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PubMed2006

In vivo IL-10 gene delivery attenuates bleomycin induced pulmonary fibrosis by inhibiting the production and activation of TGF-beta in the lung.

BACKGROUND: Idiopathic pulmonary fibrosis is a devastating disorder for which there is no effective treatment. Transforming growth factor (TGF)-beta plays a critical role in provoking fibrosis. Interleukin (IL)-10 is a potent immunosuppressive cytokine but its effect on the fibrosing process is unclear. A study was undertaken to examine whether IL-10 affects the production and activation of TGF-beta and thus can attenuate the fibrosis. METHODS: Mice were given an intratracheal injection of bleomycin. On day 1 or 14, IL-10 gene was delivered by rapid intravenous injection of Ringer's solution containing plasmid. Two weeks after the plasmid injection the mice were examined for fibrosis. The effect of IL-10 on TGF-beta production by alveolar macrophages was assessed. RESULTS: Even when delivered during the fibrosing phase, IL-10 gene significantly suppressed the pathological findings, hydroxyproline content, and production of both active and total forms of TGF-beta1 in the lung. Immunohistochemical analyses showed that alveolar macrophages were one of the major sources of TGF-beta1 and IL-10 diminished the intensity of the staining. IL-10 also suppressed the expression of alphaV beta6 integrin, a molecule that plays an important role in TGF-beta activation, on lung epithelial cells. Alveolar macrophages from bleomycin injected mice produced TGF-beta1 spontaneously ex vivo, which was significantly suppressed by treatment of the mice in vivo or by treatment of the explanted macrophages ex vivo with IL-10. CONCLUSION: IL-10 suppresses the production and activation of TGF-beta in the lung and thus attenuates pulmonary fibrosis, even when delivered in the chronic phase.

Animals↗
PubMed1987

Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis.

Lung inflammatory cells of patients with idiopathic pulmonary fibrosis (IPF) were evaluated for their ability to injure 51Cr-labeled AKD alveolar epithelial cells in the presence and absence of IPF alveolar epithelial lining fluid (ELF). The IPF cells were spontaneously releasing exaggerated amounts of superoxide (O.2) and hydrogen peroxide (H2O2) compared with normal (P less than 0.02). Cytotoxicity of the AKD cells was markedly increased when the IPF inflammatory cells were incubated with autologous ELF (P less than 0.02). The majority of IPF patients had ELF myeloperoxidase levels above normal (P less than 0.002). Incubation of IPF ELF with AKD cells in the presence of H2O2 caused increased cellular injury (P less than 0.01 compared with control), which was suppressed by methionine, a myeloperoxidase system scavenger. IPF patients with high concentrations of ELF myeloperoxidase deteriorated more rapidly than those with low ELF myeloperoxidase (P less than 0.05). Thus, IPF is characterized by an increased spontaneous production of oxidants by lung inflammatory cells, the presence of high concentrations of myeloperoxidase in the ELF of the lower respiratory tract, and a synergistic cytotoxic effect of alveolar inflammatory cells and ELF on lung epithelial cells, suggesting oxidants may play a role in causing the epithelial cell injury of this disorder.

Body Fluids↗
PubMed2004

Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis.

STUDY OBJECTIVES: Treatment of patients with idiopathic pulmonary fibrosis (IPF) conventionally includes corticosteroids and cytotoxic agents. No study to date has adequately evaluated the benefits of this approach. This study retrospectively compared combination corticosteroid and cyclophosphamide therapy in a large population of patients who meet the current consensus definition of IPF. DESIGN: Patients were identified retrospectively and treatment addressed on an intention-to-treat basis. Treated and untreated patients were matched by age and percentage of predicted FVC (FVC%) at the time of the initial visit. SETTING: Two academic tertiary referral centers. PATIENTS OR PARTICIPANTS: The diagnosis of IPF was based on current consensus criteria. A total of 164 patients (82 treated and 82 untreated) were included. INTERVENTIONS: Treatment consisted of combined corticosteroid and cyclophosphamide therapy using a standardized protocol. MEASUREMENTS AND RESULTS: There was no difference in age, FVC%, gender, or smoking status between groups. No survival difference was found between patients who were treated (median survival, 1,431 days) or untreated (median survival, 1,665 days) [p = 0.58]. The lack of treatment effect persisted when only those patients with a diagnosis by surgical biopsy (n = 24) or FVC% >/= 60 (n = 107) were analyzed. CONCLUSIONS: Our data suggest that combined corticosteroid and cyclophosphamide therapy has no impact on survival in patients with IPF. This finding supports the evolving concept that chronic inflammation plays a minimal role in the progression of IPF and reinforces the importance of careful consideration of the risks and benefits of such therapies prior to their institution.

Adrenal Cortex Hormones↗
PubMed1999

Myofibroblasts and S-100 protein positive cells in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated interstitial pneumonia.

The aim of this study was to investigate whether idiopathic pulmonary fibrosis (IPF) can be distinguished from rheumatoid arthritis (RA)-associated interstitial pneumonia (RA-IP) by means of quantitatively assessing myofibroblasts and S-100 protein positive dendritic cells. Seven patients with IPF and twelve with RA, in whom the pathological findings were consistent with usual interstitial pneumonia (UIP) were studied. Antibodies to vimentin, alpha-smooth muscle actin (alpha-SMA) and S-100 protein were used for immunohistochemical studies performed using the streptavidin/biotin/peroxidase complex method, applied to dewaxed sections from each case. In fibrosis of RA-IP, appearance of both vimentin- and alpha-SMA-positive cells, namely myofibroblasts, was widely observed, together with the pathological patterns of honeycombing, UIP and bronchiolitis obliterans-organizing pneumonia (BOOP). Fibrosis, in cases of chronic IPF, was found to be characterized mainly by vimentin-positive but alpha-SMA-negative fibroblasts. Pulmonary tissues from RA-IP patients especially when associated with a BOOP pattern, contained many cells positive for S-100 protein. However, such cells were generally hard to find in cases of IPF. These findings suggests that idiopathic pulmonary fibrosis and rheumatoid arthritis-associated interstitial pneumonia can be differentiated from each other, to some extent, based on the appearance of myofibroblasts and the presence of S-100-positive dendritic cells.

Actins↗
PubMed2000

Patients with pulmonary fibrosis: cardiac function assessed with MR imaging.

PURPOSE: To detect abnormalities in cardiac function by using magnetic resonance (MR) imaging in patients with mild to moderate pulmonary fibrosis and to evaluate the relationship between pulmonary function and cardiac function. MATERIALS AND METHODS: Sixteen patients were compared with 16 sex- and age-matched healthy control subjects. Systolic function was assessed by using multisection multiphase cine MR imaging. Diastolic function was assessed with flow-sensitive MR imaging across the mitral and tricuspid valves. MR imaging results were compared with the severity of impairment in pulmonary function. RESULTS: Biventricular systolic function and left ventricular diastolic function were normal in patients, but right ventricular diastolic function was significantly impaired versus that of control subjects, with a ratio of peak flow during early diastolic (E) filling to peak flow during atrial contraction (A) of 0.85 +/- 0.40 versus 1.28 +/- 0.50 (P =.035). Biventricular E/A ratios were strongly correlated to age in patients and control subjects. The right ventricular E/A ratio in patients corresponded with values that are normally expected in people 20 years older. Diastolic left and right ventricular functions were significantly correlated with each other. There was no relationship between pulmonary function and cardiac function. CONCLUSION: Impairment of right ventricular diastolic function was found by using MR imaging in patients with mild to moderate pulmonary fibrosis, whereas left ventricular diastolic function and biventricular systolic function were preserved.

Adult↗
PubMed2006

[Experimental study on protective effects of curcumin on exaggerated extracellular matrix accumulation of pulmonary fibrosis rats].

OBJECTIVE: To study the protective effects of curcumin on exaggerated extracellular matrix accumulation of pulmonary fibrosis rats. METHOD: One hundred and forty-four male Sprague-Dawley rats were randomly divided into 6 groups (24 rats in each group). Rats in the model control group, positive medicine group, and high, moderate and low curcumin groups were injected with a single dose of bleomycin by trachea, and rats in sham-model control group with same volume normal saline. One day after the injection, curcumin solution of different dosages (200, 100, 50 mg x kg(-1) x d(-1)) was respectively given to rats in the high, moderate and low curcumin group daily by gastrogavage, while equal volume of normal saline was given to those in the sham-model control group and model control group, and an equal volume of prednisone (0.56 mg x kg(-1) x d(-1)) was given to those in positive medicine control group. On the 7, 14, 28 days, 8 rats per treatment group were randomly killed, the levels of III-collagen, IV-collagen, laminin and hyaluronic acid in the serum were determined, the determination of hydroxyproline in lung homogenates was analyzed, and the lung was incised to make pathological sections which were stained with HE and Mallory. RESULT: Curcumin could decreas the levels of III-collagen, IV-collagen, laminin and hyaluronic acid in the serum, and inhihit the proliferation of fibrous tissue. CONCLUSION: Curcumin may play its therapetuic role by leveling down the content of extracellular matrix in rats with pulmonary fibrosis induced by bleomycin.

Animals↗
PubMed1983

[Pulmonary fibrosis and inorganic particles].

Biological data acquired in recent years has thrown new light on the pathogenesis of pulmonary fibrosis. The key element in the genesis of fibrosis may be the alveolar macrophage which, under the influence of different stimuli, secretes numerous factors, attracting polymorphonuclear leukocytes and eosinophils, stimulating fibroblasts and activating lymphocytes. Pulmonary fibrosis induced by inhalation of inorganic particles seems to proceed by identical mechanisms, with certain differences relating to the nature of each mineral. The morphological, cytological and immunological characteristics which defend the lung from silicosis and asbestosis are particularly discussed. The in vitro reactivity of several cell types (alveolar macrophages, mesothelial cells in culture, fibroblasts) equally has revealed differences between quartz and chrysotile. Nevertheless this in vitro response is difficult to interpret compared to an in vivo response: they vary according to the cellular system used and the physico-chemical state of the particular mineral (chrysotile and leached chrysotile by oxalic acid for example). The fibrosing action of other particles (talc, metals) is also reviewed. As opposed to an inflammatory granuloma secondary to the stimulation of alveolar macrophages which represents the usual response to mineral particles, there is also an immunological granuloma of the sarcoid type which may lead to secondary fibrosis: beryllium and talc in certain circumstances may act by this mechanism.

Animals↗
PubMed2002

IL-7 inhibits fibroblast TGF-beta production and signaling in pulmonary fibrosis.

Based on studies by our group and others, we hypothesized that IL-7 may possess antifibrotic activities in an IFN-gamma-dependent and independent manner. Here, we have evaluated the antifibrotic therapeutic potential of IL-7 in both in vitro and in vivo pulmonary fibrosis models. IL-7 inhibited both TGF-beta production and signaling in fibroblasts and required an intact JAK1/STAT1 signal transduction pathway. IL-7-mediated inhibition of TGF-beta signaling was found to be associated with an increase in Smad7, a major inhibitory regulator in the SMAD family. In the presence of IL-7, Smad7 dominant negative fibroblasts restored TGF-beta-induced collagen synthesis, indicating that an IL-7-mediated increase in Smad7 suppressed TGF-beta signaling. Consistent with these in vitro findings, recombinant IL-7 decreased bleomycin-induced pulmonary fibrosis in vivo, independent of IFN-gamma. The antifibrotic activities of IL-7 merit further basic and clinical investigation for the treatment of pulmonary fibrosis.

Animals↗
PubMed1994

[Effect of promoting blood circulation to remove stasis and supplementing qi and nourishing yin on the lipid peroxide and superoxide dismutase during experimental pulmonary fibrosis].

The preventive and therapeutic effect of the traditional Chinese compound medicine Feixiankang (FXK) on the mice pulmonary fibrosis formation have been studied with the mice model. The level of LPO and the activity of SOD in the mice lung showed that LPO increased remarkably (P < 0.01), while the activity of SOD decreased significantly (P < 0.01) during the alveolar pneumonia period, although the LPO content had no significant change (P < 0.01) during experimental pulmonary fibrosis formation. In addition, the effect of FXK on the reducing of LPO was much stronger than that of the antioxidative agent Vitamin E. Also, FXK could improve the activity of SOD.

Animals↗
PubMed1994

[A case of chronic type farmer's lung which led to severe pulmonary fibrosis and spontaneous pneumothorax].

We present a case of chronic type farmer's lung which showed progressive pulmonary fibrosis and spontaneous pneumothorax 12 years after the first admission. A 56-year-old woman was diagnosed as having farmer's lung in 1981. After the first hospitalization, her chest roentgenogram showed regression with steroid therapy. After that, she sometimes worked at a dairy farm and required rehospitalization three times for recurrence. In April 1993, she was readmitted complaining of sudden chest pain and dyspnea after cough. Her chest roentgenogram on admission showed spontaneous pneumothorax. After treatment, her chest roentgenogram revealed severe pulmonary fibrosis and loss of lung volume.

Chronic Disease↗
PubMed1991

Paraquat induced pulmonary fibrosis in three survivors.

Pulmonary lesions following paraquat poisoning are believed to be almost invariably fatal. The three patients reports here survived despite persistent radiological change. One of the patients died after taking a larger dose of paraquat one year later, and at necropsy histological changes attributable to the two episodes of paraquat poisoning were apparent.

Adult↗
PubMed1989

The effect of diclofenac acid (Voltaren) on bleomycin-induced pulmonary fibrosis in hamsters.

Bleomycin is an anti-neoplastic compound which produces a time- and dose-dependent pulmonary fibrosis. The mechanisms which cause this fibrosis are not known. However, the ability of bleomycin to modulate prostaglandin synthesis, degradation and circulating levels appears to be central to the fibrosis. Previous studies, which have attempt to modulate bleomycin-induced fibrosis by prevention of prostaglandin synthesis have conflicting results. Therefore, the present study was designed to determine the effects of diclofenac acid, a nonsteroidal anti-inflammatory compound, on the development of bleomycin-induced pulmonary fibrosis. Diclofenac acid pretreatment and daily injections prevented lung collagen accumulation after intratracheal bleomycin. In addition diclofenac acid treatment resulted in significantly lower lung collagen level after intratracheal bleomycin at 14 and 21 days when compared with bleomycin alone. These data indicate that diclofenac acid treatment inhibits bleomycin-induced lung fibrosis possible through the prevention of prostaglandins synthesis.

Animals↗
PubMed1995

[Differential diagnostic significance of complex values of gas exchange during submaximal physical effort in patients with emphysema and pulmonary fibrosis].

The aim of this study was to clarify a) whether the behaviour of functional dead space ratio (VD/VE), alveolo-arterial difference of oxygen tensions (AaDO2) and the venous admixture ratio (QVA/Qt) differed at rest and during submaximal exercise, between patients with pulmonary emphysema and interstitial pulmonary fibrosis as well as from the respective findings in healthy controls, and b) whether a differentiation between these two diseases could be achieved by investigations of complex pulmonary gas exchange. Eleven patients with pulmonary fibrosis (F), which had been diagnosed by pulmonary biopsies, 11 patients with pulmonary emphysema (E) and 11 healthy controls (C) were subjected to conventional pulmonary function tests (PFTs: spirometry, bodyplethysmography, DCO) immediately followed by examinations of pulmonary gas exchange conducted at rest and during an incremental submaximal cycle spiroergometry (ERGO). With normal PFTs for C, vital capacity was diminished in F and the 1" timed vital capacity (FEV1) as well as Tiffeneau's index were reduced in E, while air way resistance and functional residual capacity were augmented in the latter group. In all patients the CO-diffusing capacity was lower compared to C, however, without differences between F and E. In both E and F, the arterial O2 tension were lower at rest as well as during ERGO when compared to C, whereas VD/VE, QVA/Qt and AaDO2 as well as the specific ventilation for O2 were higher, respectively. Alveolar ventilation was similar in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

Six-minute-walk distance predicts waiting list survival in idiopathic pulmonary fibrosis.

RATIONALE: Functional studies may be useful to predict survival in idiopathic pulmonary fibrosis (IPF). Various cutoffs of 6-min-walk distance (6MWD) have been suggested to identify patients at a high risk of death. OBJECTIVES: To examine the association between 6MWD and survival in patients with IPF listed for lung transplantation, and to identify sensitive and specific cutoffs for predicting death at 6 mo. METHODS: We performed a retrospective cohort study of 454 patients classified as having IPF listed for lung transplantation with the United Network for Organ Sharing between June 30, 2004 and July 22, 2005. MEASUREMENTS AND MAIN RESULTS: Lower 6MWD was associated with an increased mortality rate (p value for linear trend < 0.0001). Patients with a walk distance less than 207 m had a more than fourfold greater mortality rate than those with a walk distance of 207 m or more, despite adjustment for demographics, anthropomorphics, FVC % predicted, pulmonary hypertension, and medical comorbidities (adjusted rate ratio, 4.7; 95% confidence interval, 2.5-8.9; p < 0.0001). 6MWD was a significantly better predictor of 6-mo mortality than was FVC % predicted (c-statistic = 0.73 vs. 0.59, respectively; p = 0.02). CONCLUSIONS: Lower 6MWD was strongly and independently associated with an increased mortality rate for wait-listed patients classified as having IPF. 6MWD was a better predictor of death at 6 mo than was FVC % predicted.

Exercise Test↗
PubMed1985

Alveolar wall basement membranes in bleomycin-induced pulmonary fibrosis.

The ultrastructural characteristics of alveolar wall basement membranes (BM) were defined in an experimental model of pulmonary fibrosis. Lungs of adult hamsters were examined 2 to 60 days after a single intratracheal instillation of 0.5 units of bleomycin sulfate. Sections of lung fixed with tannic acid and glutaraldehyde were analyzed for epithelial basement membrane (EPI-BM) thickness and duplication, and tissue incubated in ruthenium red prior to fixation was evaluated for distribution of EPI-BM anionic sites. There were no major alterations in capillary EPI-BM. Six days after bleomycin, during acute inflammation, there was focal injury to alveolar epithelial cells and resultant denudation of EPI-BM. Denuded EPI-BM was folded with the lamina densa 60% thicker than in control animals, suggesting its active or passive retraction. Despite type 2 cell hyperplasia and repopulation of the epithelium, there was no duplication of EPI-BM. Thirty and 60 days after bleomycin, the epithelium was intact, inflammation had subsided, and widespread but focal fibrosis was present. This stage was characterized by thickening and duplication of the EPI-BM; 10% of EPI-BM on the thin side of the alveolar wall were duplicated at 30 days and 30% at 60 days. Duplication and thickening, although worse in fibrotic areas, also occurred in normal-appearing areas of lung, showing that EPI-BM changes may be the only residuum of previous damage. Duplication of EPI-BM in this model of pulmonary fibrosis is a late rather than an early feature of disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗