patients. In a retrospective longitudinal study, 83 serum samples from 6 SSc patients were analyzed during a followup period of 0.6-6.3 years. RESULTS: SP-D and KL-6 concentrations at the first visit were higher in patients with SSc, especially those with PF, compared with healthy controls. Increased concentrations of SP-D were associated with decreased DLCO and decreased vital capacity in SSc patients more strongly than those of KL-6. The sensitivity and specificity for PF were 91% and 88% for SP-D and 39% and 100% for KL-6, respectively. In the longitudinal study, both SP-D and KL-6 concentrations were associated with activity of PF in patients with SSc. SP-D concentrations changed more rapidly than KL-6 concentrations, in parallel with the PF activity. CONCLUSION: SP-D was a more sensitive marker for PF than KL-6. By contrast, KL-6 showed higher specificity than SP-D. Combined use of these 2 serum markers would be more helpful to diagnose and monitor the PF activity in patients with SSc than single use of each marker.

Adult↗

PubMed2004

Comparison of the morphological and biochemical changes in normal human lung fibroblasts and fibroblasts derived from lungs of patients with idiopathic pulmonary fibrosis during FasL-induced apoptosis.

It is increasingly recognized that the morphological changes of apoptosis vary between cell types. This heterogeneity reflects the wide range of cellular proteins and enzymes involved in apoptotic pathways. Fibroblast apoptosis is crucial to the regression of scars and the restitution of healthy tissue during wound repair and may be aberrant in diseases such as idiopathic pulmonary fibrosis (IPF). The biochemical and morphological changes characterizing fibroblast apoptosis are unknown and may provide insights into the specific enzymatic mediators activated in these cells. This study aimed to examine the morphological changes of fibroblast apoptosis in both primary normal lung fibroblasts (normal-Fb) and fibroblasts obtained from patients with idiopathic pulmonary fibrosis (IPF-Fb) and to correlate these changes with conventional biochemical markers. Transmission electron microscopy (TEM) and video time-lapse microscopy demonstrated no difference in the duration of fibroblast apoptosis in response to FasL (6 +/- 0.3 h in normal-Fb and 6.4 +/- 0.2 h in IPF-Fb). However, IPF-Fb were more resistant to FasL-induced apoptosis compared with normal-Fb. Although the majority of morphological changes of normal-Fb and IPF-Fb were similar, the formation of filopodia and condensation of the cytoskeletal bundles in IPF-Fb, and more prominent vacuolation in normal-Fb, were the significant differences between these cell subtypes. Loss of the mitochondrial membrane potential occurred prior to caspase-3 activation, while phosphatidylserine expression, cytokeratin-18 cleavage, and DNA fragmentation commenced after caspase-3 activation. These observations not only suggest that specific enzymatic effectors may be preferentially activated during fibroblast apoptosis, but also provide potential insights into the pathogenesis of IPF.

Apoptosis↗

PubMed2002

Cyclosporin A upmodulates bleomycin-induced pulmonary fibrosis in BALB/c mice.

BACKGROUND: Intratracheal instillation of bleomycin (Bleo) into rodents serves as a model for human lung fibrosis. Various mouse strains respond differently to Bleo, and BALB/c mice are relatively resistant. OBJECTIVE: Since T lymphocytes have been shown to play a major role in this model, the effect of the immunomodulator cyclosporin A (CyA) on lung fibrosis was studied in Bleo-'resistant' BALB/c mice. METHODS: Pulmonary fibrosis was induced by a single intratracheal (IT) instillation of Bleo. One of the four following treatments was given to one of four groups of female BALB/c mice: (1) Bleo-CyA: IT Bleo and daily intraperitoneal (IP) injections of CyA 100 mg/day starting 1 day before IT instillation of Bleo; (2) Bleo-Sal: IT Bleo and IP injections of saline; (3) Sal-CyA: IT saline and IP CyA 100 mg/kg; (4) Sal-Sal: IT and IP saline. The animals were killed on day 14. Fibrosis was evaluated by analysis of hydroxyproline and by quantitative image analysis of the fibrosis fraction. Ex vivo IFN-gamma, IL-4, IL-13 and IL-5 secretion by peribronchial lymphatic tissue lymphocytes was measured. RESULTS: Pretreatment with CyA upmodulated Bleo-induced lung fibrosis in the Bleo-'resistant' BALB/c mice; hydroxyproline was higher in Bleo-CyA compared to Bleo-Sal animals and both hydroxyproline and fibrosis fraction measurements were higher in Bleo-CyA compared to Sal-Sal. Cytokine secretion by lymphocytes demonstrated increased IFN-gamma/IL-4 and IFN-gamma/IL-13 mean secretion ratios in the Bleo-CyA animals compared to the Bleo-Sal animals. CONCLUSIONS: These results indicate that CyA upmodulates Bleo-induced lung fibrosis in Bleo-'resistant' BALB/c mice by allowing the emergence of a Th1 inflammatory response.

Animals↗

PubMed2005

Pulmonary hypertension in patients with idiopathic pulmonary fibrosis.

STUDY OBJECTIVES: To determine the impact on survival and clinical correlates of pulmonary hypertension (PH) occurring in patients with idiopathic pulmonary fibrosis (IPF). DESIGN: Retrospective study. SETTING: Tertiary care, referral medical center. PATIENTS: Among 487 consecutive patients with IPF, we identified 136 patients who underwent transthoracic echocardiography within 3 months of their initial evaluation at our institution. Patients with left ventricular dysfunction, valvular heart disease, incomplete follow-up, and those in whom pulmonary artery pressures could not be assessed were excluded; the remaining 88 patients were included in this study. Correlations were performed between echocardiographic measures of PH and clinical variables including survival. MEASUREMENTS AND RESULTS: The mean (+/- SD) estimated systolic pulmonary artery pressure (SPAP) for the 88 patients was 48 +/- 16 mm Hg (range, 28 to 116 mm Hg). Among pulmonary function parameters, SPAP correlated best with diffusing capacity of the lung for carbon monoxide (D(LCO)), to which it was inversely related. For survival analysis, patients were stratified into three groups: < or = 35 mm Hg (14 patients), 36 to 50 mm Hg (47 patients), and > 50 mm Hg (27 patients). Using the Kaplan-Meier method, the median survival rates for these three groups were 4.8 years, 4.1 years, and 0.7 years, respectively. Those patients with SPAP > 50 mm Hg had significantly worse survival compared to other subgroups (p = 0.009). CONCLUSION: In patients with IPF, PH correlates inversely with D(LCO) and has a significant adverse impact on survival, particularly when SPAP is > 50 mm Hg.

Aged↗

PubMed1994

Experimental induction of pulmonary fibrosis in Syrian golden hamsters by N-methyl-N-nitrosourethane.

A range finding study for experimental induction of pulmonary fibrosis in which female Syrian golden hamsters received five subcutaneous injections of 0.8, 0.6, 0.4, 0.2 or 0 mg of N-methyl-N-nitrosourethane (MNUR) once a week or once per two weeks revealed most of the animals of the 0.8 mg group to die of acute pulmonary injury due to MNUR while typical interstitial pneumonia was induced in the 0.6 mg group. Based on these results hamsters were given five subcutaneous injections of 0.6 mg/animal of MNUR once per two weeks and then reared without any treatment for 12 weeks. Marked interstitial edema and intraalveolar infiltration of macrophages due to alveolar capillary damage were seen in treated animals at week 1, and secondary diffuse fibrotic thickening of the alveolar septa, as evidenced by increased type III collagen demonstrated immunohistochemically, was marked thereafter. The content of hydroxyproline in the lung was significantly increased from week 4. The present study indicates that lung injuries attributable to primary damage of alveolar capillaries progress to diffuse alveolar fibrosis in hamsters treated with MNUR, suggesting that this animal model might be of advantage for pathogenetic analysis of the relationship between pulmonary fibrosis and lung cancer development.

Animals↗

PubMed1980

Collagen biosynthesis in bleomycin-induced pulmonary fibrosis in hamsters.

Bleomycin results in pulmonary interstitial fibrosis characterized by accumulation of collagen. We studied the mechanisms of this accumulation in hamsters 4 to 24 days after intratracheal injection of 1 U of bleomycin. Lung collagen was significantly increased within 11 days. Collagen synthesis was increased 10-fold in explant cultures obtained 8 days after injection. Prolyl hydroxylase activity and the degradation of newly synthesized collagen were also increased proportionally to collagen synthesis. Total protein synthesis also increased but not as much as collagen synthesis. We conclude that the accumulation of collagen in the lung following proceeds from an increased rate of collagen synthesis that is maximal early after injection and persists for at least 24 days after exposure.

Animals↗

PubMed1987

Excessive helper T-cell function in patients with idiopathic pulmonary fibrosis: correlation with disease activity.

Peripheral blood T lymphocytes from patients with idiopathic pulmonary fibrosis and matched normal controls were examined for their helper function in an in vitro antibody synthesis assay. This assay measures the dose-related T-cell regulation of antibody production by B cells in the presence of pokeweed mitogen. Eight patients of 14 expressed significantly increased helper T-cell activity, three exhibited no change, and three had depressed helper T-cell function. All of the patients with excessive helper T-cell function had an active neutrophilic alveolitis as determined by bronchoalveolar lavage on the day of study. Five of the 14 patients studied were determined to have a low percentage of neutrophils (less than 10%) in their BAL fluid. None of these were found to express excessive helper T-cell function; in fact three of the five had depressed helper T-cell function. No correlation between steroid therapy or smoking history and the expression of excessive helper function was observed. None of the peripheral blood T-cells from IPF patients were actively producing IL-2 in vitro without further stimulation, providing evidence against constitutive production in vivo. T cells were also examined for their ability to produce lymphokines promoting fibroblast proliferation. Enhanced stimulation of fibroblast proliferation was shown to positively correlate with disease activity as determined by the degree of neutrophilic alveolitis (r = 0.68). The significant correlation between neutrophilic alveolitis and excessive helper T-cell function observed here suggests that altered systemic immunoregulation accompanies local inflammation. The further participation of patient T cells in promoting fibroblast proliferation may contribute to the development of fibrosis, or to the contrary may be an attempt to limit the fibrotic process.

Aged↗

PubMedDate not supplied

Lung cancer in patients with idiopathic pulmonary fibrosis: CT findings.

PURPOSE: The frequency of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) is higher than that of general population. To evaluate CT findings of lung cancer associated with IPF, we analyzed 32 patients with lung cancer associated with IPF. METHOD: We analyzed retrospectively 32 patients with histologically confirmed lung cancer out of 244 consecutive cases diagnosed as IPF by either CT and clinical findings (n = 220) or histologically (n = 24). The patients were 40-85 years old (mean 66 years, M/F = 31/1). Scanning techniques were conventional CT in 24 patients, high-resolution CT (HRCT) in 2 patients, and both conventional CT and HRCT in 6 patients. We analyzed the CT patterns, locations, and histologic types of lung cancer. RESULTS: The frequency of lung cancer in patients with IPF was 13.1% (32/244). In 17 of 32 patients, the CT findings of lung cancer were ill defined lesions mimicking air-space consolidation. Lung cancer was located mainly in the lower lobes (21/32) and peripheral portion (21/32). Histologically, squamous cell carcinoma was the most common type (18/32). CONCLUSION: Typical CT findings of lung cancer were ill defined consolidation-like masses at the peripheral portion where the most advanced fibrosis was located.

Adenocarcinoma↗

PubMed1985

Monocrotaline-induced pulmonary fibrosis in rats: amelioration by captopril and penicillamine.

The purpose of this study was to determine whether Captopril (an angiotensin converting enzyme inhibitor) or D-penicillamine (an inhibitor of collagen crosslinking) can ameliorate pulmonary fibrosis induced by the plant alkaloid monocrotaline. Rats were randomly assigned to one of six treatment groups: (1) control; (2) Captopril, 60 mg/kg/day, p.o.; (3) D-penicillamine, 30 mg/kg/day, p.o.; (4) monocrotaline, 2.4 mg/kg/day, p.o.; (5) monocrotaline plus Captopril, as above; (6) monocrotaline plus penicillamine, as above; and were killed after 6 weeks of continuous drug administration. Monocrotaline-treated rats exhibited several anatomic correlates of pulmonary hypertension, including cardiomegaly, right heart enlargement, and muscularization of the pulmonary arteries and arterioles. These monocrotaline reactions were accompanied by decreased lung activities of angiotensin converting enzyme (ACE) and plasminogen activator (PLA), indicative of endothelial dysfunction; and by increased lung hydroxyproline concentration, indicative of interstitial fibrosis. The presence of interstitial fibrosis was confirmed by electron microscopy. When given concomitantly with monocrotaline, both Captopril and penicillamine partially prevented the cardiomegaly, right heart enlargement, and vascular muscularization. Both agents also diminished the decreased lung PLA activity and increased hydroxyproline concentration observed in monocrotaline-treated animals. Neither modifying agent influenced the monocrotaline-induced decrease in lung ACE activity. Compared with control rats, the rats receiving Captopril alone exhibited decreased heart weight and increased serum ACE activity, and animals receiving penicillamine alone did not differ significantly from control animals for any of the endpoints studied. These data demonstrate that Captopril and penicillamine ameliorate monocrotaline-induced pulmonary fibrosis in rats. Penicillamine, known to inhibit radiation-induced lung injury, thus is shown to be effective in a second model of pulmonary fibrosis. Perhaps more importantly, the hydroxyproline data demonstrate that the ACE inhibitor Captropril exhibits antifibrotic activity in monocrotaline-treated rat lung.

Animals↗

PubMed2004

Vegetable, fruit, and cereal intake and risk of idiopathic pulmonary fibrosis in Japan.

AIMS: There has been little interest in the role of nutrition in prevention of idiopathic pulmonary fibrosis (IPF). We investigated the relationship between dietary intake of vegetables, fruit, cereals, antioxidants, and fiber and the risk of IPF in Japan. METHODS: Included were 104 cases aged 40 years or over who were within 2 years of the diagnosis in accordance with the most recent criteria. Controls aged 40 years or over comprised 56 hospitalized patients diagnosed as having acute bacterial pneumonia and 4 outpatients with common cold. Information on dietary factors was collected using a validated self-administered diet history questionnaire. Adjustment was made for age, sex, region, pack-years of smoking, employment status, occupational exposure, saturated fatty acid intake, and body mass index. RESULTS: Consumption of fruit in the second and third quartiles was associated with a statistically significant reduced risk of IPF. Although not statistically significant, a beneficial association between soluble fiber intake and IPF was found. No statistically significant dose-response relationship was observed between intake of green and yellow vegetables, other vegetables, cereals, beta-carotene, vitamins C and E, or insoluble fiber and the risk of IPF. CONCLUSION: Our findings suggest that fruit intake may confer protection against the development of IPF.

Adult↗

PubMed1996

[Two patients with idiopathic pulmonary fibrosis and monoclonal gammopathy].

A 67-year-old man and a 70-year-old man were admitted to our hospital because of dyspnea and dry coughing. Chest X-ray films showed bilateral reticulonodular shadows in the middle and lower lung fields. Specimens were obtained by open lung biopsies and the findings were compatible with those of usual interstitial pneumonia. Immunoelectrophoresis revealed monoclonal gammopathy in both patients. The levels of interleukin 6 in bronchoalveolar lavage fluid were high. In these two patients, idiopathic pulmonary fibrosis was associated with multiple myeloma and monoclonal gammopathy, and the levels of interleukin-6 in bronchoalveolar lavage fluid were high. These findings may help to elucidate the pathogenesis and development of idiopathic pulmonary fibrosis.

Aged↗

PubMed1996

[Relationship between the physiochemical properties of asbestos and pulmonary fibrosis].

The work presents a review of the literature on the effect of physiochemical properties on the intensity of pulmonary fibrosis. Exposure to asbestos fibres induces inflammatory processes which contribute to collagen deposition in the lung tissue. The toxicity of asbestos fibres depends on physiochemical properties of asbestos. Owing to their advantageous aerodynamics, straight needle-like amphiboles can penetrate much easier into the pulmonary tissue than curly serpentine fibres. With magnesium as its main cation, chrysotile has an unstable structure and tends towards the fragmentation into smaller particles. Therefore, its phagocytosis by macrophages and its clearance from the lung tissue are more effective than those of amphiboles. On the other hand, chrysotile undergoes longitudinal fragmentation into thin elementary particles, thus, it proliferates easier respirable fibres in the pulmonary tissue. Fibrosis induced by long fibres (L < 5 microns) is more extensive than that produced by short fibres (L < 5 microns) because of incomplete phagocytosis by macrophages which releases a stimulus to the synthesis of fibronectin and collagen.

Animals↗

PubMed2006

The distance-saturation product predicts mortality in idiopathic pulmonary fibrosis.

INTRODUCTION: The 6-min walk test (6MWT) has prognostic value in various pulmonary disorders including idiopathic pulmonary fibrosis (IPF). We determined the individual prognostic accuracy of distance walked and oxygen saturation during the 6MWT in patients with IPF. We defined a new composite index, the distance-saturation product (DSP), which is the product of distance walked and lowest oxygen saturation during the 6-min walk test. We compared the performance of the DSP to the individual 6MWT parameters in predicting mortality. METHODS: We evaluated pulmonary function tests, 6-min walk parameters and the DSP between survivors and non-survivors. The ability of each measure to discriminate outcomes was determined by receiver operator curves. RESULTS: 81 patients (48 survivors, 33 non-survivors) were included. Pulmonary function tests were similar and did not correlate with survival. Desaturation was greater (89.4% versus 83.7%, P<0.001) and distance walked was lower (406.9 versus 181.3m, P = 0.005) in non-survivors. The DSP was significantly lower among non-survivors (364.8 versus 153.5m%, P < 0.001) and predicted mortality more accurately than either individual 6MWT component (P = 0.035 versus desaturation, P=0.040 versus distance). A DSP <200 m% was associated with a seven-fold greater risk of 12-month mortality and an 18.0% shorter median survival compared with a DSP > 200 m% (P < 0.001). DISCUSSION: Each component of the 6-min walk independently predicted mortality in IPF with greater accuracy than spirometry. However, a composite of both parameters, the DSP, provides slightly greater accuracy and represents a novel measure for assessing survival in patients with IPF.

Exercise Test↗

PubMed2000

Alterations in large and small proteoglycans in bleomycin-induced pulmonary fibrosis in rats.

In bleomycin (BM)-induced lung fibrosis, alterations have been shown in the expression and deposition of small proteoglycans (PGs). Less, however, is known about changes in large PGs. We investigated changes in large aggregating (versican [VS]), basement membrane (heparan sulfate proteoglycan [HSPG]), and small (biglycan and fibromodulin) PGs during the development of BM-induced pulmonary fibrosis. BM (1.5 U) was instilled intratracheally into male Sprague-Dawley rats. Control rats received saline. At 7, 14, and 28 d after administration of BM, lungs were excised; one lung was fixed in formalin and 5-microm sections were cut and stained with hematoxylin-eosin. The other lung was used for PG extraction. PGs were extracted with guanidine and were separated through composite gel polyacrylamide gel electrophoresis (PAGE) (large PGs) and sodium dodecylsulfate-PAGE (small PGs). Gels were either stained or electrophoretically transferred and probed with antibodies to VS, HSPG, biglycan, and fibromodulin. Histologic samples showed prominent inflammation, with abundant proteinaceous material, most evident in the samples obtained at 7 and 14 d after administration of BM. By 28 d after BM, much of the inflammatory response had resolved, and heterogeneous distribution of fibrosis was observed. Immunoblots showed a relative abundance of VS at 7 and 14 d. Control lungs stained minimally for VS. Levels of HSPG, biglycan, and fibromodulin were increased maximally at 14 d after administration of BM. Immunocytochemistry showed intense immunostaining of biglycan and fibromodulin in the areas of injured lung tissue from rats 14 and 28 d after BM administration. Control lungs revealed minimal staining for small PGs. Our findings indicate that changes in all subclasses of PGs occur during the development of BM-induced pulmonary fibrosis.

Animals↗