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At least 163 records · Page 9Linked to original sources
PubMed2003

Release of biologically active TGF-beta1 by alveolar epithelial cells results in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal fibrotic lung disease. Transforming growth factor (TGF)-beta1 is present in a biologically active conformation in the epithelial cells lining lesions with advanced IPF. To determine the role of aberrant expression of biologically active TGF-beta1 by alveolar epithelial cells (AECs), the AECs of explanted normal rat lungs were transfected with the TGF-beta1 gene using the retrovirus pMX-L-s223,225-TGF-beta1. In situ hybridization using a digoxigenin-labeled cDNA of the puromycin resistance gene contained in the pMX demonstrated that pMX-L-s233,225-TGF-beta1 was selectively transfected into AECs of the explants. Conditioned media overlying explants obtained 7 days after being treated with pMX-L-s223,225-TGF-beta1 contained 14.5 +/- 3.15 pg/ml of active TGF-beta1. With the use of Masson's trichrome staining of explant sections obtained 14 days after transfection, there were lesions similar to those in IPF, characterized by type II AEC hyperplasia, interstitial thickening, extensive increase in interstitial and subepithelial collagen, an increase in the number of fibroblasts, and areas resembling fibroblast buds. Collagens I, III, IV, and V and fibronectin were increased in explants treated with pMX-L-s223,225-TGF-beta1. The findings in the current study suggest that IPF may be a disorder of epithelial cells and not inflammatory cells.

Animals↗
PubMed2002

Conserved CDR 3 region of T cell receptor BV gene in lymphocytes from bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an inflammatory lung disease characterized by the accumulation of inflammatory cells and deposition of collagen, resulting in lung remodelling. High numbers of T cells are present in bronchoalveolar lavage fluid (BALF) of IPF patients, although the characteristics of these cells are yet to be determined. To elucidate the pathogenic mechanisms of IPF, we analysed the T cell receptor (TCR) of BALF lymphocytes in three patients with IPF and three healthy subjects as control. TCR repertoire of BALF lymphocytes and T cell clonality were examined by family PCR and Southern blot analysis, and single-strand conformation polymorphism (SSCP), respectively. We observed that the TCR repertoire in the lung was heterogeneous, both in the control subjects and three patients with IPF. SSCP analysis demonstrated an increase in the number of accumulated T cell clones in BALF of two of the three patients, but not in the healthy subject. Furthermore, junctional sequence analysis showed the presence of conserved amino acid motifs (ETGRSG, LAxG, QGQ, GxQP, GRxG, VAR, PGT, GTI, GGT, TGR, LxLxQ, SGQ) in the TCR-CDR 3 region of BAL lymphocytes in patients with IPF, whereas only two amino acid motifs (VTTG, GGE) were found in the control. Our findings suggest that T cells in BALF of patients with IPF expand oligoclonally in the lung, suggesting antigen stimulation of these cells.

Adult↗
PubMed2005

Major histocompatibility complex and alveolar epithelial apoptosis in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblast expansion, and tissue remodeling. It is considered a multifactorial disease but the possible involved genes are largely unknown. Interestingly, studies regarding the possible role of major histocompatibility complex (MHC) are scanty and show contradictory results. In this study, we evaluated the polymorphisms of the MHC, locus HLA-B, -DRB1, and -DQB1 in a cohort of 75 IPF patients and 95 controls by using PCR and hybridization with sequence-specific oligonucleotide probes. In addition, we examined the effect of bronchoalveolar lavage (BAL) from IPF patients with different MHC haplotypes on alveolar epithelial growth rate by WST-1 cell viability assay and on epithelial apoptosis by flow cytometry and by cleaved caspase-3 in cell homogenates. Three haplotypes were significantly increased in IPF: (1) HLA-B*15-DRB1*0101-DQB1*0501 (OR=10.72, CI=1.43-459.6; pC=0.011); (2) HLA-B*52-DRB1*1402-DQB1*0301 (OR=4.42, CI=1.21-24.1; pC=0.024); and (3) HLA-B*35-DRB1*0407-DQB1*0302 (OR=4.73, CI=1.53-19.5; pC=0.005). BAL from patients with the later haplotype significantly reduced epithelial growth rate ( approximately 30%) and caused epithelial cell apoptosis assayed by cleaved caspase-3 (351.7+/-16.5 pg/10(6) cells versus 264+/-24 from controls, and 274+/-36.8 and 256.5+/-10.7 from the other haplotypes; P<0.05), and DNA breaks labeling by flow cytometry (23.7+/-6.9% versus 3.1+/-0.7% from controls, and 6.5+/-0.6% and 7.6+/-1.2% from the other two haplotypes; P<0.01). These findings suggest that some MHC polymorphisms confer susceptibility to IPF, which might be related with the induction of epithelial cell apoptosis, a critical process in the development of the disease.

Adult↗
PubMed1983

Effect of intermittent high dose parenteral corticosteroids on the alveolitis of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder in which chronic accumulation of neutrophils within the alveolar structures occurs. These cells with their large stores of preformed mediators likely play a major role in subsequent lung derangement. To evaluate the adjunctive use of intermittent high dose "pulse" corticosteroid therapy as a means of inhibiting neutrophil accumulation in the IPF lung, 5 patients were treated in a single blind random fashion with "high dose" corticosteroids (2 g methylprednisolone given intravenously once a week plus 0.25 mg/kg prednisone given orally daily) and 8 patients were treated with "low dose" corticosteroids only (0.25 mg/kg prednisone given orally daily). All patients had biopsy-proved disease in midcourse, and the 2 groups were matched for clinical and physiologic criteria. To evaluate the effect of these therapies on the quantity of neutrophils in the lungs of these patients, both groups underwent bronchoalveolar lavage and 67Ga scanning at the beginning and end of the 6-month study period; both methods gave an estimate of the intensity of the neutrophil alveolitis in these patients. Low dose corticosteroids had little effect on neutrophil accumulation (% neutrophils in lavage, - 5 +/- 8% change from baseline; 67Ga uptake, + 27 +/- 14% change from baseline), whereas high dose corticosteroids significantly reduced neutrophil accumulation (% neutrophils in lavage, - 46 +/- 8% change from baseline, p less than 0.02 compared with that in the low dose group; 67 Ga uptake, - 23 +/- 11% change from baseline, p less than 0.05 compared with that in the low dose group). In addition, 2 patients in the high dose group were reevaluated 6 months after cessation of the intermittent high dose pulse corticosteroids. Both had marked increases in lavage neutrophils compared with when they were receiving the high dose therapy (10 to 22% and 18 to 52%, respectively). These findings suggest that massive doses of intermittent intravenously administered corticosteroids may help to suppress the neutrophil component of the alveolitis of IPF.

Administration, Oral↗
PubMed1996

Idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), or cryptogenic fibrosing alveolitis as it is known in the United Kingdom and Europe, is perhaps one of the most complex and frustrating pulmonary disorders. The cause of this illness is unknown. Treatment often founders in a mire of discontent, dissatisfaction, and failure. In fact, the philosophic homily "If you do not know where you are going, then any road will take you there" in a curious way sums up the trials and tribulations of treating idiopathic interstitial fibrosis.

Adult↗
PubMed2000

Interferon-gamma 1b: impact of new indications (idiopathic pulmonary fibrosis).

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease with inadequate response to conventional treatment with corticosteroids and/or immunosuppressive agents in most patients. Interferon-gamma (IFN-gamma), an antifibrotic agent, has been proposed as a novel therapeutic approach. Several investigators have shown a relative decrease in systemic and pulmonary IFN-gamma activity in patients with IPF. Experimental evidence from animal and human studies also suggests that IFN-gamma administration may ameliorate lung fibrosis. Clinical experience is, however, limited to a single clinical trial that showed objective functional improvement in a small number of patients treated with IFN-gamma and low-dose corticosteroids. Further research is needed to characterise the efficacy, safety and optimum route of administration of this agent before it can be recommended for use in routine clinical practice.

Humans↗
PubMed2004

Enhanced expression of interleukin-18 and its receptor in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is a major interstitial lung disease (ILD). Recently, we established a new mouse model for ILD in which daily administration of interleukin (IL)-18 with IL-2 induces lethal lung injury, suggesting that IL-18 is involved in the pathogenesis of ILD. Here, utilizing immunohistochemistry, we have analyzed IL-18 and IL-18 receptor (IL-18R) alpha expression in the lungs of 18 patients with IPF/UIP and 13 control subjects by using monoclonal anti-IL-18 antibodies and a new monoclonal antibody for IL-18Ralpha (H44). IL-18 was expressed in bronchoalveolar epithelium, alveolar macrophages, and the endothelium of small vessels in control subjects, and was abundantly expressed in the majority of pulmonary cells in patients with IPF. IL-18Ralpha was expressed in bronchoalveolar epithelium and alveolar macrophages in control subjects, and was strongly expressed in interstitial cells in patients with IPF, especially in the fibroblastic foci (FF). Interestingly, IL-18Ralpha expression was only weakly observed in areas showing established fibrosis. Semiquantitative analysis revealed that the histologic FF score was significantly correlated with the IL-18Ralpha expression level in FF lesions. Moreover, IL-18 levels in the serum and bronchoalveolar lavage fluid of patients with IPF were significantly higher than those in control subjects. Our findings suggest IL-18 and IL-18R are involved in the pathogenesis of IPF/UIP.

Adult↗
PubMed1983

Pulmonary hemodynamics in idiopathic pulmonary fibrosis and other interstitial pulmonary diseases.

65 patients with interstitial lung diseases were subdivided into two groups: idiopathic pulmonary fibrosis (IPF) and other interstitial pulmonary diseases (OIP) according to histopathological, immunological and follow-up findings. Arterial blood gases and pulmonary hemodynamics at rest and during steady-state exercise were compared in these two groups (IPF = 31 patients, OIP = 34 patients). The resting PaO2 was significantly lower in the IPF group (p less than 0.001) and regularly worsened during exercise in this group (from 69.6 +/- 11.6 to 56.0 +/- 9.4 mm Hg, p less than 0.001) whereas it did not vary significantly in the OIP group (from 79.2 +/- 13.1 to 75.3 +/- 14.1 mm Hg, NS). Pulmonary artery mean pressure (PPA) was higher in the IPF group (p less than 0.001) as were all indices of pulmonary vascular resistance (PVR). During exercise, PPA markedly increased in the IPF group (from 21.7 +/- 7.8 to 45.3 +/- 16.2 mm Hg) but modestly in the OIP group (from 15.5 +/- 3.7 to 28.3 +/- 9.8 mm Hg). The best relationships were found between PPA, PVR and PaO2, which suggests that pulmonary arterial hypertension in these diseases is not only due to anatomical factors but also to alveolar and arterial hypoxia. Arterial blood gases and pulmonary hemodynamics at rest and during exercise may be of interest for the discrimination of 'true' interstitial fibrosis (IPF) from other interstitial lung diseases (OIP).

Adolescent↗
PubMed2006

Increased uptake of 111In-octreotide in idiopathic pulmonary fibrosis.

UNLABELLED: Idiopathic pulmonary fibrosis (IPF) is characterized by an uncontrolled accumulation and activation of lung fibroblasts. A modulation of fibroblast activation has been observed in various systems with octreotide, a synthetic somatostatin analog with strong affinity for the somatostatin receptor subtype 2 (sst2). One aim of our study was to evaluate the expression of somatostatin receptors in the lungs of patients with IPF. A second aim was to evaluate the relationship between 111In-octreotide uptake and the effect of pulmonary fibrosis as assessed by lung function tests and parameters and by radiologic findings. METHODS: We investigated 11 patients with IPF, 6 patients with pulmonary fibrosis associated with systemic sclerosis (SSc), and 19 patients with disease not of the lung (control patients). The expression of somatostatin receptors was evaluated in vivo using 111In-octreotide scintigraphy. We evaluated the relationship between 111In-octreotide uptake and the activity of pulmonary fibrosis as assessed by lung function tests, bronchoalveolar lavage (BAL) cellularity, and high-resolution CT (HRCT) of the chest. Planar images and thoracic SPECT (24 h) were performed after injection of 222 MBq of 111In-octreotide. Lung uptake was quantified using the lung-to-background ratio (L/B). In addition, the expression of sst2 was evaluated in vitro, in frozen lung-tissue samples using autoradiography, and in human cultures of lung fibroblasts using a ligand-binding assay. RESULTS: Compared with lung uptake in control patients (median L/B, 1.25; range, 1.14-1.49), lung uptake was increased in all 11 IPF patients (median L/B, 2.63; range, 1.59-3.13; P < 0.001) and in 4 of 6 SSc patients (median L/B, 1.68; range, 1.42-2.16). The L/B was lower in SSc patients than in IPF patients (P = 0.011). Increased uptake correlated with the alteration of lung function (carbon monoxide diffusing capacity [rho = -0.655; P = 0.038], diffusing capacity for carbon monoxide and alveolar volume ratio [rho = -0.627; P = 0.047], vital capacity [rho = -0.609; P = 0.054], and total lung capacity [rho = -0.598; P = 0.058]) and with the intensity of alveolitis (total BAL cellularity [rho = 0.756; P = 0.045], neutrophil counts [rho = 0.738; P = 0.05]), and HRCT fibrosis score (rho = 0.673; P = 0.007). Autoradiography suggested that vascular structures were a prominent binding site. Lung fibroblasts expressed somatostatin receptors in vitro as measured by binding assay. CONCLUSION: Our preliminary results identified an increased expression of sst2 in (mainly idiopathic) pulmonary fibrosis. Lung uptake correlates with the alteration of lung function and with the intensity of alveolitis.

Adult↗
PubMed1999

[A pathological study on pulmonary fibrosis caused by chronic obstructive pulmonary disease].

OBJECTIVE: To estimate the morphologic characteristics of chronic obstructive pulmonary disease (COPD) induced pulmonary fibrosis. METHODS: 41 autopsy cases of COPD were chosen as the study group and other 10 autopsy cases died from non-respiratory diseases as control group. Histochemical stain and image quantitative analysis were used to identify the type of collagen. RESULTS: In 36 cases (88%) of study group, fibrosis proliferation could be seen in peri-bronchial area, especially in the bronchi under grade VI. Respiratory bronchiole and alveoli were also involved in 11 cases. The main component of collagen in fibrosis area was identified as type III collagen by sirius red stain, reticular fiber could also be seen by Gomori stain. The type III collagen in alveoli distributed interruptedly. Image quantitative analysis showed: the integral optical density (A) of type III collagen was much higher than that of type I collagen in peri-bronchial area (P < 0.01); Both A of type III and type I collagen in peri-bronchial area were higher than that in alveolar area (P < 0.01). Mucous purulent plugs, interrupted elastic fibers in bronchial wall and chronic inflammation accompanied with lymphocytes infiltration in fibrosis area could also be seen. CONCLUSIONS: COPD induced pulmonary fibrosis distributed mainly in peri-bronchial area, especially in the bronchi under grade VI. The main component of proliferative collagen was type III collagen. The genesis of pulmonary fibrosis might be associated with chronic inflammation accompanied with lymphocytes. Peri-bronchial fibrosis, interrupt of elastic fibers in bronchial wall caused the bronchial lumen narrowed or collapsed making both airway obstruction and ventilation insufficiency deteriorated.

Aged↗
PubMed2005

A pilot study of aerosolized N-acetylcysteine for idiopathic pulmonary fibrosis.

OBJECTIVE: Idiopathic pulmonary fibrosis poses a significant therapeutic challenge because of its progressive course. Since oxidative stress plays an important role in the pathogenesis of idiopathic pulmonary fibrosis, an open, randomized trial of long-term inhalation therapy with the antioxidant, N-acetylcysteine was conducted. METHODOLOGY: A total of 30 patients with idiopathic pulmonary fibrosis were randomly assigned to one of the following inhalation therapies: N-acetylcysteine (352 mg per day) or bromhexine hydrochloride (4 mg per day) as the control. Efficacy was assessed by analysing changes occurring from baseline to 12 months in pulmonary function, the 6-min walking test, high-resolution CT, health-related quality of life, and serum KL-6-values. RESULTS: Four patients (n=2 in each group) died within 12 months due to progression of idiopathic pulmonary fibrosis. A total of 22 patients (control, n=12; N-acetylcysteine, n=10) completed the study. At 12 months there were significant differences between the N-acetylcysteine and control groups in terms of mean changes in lowest SaO(2) during the 6-min walking test (-0.3+/- 2.1% vs -6.8+/-1.8%, P<0.05), serum KL--6 (-482+/-220 U/mL vs 176+/-204 U/mL, P<0.05), and the ground-glass score on high-resolution CT (-1.3+/-1.6 vs 6.7+/-1.5, P<0.01). No significant differences were observed in pulmonary function, 6-min walking distance or quality of life. CONCLUSIONS: These data suggest that although long-term aerosolized N-acetylcysteine administration did not influence pulmonary function or quality of life, it may delay disease progression as evidenced by exercise desaturation, high-resolution CT, and serum KL-6.

Acetylcysteine↗
PubMed2006

Incidence and prevalence of idiopathic pulmonary fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis is a chronic interstitial lung disease of unknown etiology; its epidemiology in the United States has not been well characterized. OBJECTIVE: To estimate the annual incidence and prevalence of idiopathic pulmonary fibrosis in the United States. METHODS: Retrospective cohort design utilizing a large health care claims database spanning the period January 1996 through December 2000. MEASUREMENTS AND MAIN RESULTS: Persons with idiopathic pulmonary fibrosis were identified based on diagnosis and procedure codes. Using broad case-finding criteria, prevalence was estimated to range from 4.0 per 100,000 persons aged 18 to 34 yr to 227.2 per 100,000 among those 75 yr or older; annual incidence was estimated to range from 1.2 to 76.4 per 100,000. Using narrow case-finding criteria, prevalence ranged from 0.8 to 64.7 per 100,000 persons; comparable figures for incidence were 0.4 to 27.1 per 100,000 persons. Extrapolating these rates to the overall United States' population, prevalence was estimated to be 42.7 per 100,000 (incidence, 16.3 per 100,000) using broad criteria; with narrow criteria, prevalence was estimated to be 14.0 per 100,000 (incidence, 6.8 per 100,000). CONCLUSIONS: Our results suggest that idiopathic pulmonary fibrosis is probably more common in the United States than previously reported.

Adult↗
PubMed2001

p53 gene alteration in atypical epithelial lesions and carcinoma in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is well known to be associated with lung cancer. Several atypical epithelial lesions are frequently observed in the fibrotic area in IPF patients, and they have been suspected to be related to lung carcinogenesis. Several studies have suggested that p53 protein accumulation and mutation occur in the early pathogenesis of squamous cell carcinoma of the lung, suggesting some abnormality of the p53 tumor-suppressor gene in interstitial lung diseases. To examine the cause of the high frequency of lung cancer in IPF, we examined the p53 changes in atypical epithelial lesions and carcinoma in patients with IPF by immunohistochemistry and mutational analysis. We examined 19 lung cancer patients with IPF who underwent surgical resection for lung cancer in our institute. Paraffin-embedded tissues were treated by microwave and stained with an anti-p53 antibody (RSP53) by the avidin-biotin-peroxidase complex method. Mutations in exons 5 through 8 of the p53 gene were also examined by polymerase chain reaction mediated single-strand conformation polymorphism (polymerase chain reaction-single-strand conformation polymorphism) analysis and DNA sequencing. p53 protein was immunohistochemically detected in 13 (62%) of 21 squamous cell carcinomas, 3 (60%) of 5 squamous metaplasia with atypia, 16 (54%) of 30 squamous metaplasia, and 1 (4%) of 26 other hyperplastic lesions. p53 mutation was detected in 12 (57%) of 21 squamous cell carcinomas, 2 (40%) of 5 squamous metaplasia with atypia, 7 (23%) of 30 squamous metaplasia, and 0 (0%) of 26 other hyperplastic lesions. In conclusion, there are frequent p53 gene alterations in squamous metaplasia, which is distributed in the peripheral zone of the fibrotic area in patients with IPF. The present findings might provide a clue to the molecular mechanisms underlying the high incidence of lung cancer, especially peripheral-type squamous cell carcinoma in IPF patients, and suggest that p53 gene alterations play an important role in the early stages of lung carcinogenesis in patients with IPF.

Aged↗
PubMed2004

Feitai attenuates bleomycin-induced pulmonary fibrosis in rats.

Pulmonary fibrosis is a common consequence of numerous pulmonary diseases. The current therapeutic approaches for this condition are unsatisfactory. Feitai, a composite formula consisting of several herbs, is used in China as a folk remedy for treating patients with pulmonary tuberculosis. In this study, we extensively investigate the effects and mechanisms of Feitai on bleomycin (BLM)-induced pulmonary fibrosis in rats. One hundred and twenty male Sprague-Dawley rats were randomly divided into four groups, referred to as the saline-water, saline-Feitai, BLM-water, and BLM-Feitai groups. Following a single instillation of BLM (5 mg/kg) or saline, rats were orally administered Feitai at a dose of 3 g/kg body weight or sterilized distilled water once daily. Rats were killed at 7, 14, or 28 d post-BLM. Inflammatory cell count, protein concentration, and lactate dehydrogenase activity in bronchoalveolar lavage fluid were measured, and myeloperoxidase activity and lipid peroxide content in lung homogenates were analyzed. Treatment with Feitai inhibited lung fibrotic progression induced by BLM, as indicated by the decrease in lung hydroproline content and lung fibrosis score at 28 d post-BLM. This was accompanied by significant amelioration of BLM-induced body weight loss, lung edema, and inflammatory response during the development of lung injury in the acute phase. The results strongly indicate the beneficial effects of Feitai in protecting against BLM-induced pulmonary fibrosis. Furthermore, the inflammatory response and lipid peroxidation were inhibited by Feitai, suggesting that the effect of this formula on BLM-induced lung injury and fibrosis is associated with antiinflammatory and antioxidant properties.

Animals↗