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PubMed2003

T-helper 1 cells induce alveolitis but do not lead to pulmonary fibrosis in mice.

T-helper (Th)1 cells have a pivotal role in the pathogenesis of hypersensitivity pneumonitis. Continued low-level exposure to the antigens may induce chronic hypersensitivity pneumonitis with lung fibrosis. Although such exposure may activate Th1 cells in the lung, it is not known whether activation of Th1 cells per se can lead to pulmonary fibrosis. To determine this, the lung pathology induced by Th1 clones was investigated. Mice (BALB/c) were injected intraperitoneally with Th1 clones 1-4 times. Each injection was performed 4 days apart and was followed by repeated exposure to aerosolised ovalbumin (OVA) once a day for 5 days. The number of macrophages and lymphocytes in bronchoalveolar lavage fluids (BALF) increased as the number of Th1 transfers increased. The number of neutrophils also increased but peaked in the second transfer and then decreased following further transfers. Increased cell infiltration, thickness of alveolar walls and number of type II cells in the lung occurred. However, histological findings showed no evidence of fibrosis and hydroxyproline levels did not increase. Findings of histology and BALF were ameliorated 2 weeks after the discontinuation of OVA exposure, indicating the reversibility of the Th1-induced pathology. In conclusion, adoptive transfer of T-helper 1 cells results in reversible alveolitis but does not lead to pulmonary fibrosis.

Adoptive Transfer↗
PubMed2026

Familial pulmonary fibrosis: a UK consensus framework for the investigation and management of patients and their relatives.

Background: There is a growing recognition that genetic predisposition contributes to the development of fibrotic interstitial lung disease. Adult onset monogenic disease is most commonly due to dysfunctional telomere maintenance, with a small proportion caused by surfactant biology disorders. These conditions can be associated with additional intrapulmonary and extrapulmonary features which themselves may require surveillance or treatment, making it important to make a genetic diagnosis. The recent introduction in England of a genetic testing panel accessible to respiratory physicians means that genetic information for these individuals is increasingly available but there is currently little standardisation of the subsequent management of patients and their relatives, which can be complex.Aims: This consensus considers the causes and clinical features of familial pulmonary fibrosis and provides a suggested framework for genetic investigation and clinical management of both patients and their relatives.Narrative: We suggest an initial workup that may help identify those with monogenic disease, with focus on key points in the history and examination that may identify features of a telomere or surfactant biology disorder. We highlight that clinical and radiological presentations are diverse and discuss the importance of making a genetic diagnosis to inform multidisciplinary management and facilitate screening of close family members. We also discuss the many outstanding uncertainties and challenges, including the investigation and management of non-monogenic familial pulmonary fibrosis and the management of asymptomatic family members who have inherited a potentially disease-causing genetic variant.Conclusions: We suggest a pathway for the workup and management of patients with familial pulmonary fibrosis, aiming to standardise clinical care for patients and their relatives and provide a framework for the development of a national database to facilitate disease phenotyping and clinical research to improve the evidence base for clinical practice.

Lung Diseases, Interstitial↗
PubMed1998

Predictive value of response to treatment of T-lymphocyte subpopulations in idiopathic pulmonary fibrosis.

T-cell types are important in maintaining immune homeostasis in the lung and their imbalance may be associated with several diseases. We examined the relationship between bronchoalveolar lavage (BAL) T-cell subset profiles and the clinical course of 46 patients with idiopathic pulmonary fibrosis (IPF). A flow cytometry cell sorter (FACS) was used to analyse the T-cell subsets. Pulmonary function tests (PFT) were performed at baseline and 6-12 months later. Patients were divided into two groups according to their CD4/CD8 ratio: CD4/CD8 >1 (group 1, n=21); and CD4/CD8 <1 (group 2, n=25). A lower percentage of lymphocytes, a higher percentage of CD8/S6F1 cells (cytotoxic T-lymphocytes) and a higher percentage of neutrophils were found in the BAL in group 2 compared to group 1 (11+/-7.5% versus 19+/-13.2%; p=0.024 and 29.8+/-17.6% versus 13.3+/-6.9%; p=0.068, respectively for lymphocytes and cytotoxic T-lymphocytes; and 8+/-11% versus 29+/-27%; p=0.003 for neutrophils). Inversely, in the peripheral blood, the distribution of CD8/S6F1 cells was lower in group 1 than in group 2 (8.3+/-6.9% versus 33.4+/-16.5%; p=0.0048). The patients were followed over a period of 1 yr in order to test whether those findings could determine efficacy of therapy. The baseline transfer factor of the lung for carbon monoxide (TL,CO) capacity in group 1 and group 2 was 59+/-22% and 51+/-21%, respectively (p=0.29), but only in group 1 was the TL,CO capacity improved significantly in response to steroids treatment after 6-12 months. IPF patients with a higher percentage of lymphocytes, a lower percentage of neutrophils, CD4/CD8 >1 and a low percentage of CD8/S6F1 may have a more benign course of disease. These parameters may identify an early stage of reversible disease responsive to therapy. We conclude that these measurements may be a useful tool in monitoring response to treatment in patients with idiopathic pulmonary fibrosis.

Bronchoalveolar Lavage Fluid↗
PubMed1988

Gas exchange at a given degree of volume restriction is different in sarcoidosis and idiopathic pulmonary fibrosis.

PURPOSE: It is likely that the relationship between lung volume changes and gas exchange in patients with idiopathic pulmonary fibrosis (IPF) and patients with sarcoidosis is different since the two conditions vary widely in histopathology and prognosis. Few studies, however, have examined this relationship. The goal of this investigation was to measure diffusing capacity and gas exchange in patients with IPF and sarcoidosis in whom the reduction of lung volume was equivalent. PATIENTS AND METHODS: In 21 patients with IPF and 20 patients with pulmonary sarcoidosis with comparable reductions in lung volume, the single breath diffusing capacity for carbon monoxide and gas exchange at rest and during exercise were compared. RESULTS: The relationship between lung volume and gas transfer differed in the two groups of patients. Resting and exercise gas exchange tended to be relatively normal and the diffusing capacity was higher in patients with sarcoidosis than in those with IPF. These differences could not be attributed to disparities in race, age, smoking habits, or the radiographic stage of sarcoidosis. CONCLUSION: The preservation of gas exchange in sarcoidosis as opposed to IPF, despite equivalent degrees of volume restriction, suggests that different pathophysiologic mechanism underlie the volume loss and gas exchange defects seen in these disorders. Furthermore, these findings suggest that diffusing capacity may not be a sensitive indicator of pulmonary pathology in sarcoidosis since lung volume can be altered independently of abnormalities in the diffusing capacity.

Adult↗
PubMed2004

Increased surfactant protein-A levels in patients with newly diagnosed idiopathic pulmonary fibrosis.

STUDY OBJECTIVES: To measure surfactant protein-A (SP-A) in the BAL of patients with idiopathic pulmonary fibrosis (IPF). DESIGN: We examined SP-A in BAL and lung tissue of patients with IPF who met the stricter recommended criteria for IPF at the time of diagnosis and prior to the beginning of treatment. PATIENTS: Twenty-six patients with IPF confirmed at biopsy and 22 patients with hypersensitivity pneumonitis (HP) were compared with 9 normal volunteers. INTERVENTIONS: All patients were subjected to pulmonary function testing, BAL, and lung biopsy prior to the beginning of treatment. MEASUREMENTS AND RESULTS: We measured SP-A in BAL fluids and performed SP-A immunohistochemistry on lung specimens. Lung tissues of patients with IPF showed extensive type II cell hyperplasia, usually containing greatly increased levels of immunoreactive SP-A. By enzyme-linked immunosorbent assay, we found a twofold increase over normal values in BAL SP-A without changes in total phospholipids. These data were in agreement with semiquantitative assessments of SP-A by protein immunoblotting and by Western blotting of sodium dodecyl sulfate gels. Patients with HP exhibited a threefold increase of BAL SP-A. CONCLUSIONS: The reasons for the difference between our results and previously published reports describing decreased SP-A levels in IPF is not clear. It may relate to the stricter criteria for diagnosis, the absence of treatment prior to BAL, differences in the patient population, or to other methodologic differences.

Adult↗
PubMed2000

The Fas/Fas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice.

Recent studies suggest that Fas-Fas-ligand (FasL) interactions play an important role in the development of lung injury and fibrosis. However, evidence to support this concept is still indirect. To determine whether Fas-FasL interaction is required for the development of bleomycin-induced pulmonary fibrosis in mice, we used Fas-deficient (lpr) and FasL-deficient (gld ) mice as animal models. After intratracheal instillation of bleomycin, we examined the lungs of mice through bronchoalveolar lavage, histologic studies, DNA nick-end labeling, and hydroxyproline assay. The development of cellular infiltrates, bronchiolar and alveolar epithelial apoptosis, and fibrosis following bleomycin instillation in the lungs in lpr mice and gld mice was similar to their development in wild-type mice. The results of this study show that bleomycin-induced pulmonary fibrosis does not require Fas-FasL interaction, and that epithelial cell apoptosis after bleomycin exposure is mediated by Fas-independent pathways.

Animals↗
PubMed2000

The prognostic value of perfusion lung scintigraphy in patients who underwent single-lung transplantation for emphysema and pulmonary fibrosis.

UNLABELLED: The objective of this study was to evaluate the role of quantitative perfusion lung scintigraphy (QPLS) in predicting the development of chronic rejection in patients who underwent single-lung transplantation. METHODS: Eighteen patients (15 men, 3 women; age range, 41-60 y; mean age, 54.6+/-6.0 y) who underwent single-lung transplantation for emphysema (n = 14) or pulmonary fibrosis (n = 4) were studied. Patients were evaluated using QPLS and pulmonary function tests before surgery and at 1-3 mo and 1-3 y after transplantation. Relative perfusion of the transplanted lung was calculated from standard perfusion lung scintigrams. Values for forced expiratory volume in the first second (FEV1) were obtained from lung function tests at the same time points. The maximal and minimal relative perfusion and FEV1 values in the early (1-3 mo) and late (1-3 y) follow-up periods were identified for each patient. Receiver operating curve (ROC) analysis was performed on all parameters. RESULTS: In total, 82 lung scans were performed (mean, 4.8+/-1.55 per patient) and 484 FEV1 test determinations were obtained (mean, 30.0+/-15.6 per patient) during a follow-up period ranging from 8 to 84 mo (mean, 39.6+/-19.3 mo). In 7 of the 18 patients, chronic rejection developed, whereas 11 patients had a favorable outcome. No significant difference was found in the number of complications (acute rejection and infection episodes) between patients with a favorable outcome and patients with chronic rejection, up to 1 y after transplantation. At 1-3 mo, minimal relative perfusion values were 67.1%+/-12.2% in the favorable outcome group and 50.8%+/-9.6% in the chronic rejection group (P = 0.02). Before surgery and at 1-3 y, minimal relative perfusion was not significantly different between the 2 groups. The difference in maximal relative perfusion at 1-3 y was marginally significant, with 76.5%+/-8.9% in the favorable group and 64.3%+/-15.0% in the chronic rejection group (P = 0.051). FEV1 values were not significantly different preoperatively and 1-3 mo after surgery between the chronic rejection and the favorable outcome groups. Late in the follow-up period (1-3 y), FEV1 values in the chronic rejection and favorable outcome groups were 35.6%+/-7.9% and 56.9%+/-13.6%, respectively (P = 0.002). ROC analysis of minimal relative perfusion at 1-3 mo identified a threshold of 57% under which the sensitivity and specificity for chronic rejection were 83% and 88%, respectively. Minimal FEV1 for the same period identified a threshold of 48% under which the sensitivity and the specificity were 80% and 67%, respectively. CONCLUSION: QPLS early after transplantation in our patients predicted the development of chronic rejection in patients with single-lung transplantation for emphysema and pulmonary fibrosis, whereas surgical complications, acute rejection, infection episodes, and lung function tests did not predict the outcome. This early prediction could not be obtained from lung function tests performed at the same time.

Adult↗
PubMed2005

Pulmonary alveolar proteinosis and end-stage pulmonary fibrosis: a rare association.

We present the high resolution CT features of marked pulmonary fibrosis in a patient known to have pulmonary alveolar proteinosis (PAP) confirmed on open lung biopsy. Significant fibrosis in PAP is an extremely rare occurrence with only a few case reports. Our case demonstrated a predominantly central distribution, which has not been described previously.

Adult↗
PubMed1988

Cadmium-chloride-induced air-space enlargement with interstitial pulmonary fibrosis is not associated with destruction of lung elastin. Implications for the pathogenesis of human emphysema.

To determine whether lung elastin is lost during the evolution of cadmium-induced air-space enlargement with pulmonary fibrosis, the lung elastin of 5- to 7-day-old golden Syrian hamster pups was radiolabeled by giving [3H]valine. At maturity, a single intratracheal instillation of 0.5 ml of 0.025% CdCl2 solution was given. Lung mechanics, histologic examination, and biochemistry were studied 5, 10, 21, 42, 105, and 180 days after the cadmium treatment. The animals developed fibrosis and air-space enlargement with decreased lung volumes, compliance, and forced expiratory flow; their functional residual capacity was increased. The total lung collagen and total lung elastin were increased, but there was no loss of radiolabel in lung elastin. We conclude that CdCl2-induced air-space enlargement with pulmonary fibrosis is not accompanied by loss of neonatally formed lung elastic fibers. We hypothesize that air-space enlargement with fibrosis represents a stereotyped response of the lung to fibrosing injuries, which we hypothesize is due to forces from more fibrotic and atelectatic areas causing overdistension of less abnormal air spaces. The air-space enlargement of fibrosing human diseases such as sarcoidosis and eosinophilic granuloma may have a similar basis. Evidence is reviewed that human centrilobular emphysema may be a form of focal air-space enlargement with interstitial fibrosis; there may be mechanisms in addition to elastase-antielastase imbalance that cause human emphysema.

Animals↗
PubMed1992

Chronic extrinsic allergic alveolitis in a family with idiopathic pulmonary fibrosis: the importance of histological diagnosis.

We report a patient who presented with progressive exertional dyspnoea, chronic cough and radiographic signs of interstitial lung disease. Since several of his family members were known to have familial idiopathic pulmonary fibrosis he was also suspected to suffer from this disease. After thorough investigation, including histological examination of lung biopsies obtained by thoracoscopy, a diagnosis of chronic extrinsic allergic alveolitis was made. Current knowledge of familial idiopathic pulmonary fibrosis is discussed. This case report underlines the importance of a histological diagnosis in interstitial lung disease.

Alveolitis, Extrinsic Allergic↗
PubMed1994

Determinants of survival in idiopathic pulmonary fibrosis.

To identify the determinants of survival in patients with idiopathic pulmonary fibrosis (IPF), we performed a survival analysis on 74 subjects with IPF. The study subjects were on average 64 yr of age (range, 25 to 83 yr), 62% were male, and 29% were never smokers. A tissue diagnosis was made in 67 (91%) of our study subjects. These subjects were followed for a mean period of 4 yr (range, 1.4 to 118.8 months) after the onset of pulmonary symptoms. During the period of observation, 41 subjects died (median survival = 28.2 months) and 33 continue to survive (median follow-up period = 60.9 months). A univariate analysis demonstrated that diminished survival was significantly associated with male gender (hazard ratio = 1.98; 95% confidence interval [CI] = 1.01-3.85), a higher FEV1/FVC ratio (hazard ratio = 1.82 [per 10% increase in the FEV1/FVC ratio]; 95% CI = 1.21-2.73), a lower percent predicted FVC (hazard ratio = 0.74; 95% CI = 0.60-0.91), a lower percent predicted total lung capacity (TLC) (hazard ratio = 0.75; 95% CI = 0.60-0.94), a lower percent predicted diffusing capacity of carbon monoxide (DLCO) (hazard ratio = 0.69; 95% CI = 0.53-0.89), a higher ILO profusion category on chest radiograph (hazard ratio = 3.52; 95% CI = 1.58-7.87), and an enhanced release of prostaglandin E2 (PGE2) by cultured alveolar macrophages (hazard ratio = 1.32 [per 10 pm/ml of PGE2]; 95% CI = 1.07-1.62).(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchoalveolar Lavage Fluid↗
PubMed1998

[Gene expression of messenger RNA coding for procollagen and tumour necrosis factor-alpha in lungs undergoing bleomycin-induced pulmonary fibrosis].

OBJECTIVE: mRNA for tumour necrosis factor-alpha(TNF-alpha) and procollagen I [pro alpha 1(I)] and III (pro alpha 1(III) was measured in bleomycin treated mice to evaluate their roles in pulmonary fibrosis. METHOD: 30 male Wistar rats were divided into normal control group and groups treated by bleomycin on days 3, 7, 14, 21, 30. Each group included 5 rats, and the rats were treated by single intratracheal instillation with sterile saline solution or with 5 mg/kg body weight of bleomycin. The rats were sacrificed at different days, and total RNA from the lungs of bleomycin or saline solution instilled rats was extracted. Expression of TNF-alpha, pro alpha 1 (I) and pro alpha 1 (III) mRNA was measured by dot blot and Northern blot hybridization. RESULT: The levels of TNF-alpha mRNA in lungs of bleomycin groups on days 3,7 were significantly higher than those of control group (t = 10.33 and 12.54 respectively; P < 0.01). The levels of pro alpha 1 (I) and pro alpha 1(III) mRNA in lungs of bleomycin group on day 7 were higher than those of control group(t = 10.56 and 24.23 respectively; P < 0.01), After reaching the peak levels in two weeks, the levels of pro alpha 1(III) mRNA in lungs of bleomycin group on day 30 declined slowly to approximately the values of normal control group (t = 1.95; P > 0.05); but the levels of pro alpha 1(I) mRAN on day 30 after bleomycin administration were higher than those of control group (t = 16.67; P < 0.01). The mRNA coding pro alpha 1(I) and pro alpha 1(III) in lungs of rats had two mRNA species. CONCLUSION: The results suggested that the metabolism of mRNAs for pro alpha 1 (I) and pro alpha 1 (III) may be preferentially perturbed, and that increase of collagen gene expression in the transcriptional level might be involved in the mechanism of collagen accumulation. The increased expression of TNF-alpha gene may play an important role in the early events of bleomycin-induced pulmonary fibrosis.

Animals↗
PubMed2004

Effects of interferon-gamma 1b on biomarker expression in patients with idiopathic pulmonary fibrosis.

In a recent study of IFN-gamma 1b in 330 patients with idiopathic pulmonary fibrosis (IPF), progression-free survival was unchanged; however, a trend toward lower mortality was seen in IFN-gamma 1b-treated patients compared with placebo-treated patients (9.9 vs. 16.7%; p = 0.08). The purpose of this randomized, double-blind, placebo-controlled trial was to characterize molecular effects of subcutaneous IFN-gamma 1b (200 microg) thrice weekly for 6 months versus placebo in 32 patients with IPF. Messenger RNA in transbronchial lung biopsies and bronchoalveolar lavage cell pellet and protein levels in bronchoalveolar lavage fluid (BALF) and plasma were evaluated. After IFN-gamma 1b treatment, IFN-inducible T cell-alpha chemoattractant/CXCL11 (a chemokine with immunomodulatory, antiangiogenic, and defensin-like antimicrobial properties) increased in BALF (p = 0.016) and plasma (p < 0.001); BALF levels of epithelial neutrophil-activating protein-78/CXCL5 (p = 0.054), platelet-derived growth factor A (p = 0.033), and Type I procollagen (p = 0.096) were lower; and IFN-gamma levels were higher (p = 0.093) versus placebo. For messenger RNA in transbronchial biopsies, trends (p > 0.05 and <or= 0.10) associated with IFN-gamma 1b treatment included an increase in IFN-inducible T cell-alpha chemoattractant/CXCL11, a decrease in elastin, and smaller increases for Type III procollagen and platelet-derived growth factor B. Changes in biomarkers of fibrosis, angiogenesis, proliferation, immunomodulation, and antimicrobial activity suggest that IFN-gamma 1b may affect IPF through multiple pathways.

Aged↗
PubMed1996

Expression of TGF-beta 1, PDGF and IGF-1 mRNA in lung of bleomycin-A5-induced pulmonary fibrosis in rats.

OBJECTIVE: To investigate the influence of alveolar macrophages (AMs), fibroblasts and interstitial cells on development of lung fibrosis, and the interactions among TGF-beta 1 PDGF and IGF-1 and these cytokines-effects on lung fibrosis. MATERIAL AND METHODS: Expressions of TGF-beta 1, PDGF and IGF-1 mRNA in the lung cells and lung tissues in different stages of Bleomycin-A5-induced pulmonary fibrosis in rats were studied through Northern hybridization. RESULTS: The expressions of TGF-beta 1 and PDGF mRNA reached their peaks in AMs of pulmonary fibrosis in rats on the 7th day after Bleomycin-A5 instillation. It was similar with that in the lung tissues. IGF-1 mRNA remained relatively stable in AMs during the course. PDGF and IGF-1 mRNA increased gradually in fibroblasts, and reached the highest expressions in the interstitial cells. There was almost no TGF-beta 1 mRNA expression in all groups of fibroblasts. CONCLUSIONS: AMs are the main sources of TGF-beta 1 and PDGF in the lung tissues with fibrosis induced by Bleomycin-A5 AMs are activated in the first weekend and secrete TGF-beta 1 and PDGF to promote fibroblasts proliferation and fibrosis. As fibrosis developed, fibroblasts have established PDGF and IGF-1 autocrine and these three cytokines paracrine nets combined with the interstitial cells to promote lung fibrosis.

Animals↗
PubMed1981

Actin-containing cells in human pulmonary fibrosis.

Lung tissue from five patients with varying degrees of diffuse pulmonary fibrosis was examined for the presence of nonmuscle cells containing the contractile protein actin. Histochemical studies using light- and electron-microscopic techniques suggested that the fibrotic tissue, in areas lacking smooth muscle, had within it numerous cells with cytoplasmic microfilaments composed of actin. Similar cells rarely were observed in control lung tissue. The orientation of these cells within the parenchyma, as well as the arrangement and density of the filaments in the cell, suggests a contractile function. Cells with contractile properties might play a role in the altered dynamics of the lung in diffuse fibrotic pulmonary disease.

Actins↗
PubMedDate not supplied

Spectrum and diagnosis of idiopathic pulmonary fibrosis.

OBJECTIVE: To study the clinical profile of patients with idiopathic pulmonary fibrosis (IPF) and methods used for diagnosis. METHODS: Prospective analysis of symptoms, signs, radiology and lung biopsy of patients freshly diagnosed to have IPF over a 16-month period. RESULTS: During the study period, 76 patients (35 men) with a mean age of 50.6 +/- 11.9 years were diagnosed to have IPE Breathlessness (98.6%) and dry cough (92.1%) were the most common presenting symptoms. Transbronchial lung biopsy (TBLB) was performed in 38 (50%) patients. Histopathological examination revealed features consistent with IPF in 35 (92.1%) patients; two of the remaining three patients underwent open lung biopsy. Other patients were diagnosed based on clinical features and high resolution chest tomography (HRCT) findings. HRCT was performed in 69 (90.8%) patients; all had features suggestive of diffuse interstitial fibrosis. CONCLUSION: IPF is diagnosed more commonly now than in the past. Indian patients may be developing the disease a decade earlier than their counterparts in the West. TBLB and HRCT are useful in establishing diagnosis. IPF should be considered a distinct clinical entity rather than a diagnosis of exclusion.

Female↗
PubMed1987

[Pulmonary fibrosis after postoperative tangential irradiation in breast cancer].

Incidence rate of pulmonary fibrosis with elevation of diaphragma was calculated for 118 postoperated breast cancer patients who were tangentially irradiated at the Department of Radiology Kyushu University from 1961 to 1980 and followed more than 5 years. 5%, 50% occurred at 40-45 Gy, 60-65 Gy, Rubin's Table (1972) is possible correct.

Actuarial Analysis↗