Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0034069 (pulmonary fibrosis)
7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-beta (TGF-beta) is a cytokine that promotes extracellular matrix accumulation and inhibits matrix degradation. Although the natural course of sarcoidosis is usually favourable, granuloma healing in the lung may result in pulmonary fibrosis and respiratory impairment in some patients. In this study TGF-beta1 was evaluated in bronchoalveolar lavage (BAL) fluid and culture supernatants of alveolar macrophages (AM) from 73 patients with biopsy-proven sarcoidosis. Disease activity was defined when patients recently developed or increased symptoms (cough, dyspnoea, systemic symptoms) and/or demonstrated increasing opacities on chest radiography. Pulmonary function tests were performed in all patients including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and the diffusing capacity of the lung for carbon monoxide (DL,CO). Fourteen patients with idiopathic pulmonary fibrosis (IPF) and 14 healthy subjects were investigated as a control group. Immunohistochemistry was used to evaluate the cell distribution of TGF-beta1 on lung specimens. TGF-beta1 levels in BAL and in AM supernatants were not different between sarcoidosis and healthy subjects, whereas they were markedly increased in IPF. However, the TGF-beta1 level was significantly increased in BAL fluid but not in AM supernatants from sarcoidosis with altered lung function, compared with patients with normal lung function. The TGF-beta1 level in BAL was increased in active sarcoidosis but this increased level was mainly related to the higher level observed in patients with altered lung function. TGF-beta1 levels in BAL correlated significantly with the lymphocyte percentage. TGF-beta1 staining assessed by immunohistochemistry was intense in epithelioid histiocytes comprising non-necrotizing granuloma and in bronchiolar epithelial cells, in hyperplastic type II pneumocytes and occasionally in AM. This study supports the hypothesis that overproduction of transforming growth factor-beta1 is associated with functional impairment in patients with pulmonary sarcoidosis.
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PMID:Transforming growth factor-beta1 in sarcoidosis. 981 68

Deposition of types I and III collagen is a typical feature in the development of pulmonary fibrosis. We assessed the propeptides of these procollagens as prognostic markers in 18 patients with fibrosing alveolitis. We analyzed the amino-terminal propeptide of type III procollagen (PIIINP) and the carboxy-terminal propeptide of type I procollagen (PICP) from samples of bronchoalveolar lavage fluid (BALF) and serum, and also estimated their concentrations in epithelial lining fluid (ELF) by the urea method. The level of PIIINP in serum (p < 0.05), BALF (p < 0.05), and ELF (p < 0.05), and the levels of PICP in BALF (p < 0.001) and ELF (p < 0.001) but not in serum, were significantly increased in the patients with fibrosing alveolitis as compared with 17 controls who had been investigated for minor respiratory symptoms. In the BALF and ELF of patients with fibrosing alveolitis, PICP but not PIIINP had significant negative correlations with the specific diffusion coefficient for carbon monoxide (DLCO/ VA). The amino-terminal propeptide of type III procollagen and the carboxy-terminal propeptide of type I procollagen in BALF correlated significantly with one another. During the follow-up period of 6 yr, seven of the 18 patients with fibrosing alveolitis died of the disease, 3 others died of malignancy, and one patient died from an unknown cause. DLCO (p < 0.05) differed significantly between the surviving patients and those who died of fibrosing alveolitis, and detectable PIIINP in BALF predicted death from fibrosing alveolitis (p = 0.05). In conclusion, these results show that PIIINP in BALF, ELF, and serum, and PICP in BALF and ELF, are increased in patients with fibrosing alveolitis. A high level of PICP in BALF, and especially in ELF, suggests a chronic process and increased synthesis of type I collagen in the lungs, whereas PIIINP in BALF and ELF suggests active disease and a poor prognosis.
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PMID:Type III and type I procollagen markers in fibrosing alveolitis. 1005 Dec 56

Until recently, renal crisis was the most significant cause of morbidity and mortality in patients with scleroderma (SSc). Nowadays, following the introduction of angiotensin-converting enzyme inhibitors used in renovascular hypertension, pulmonary fibrosis and pulmonary hypertension have become the most common causes of death in SSc. Consequently, the early diagnosis and treatment of pulmonary fibrosis is essential to improve morbidity and mortality in SSc patients. The aim of this study was to investigate the effect of intravenous cyclophosphamide pulse therapy in patients with SSc and evidence of active alveolitis assessed on a high resolution computed tomographic (HRCT) scan, and to compare the effect of cyclophosphamide pulse therapy with oral therapy. Sixteen consecutive patients with SSc were allocated alternately to the two treatment groups. Eight patients were treated with monthly cyclophosphamide pulse therapy (750 mg/ m2) for 12 months; the other eight patients were treated with oral cyclophosphamide (2-2.5 mg/kg/day) for the same period. All patients received concurrently prednisone (10 mg/day). Pulmonary function tests and HRCT scans were performed before therapy and at 6 and 12 months. In the oral cyclophosphamide group, three patients with a grade I pattern showed regression of disease extent. In the other five patients (one with grade II and four with grade III) the pattern and extent of disease remained stable during the study. No statistical differences were found in forced expiratory volume in 1 s, forced vital capacity and total lung capacity during the study period. The diffusing capacity for carbon monoxide increased significantly between baseline and 12 months (p = 0.043). In the cyclophosphamide pulse therapy group, seven patients with a grade I pattern showed regression of disease extent at 6 months (p = 0.018) and 12 months (p = 0.012). One patient with grade III remained stable during the study. In both groups the regression of the extent of disease estimated on HRCT was due to a decrease in the ground glass appearance. The extent of the reticular appearance remained stable throughout the study. Our results indicate that cyclophosphamide pulse therapy is effective in suppressing active alveolitis (ground glass appearance). Although in this study it is not possible to compare pulse therapy with oral therapy because of the different pattern seen on HRCT between the two groups, it seems that oral therapy is also effective in suppressing active alveolitis. Neither regimen improved pulmonary involvement when the reticular appearance predominated over the ground glass appearance on HRCT. It is concluded that either pulse or oral cyclophosphamide therapy may improve the outcome of SSc patients.
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PMID:Intravenous cyclophosphamide pulse therapy for the treatment of lung disease associated with scleroderma. 1063 70

We have previously detected autoantibodies against topoisomerase II alpha (anti-topo II alpha) in sera from patients with idiopathic pulmonary fibrosis. To determine whether anti-topo II alpha is also present in systemic sclerosis (SSc) patients with pulmonary involvement, we screened sera from 92 patients and 34 healthy controls. Presence of anti-topo II alpha was investigated with respect to clinical and serological features, including the frequencies of HLA class I and II alleles. Anti-topo II alpha was detected in 20/92 (21.7%) patients. No association was found with either anti-topoisomerase I (Scl-70 or anti-topo I) or anti-centromere antibodies. However, anti-topo II alpha was associated with the presence of pulmonary hypertension (PHT) (as opposed to pulmonary fibrosis), and with a decrease of carbon monoxide diffusing capacity. Anti-topo II alpha was strongly associated with the presence of the class I antigen HLA-B35. No significant association was found with HLA class II antigens. HLA-B35 also turned out to be associated with the presence of PHT. These results indicate that in SSc patients, the presence of anti-topo II alpha is associated with PHT, and that the simultaneous presence of HLA-B35 seems to add to the risk of developing PHT.
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PMID:Anti-topoisomerase II alpha autoantibodies in systemic sclerosis-association with pulmonary hypertension and HLA-B35. 1097 22

This study investigated changes in lung function, hydroxyproline (OH-pro) content of lung tissue and histopathology in anesthetized, spontaneously breathing rats after a single, selective irradiation of the right hemithorax with a single dose of 20 Gy. The objective of this animal model was to examine as to whether non-invasive lung function measurements (LFM) could be used to analyze the magnitude of the irradiation-related pneumonitis and its long-term sequel occurring in the right lung in the presence of a normal left lung. Four months after irradiation, the OH-pro content in the irradiated right lung was determined and compared with the non-irradiated contralateral left lung, as well as lungs from non-irradiated sham controls. LFM revealed significantly depressed flow-volume curves and reduced quasistatic compliance, suggesting a marked diminution of elastic recoil of the lung. Total lung capacity (TLC) was significantly decreased, while the residual volume (RV) and functional residual capacity (FRC) remained almost unchanged. One of the most predominant dysfunction of the lung was a severe maldistribution of ventilation shown by the single-breath N(2)-wash-out test. Single-breath carbon monoxide diffusing capacity (Dlco) was significantly decreased. The content of OH-pro, a marker of increased collagen, was significantly increased in the irradiated right lung but was indistinguishable from sham controls in the non-irradiated left lung. Histopathological examinations provided evidence of both inflammatory and fibrotic lesions in the irradiated lobes, including bronchiolo-alveolar hyperplasia. No changes were observed in the non-irradiated left lung. In summary, effects observed in the irradiated right lung were largely consistent with effects described in other animal models of human interstitial pulmonary fibrosis. Non-invasive LFM were considered to be particularly sensitive to study the overall extent of changes, however, the interpretation of findings appears to be complicated by the lobar heterogeneity of tissue- and flow-related functional end points.
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PMID:Rat model of lung fibrosis: comparison of functional, biochemical, and histopathological changes 4 months after single irradiation of the right hemithorax. 1129 4

Idiopathic pulmonary fibrosis (IPF) is characterized by chronic inflammation that is associated with structural damage of the lung and fibrosis. Although the etiology of IPF is unknown, it is likely to involve an interaction between environmental and multiple genetic components. Animal models of pulmonary fibrosis have shown that proinflammatory mediators are critical at both the inflammatory and fibrotic stages of the disease. Genetic variants exist in genes encoding proinflammatory mediators, as well as in genes encoding their receptors, which makes these genes candidates for the pathogenesis of IPF. In the present study, we examined 12 biallelic polymorphisms in the genes for tumor necrosis factor (TNF)-alpha (+488[G/A], -238[G/A], -308[G/A]), lymphotoxin (LT)-alpha (+720[C/A], +365[C/G], and +249[A/G], determining haplotypes LT-alpha1 to LT-alpha4), tumor necrosis factor-receptor 2 (TNF-RII) (gb:M32315: 676[T/G], 1663[A/G], 1668[T/G], 1690[C/T]), and interleukin- (IL)-6 (promoter -174[G/C], intron 4[A/G]). We also examined the haplotypes determined by the three biallelic polymorphisms in each of the TNF-alpha and LT-alpha genes. As compared with a normal control population, the IPF group showed no significant deviations in genotype, allele, or haplotype frequencies. Surprisingly, in the IPF population, but not in the control population, an increased frequency of cocarriage of the IL-6 intron 4G and the TNF-RII 1690C alleles was observed, despite the location of the two genes on different chromosomes. Moreover, using impairment of carbon monoxide transfer (DL(CO)) adjusted for duration of dyspnea as a marker of rapidity of disease progression, we found that the IL-6 intron 4GG genotype was the only genotype independently associated with lower DL(CO) levels. These findings, if independently confirmed, will be the first to suggest that disease progression in IPF may be linked to a particular genetic marker or to functional polymorphisms in other genes near that marker.
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PMID:Analysis of tumor necrosis factor-alpha, lymphotoxin-alpha, tumor necrosis factor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis. 1137 14

Heme oxygenase-1 (HO-1) is an inducible heat shock protein that regulates heme metabolism to form bilirubin, ferritin and carbon monoxide. Based on recent evidence that HO-1 is involved in the resolution of inflammation by modulating apoptotic cell death or cytokine expression, the present study examined whether overexpression of exogenous HO-1 gene transfer provides a therapeutic effect on a murine model of acute lung injury caused by the type A influenza virus. We demonstrate herein that the transfer of HO-1 cDNA resulted in (1) suppression of both pathological changes and intrapulmonary hemorrhage; (2) enhanced survival of animals; and (3) a decrease of inflammatory cells in the lung. TUNEL analysis revealed that HO-1 gene transfer reduced the number of respiratory epithelial cells with DNA damage, and caspase assay suggested that HO-1 suppressed lung injury via a caspase-8-mediated pathway. These findings suggest the feasibility of HO-1 gene transfer to treat lung injury induced by a pathogen commonly seen in the clinical setting. Since oxidative stress and lung injury are involved in many lung disorders, such as pneumonia induced by a variety of microorganisms and pulmonary fibrosis, HO-1 may be useful for wider clinical applications in gene therapy targeting lung disorders including acute pneumonia and pulmonary fibrosis.
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PMID:Adenovirus-mediated transfer of heme oxygenase-1 cDNA attenuates severe lung injury induced by the influenza virus in mice. 1159 63

Pulmonary fibrosis causes significant morbidity and mortality in patients with scleroderma. Lung inflammation identifies patients at greater risk for decline in forced vital capacity and diffusing capacity for carbon monoxide. Factors that are increased in patients with scleroderma with lung fibrosis include connective tissue growth factor, KL-6, pulmonary surfactant-D, tissue inhibitor of metalloproteinase 2, monocyte chemotactic protein-1, macrophage inhibitory protein-1 alpha, soluble interleukin-6 receptors, anti-endothelial cell antibodies, and anti-DNA topoisomerase I antibodies. Potential mechanisms of lung damage in scleroderma include increased production of profibrotic type 2 cytokines and abnormal signaling by thrombin of tenascin-C production by lung fibroblasts, with protein kinase C epsilon as an intermediate in the signaling pathway. Treatment of scleroderma lung disease with cyclophosphamide may have a beneficial effect on pulmonary function and survival. Lung transplantation provides a therapeutic option for patients with scleroderma with end-stage lung disease.
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PMID:Evaluation and management of pulmonary fibrosis in scleroderma. 1189 Aug 75

In scleroderma patients, isolated pulmonary hypertension (PHT) has been associated with selected HLA haplotypes, severe impairment of the diffusing capacity for carbon monoxide and the diagnosis of CREST. Most patients with CREST have a late-age onset of the disease, corresponding to the perimenopausal or postmenopausal period. We conducted a retrospective cohort study to determine the role of post-menopause and of the other known clinical and biological markers in the development of isolated pulmonary hypertension in Italian patients with systemic sclerosis. 189 female patients with scleroderma who had no ecographic signs of pulmonary hypertension (PHT) and radiographic signs of lung fibrosis at the first visit and did not develop significant pulmonary fibrosis during the observation time were included. Sixty-three out of 189 patients (33.3%) presented isolated pulmonary hypertension. A severe impairment of diffusing capacity for carbon monoxide at admission was found to be an early predictive element for its development. An increased risk was associated with postmenopausal condition (RR = 5.2, p = 0.000), CREST syndrome (RR = 2.8, p = 0.001) and haplotype HLA-B35 (RR = 2.8; p = 0.002). A significant positive interaction between postmenopausal condition and either HLA-B35 (RR = 15.2; p = 0.000) or the diagnosis of CREST (RR = 14.1; p = 0.000) was found. Postmenopausal condition alone or in combination with HLA-B35 and CREST syndrome is the main risk-factor for developing primary pulmonary hypertension in scleroderma patients. This suggests that hormonal replacement therapy could play a role in preventing isolated PHT in patients with systemic sclerosis.
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PMID:Post-menopause is the main risk factor for developing isolated pulmonary hypertension in systemic sclerosis. 1211 78

Patients with end-stage renal disease treated by hemodialysis with bioincompatible membranes are exposed during the dialysis period to acute effects on lung microcirculation, which may result in pulmonary fibrosis and diffusion defects in long-standing dialysis. To investigate the occurrence of these possible chronic pulmonary alterations, we determined lung function in patients with chronic renal failure not undergoing hemodialysis and in patients who had been receiving regular hemodialysis both for short and long periods of time. Forty-three patients divided into three groups were studied: 17 patients before dialysis with a mean (SD) creatinine clearance of 14.1 (6.8) ml/min 11.73 m2, 10 patients receiving regular hemodialysis for a period of less than 12 months (mean 6.4 +/- 3.5 months), and 16 patients receiving regular hemodialysis for more than 5 years (mean 8.3 +/- 3.6 years). First-use bioincompatible cellulosic dialysis membranes were used in all the cases. The following parameters were recorded: forced vital capacity (FVC), forced expiratory volume in 1s (FEV1), total lung capacity (TLC), residual volume (RV), carbon monoxide transfer factor (TLCO), accessible lung volume (VA), carbon monoxide transfer factor/accessible lung volume (KCO- that is, TLCO/VA), and arterial blood gases. Patients receiving regular hemodialysis for more than 5 years showed significantly lower values of TLCO and KCO than patients before dialysis and patients receiving regular hemodialysis for less than 12 months. Seventy-five percent of patients on long-term hemodialysis had markedly reduced TLCO or KCO values (below 80% of the reference value) as compared with 17% of patients before dialysis and 10% of patients dialyzed for less than 12 months (P < 0.001). Differences among groups for the remaining parameters were not observed. In conclusion, patients undergoing long-term regular hemodialysis with a bioincompatible membrane showed a selective reduction in pulmonary diffusing capacity possibly due to chronic pulmonary fibrosis.
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PMID:Pulmonary diffusing capacity in chronic dialysis patients. 1219 31


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