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PubMed2006

Cytokine gene polymorphisms and high-resolution-computed tomography score in idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a serious disease with unknown cause and the influence of cytokine gene polymorphisms is presumed in the etiology and pathogenesis of the disease. We used high-resolution computed tomography (HRCT) as a marker of disease stage and progression and compared the alveolar and interstitial score with IL-1, IL-4, IL-12, IL-1RA and IL-4RA cytokine gene polymorphisms. SUBJECTS AND METHODS: The IPF patients were all Caucasians from the Czech Republic and consisted of 20 females and 10 males, with a mean age of 65 years, range 36-85. The HRCT results were evaluated by an experienced viewer using the interstitial and alveolar score scales, which were based on the IPF HRCT description system from Gay SE, Kazerooni EA, Tows GB, Lynch JP, Gross BH, Cascade PN, et al. [Idiopathic pulmonary fibrosis. Predicting response to therapy and survival. Am J Respir Crit Care Med 1998;157:1063-72]. We evaluated the polymorphisms of cytokine genes utilizing a PCR with sequence-specific primers method. RESULTS: The HRCT alveolar score was more pronounced in IL-4 RA (+1902) AG heterozygotes. The HRCT interstitial score was less severe in the IL-12 (-1188) AA homozygotes. According to progression of the HRCT interstitial score, the CC homozygosity at IL-1 RA (mspa 111100), the AA homozygosity at IL-4 RA (+1902) and CC homozygosity at IL-4(+33) positions were more frequent in patients with stable disease compared to those with progressive disease. CONCLUSIONS: We assume from our data that the polymorphisms of IL-4, IL-4RA, IL-1RA and IL-12 genes (genes of cytokines with regulatory activity) might influence the phenotype of IPF as shown by measurable changes in HRCT investigations.

Adult↗
PubMed2005

High-dose acetylcysteine in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive disorder with a poor prognosis. METHODS: We conducted a double-blind, randomized, placebo-controlled multicenter study that assessed the effectiveness over one year of a high oral dose of acetylcysteine (600 mg three times daily) added to standard therapy with prednisone plus azathioprine. The primary end points were changes between baseline and month 12 in vital capacity and in single-breath carbon monoxide diffusing capacity (DL(CO)). RESULTS: A total of 182 patients were randomly assigned to treatment (92 to acetylcysteine and 90 to placebo). Of these patients, 155 (80 assigned to acetylcysteine and 75 to placebo) had usual interstitial pneumonia, as confirmed by high-resolution computed tomography and histologic findings reviewed by expert committees, and did not withdraw consent before the start of treatment. Fifty-seven of the 80 patients taking acetylcysteine (71 percent) and 51 of the 75 patients taking placebo (68 percent) completed one year of treatment. Acetylcysteine slowed the deterioration of vital capacity and DL(CO): at 12 months, the absolute differences in the change from baseline between patients taking acetylcysteine and those taking placebo were 0.18 liter (95 percent confidence interval, 0.03 to 0.32), or a relative difference of 9 percent, for vital capacity (P=0.02), and 0.75 mmol per minute per kilopascal (95 percent confidence interval, 0.27 to 1.23), or 24 percent, for DL(CO) (P=0.003). Mortality during the study was 9 percent among patients taking acetylcysteine and 11 percent among those taking placebo (P=0.69). There were no significant differences in the type or severity of adverse events between patients taking acetylcysteine and those taking placebo, except for a significantly lower rate of myelotoxic effects in the group taking acetylcysteine (P=0.03). CONCLUSIONS: Therapy with acetylcysteine at a dose of 600 mg three times daily, added to prednisone and azathioprine, preserves vital capacity and DL(CO) in patients with idiopathic pulmonary fibrosis better than does standard therapy alone.

Acetylcysteine↗
PubMed2000

Mechanisms of antifibrotic action of interferon gamma-1b in pulmonary fibrosis.

The pathology of progressive pulmonary fibrosis combines injury, chronic inflammation and exaggerated, but futile organ repair. Models of experimental organ fibrosis such as bleomycin- or irradiation-induced lung fibrosis indicate that the continuous overexpression of major growth factors such as transforming growth factor beta 1 plays a major role in the tissue reorganization process and the modulation of the accompanying immune response. Moreover, this process is combined with a reorganization of the extracellular matrix that is likely to allow for the secondary loss of transcription of the interferon gamma gene. As a result, the cytokine pattern of the evolving chronic cellular immune response shifts to the so-called T helper 2 type. Recent investigations have demonstrated that this poorly balanced immune response is a characteristic feature of human progressive lung fibrosis such as idiopathic pulmonary fibrosis. Based on the strong antifibrotic properties of interferon gamma, we combined low-dose glucocorticoids with interferon gamma-1b for the treatment of idiopathic pulmonary fibrosis, a relentlessly progressive form of human pulmonary fibrosis. This pilot investigation demonstrated that interferon gamma is able to improve pulmonary function in patients with idiopathic pulmonary fibrosis while at the same time counterbalancing mechanisms of exaggerated wound repair, such as the overinduction of transforming growth factor beta 1.

Animals↗
PubMed2003

Pulmonary fibrosis and lung cancer: risk and benefit analysis of pulmonary resection.

OBJECTIVE: Pulmonary fibrosis is associated with an increased risk of lung cancer and outcome of surgical resection in this setting is unknown. METHODS: We studied 22 patients (24 operations) with pulmonary fibrosis and non-small cell lung cancer treated between 1991 and 2000 (study group) and compared outcome with 951 other patients (964 operations) treated for non-small cell lung cancer over the same period (control patients). RESULTS: The two groups did not differ significantly in age (68 vs 65 years), smoking history (86% vs 95% smokers), forced expiratory volume in 1 second (2.5 L/min vs 2.3 L/min) or forced vital capacity (3.2 L vs 3.7 L), but patients with pulmonary fibrosis were more likely to be male (72% vs 58%, P <.05). The operative mortality was higher in patients with pulmonary fibrosis than in control patients (17% vs 3.1%, P <.01) and there was a higher procedure-specific mortality in pulmonary fibrosis for pneumonectomy (33% vs 5.1%, P <.01) and lobectomy (12% vs 2.6%, P <.01). Patients with pulmonary fibrosis had a higher incidence of postoperative lung injury, (21% vs 3.7%, P <.01) and a longer mean hospital stay (17 vs 9 days, P <.05). In patients with pulmonary fibrosis, the actuarial 3-year survival was 54%. There were 11 deaths in the study group, 4 postoperatively (all acute respiratory distress syndrome) and 7 late deaths (metastatic disease, n = 2; progressive pulmonary fibrosis, n = 5). Median follow-up (to death or last review) was 13 months (range, 0-120 months). Five patients developed postoperative acute respiratory distress syndrome and in 4 of these patients this proved to be fatal. Postoperative acute respiratory distress syndrome was associated with lower preoperative total lung carbon monoxide diffusion capacity (median, 58% vs 70%, P =.03) and lower preoperative carbon monoxide diffusion capacity corrected for alveolar volume (median, 48% vs 58%, P =.05) and a higher preoperative composite physiological index (median, 44 vs 33, P =.008). None of the preoperative lung function parameters or operative finding were predictors of late death. CONCLUSION: Patients with pulmonary fibrosis undergoing pulmonary resection for non-small cell lung cancer have increased postoperative morbidity and mortality, but an important subgroup has a good long-term outcome. Postoperative acute respiratory distress syndrome is associated with low preoperative gas transfer and a high composite physiological index. Resection of non-small cell lung cancer is appropriate in pulmonary fibrosis, provided that the level of functional impairment is carefully factored into patient selection.

Aged↗
PubMed1993

Pulmonary emphysema followed by pulmonary fibrosis of undetermined cause.

Idiopathic pulmonary fibrosis (IPF) and pulmonary emphysema (PE) have distinct clinical and pathological characteristics, and have been considered to be separate disorders. However, recent animal experiments have suggested that, with regard to their pathogenesis, the diseases have some features in common. However, there are no clinical data supporting this hypothesis. We report here 9 patients (all male, 67 +/- 2 years, mean +/- SE) who had PE followed by IPF. They were found among 152 PE patients who came to Tohoku University Hospital during the past 15 years (1976-1991). All patients were male and heavy smokers and 2 patients also had prostate cancer and gastric cancer, respectively. Three patients were alive during this study and had been diagnosed as having IPF and PE by the combination of transbronchial biopsy, selective alveolobronchogram, CT examination and lung function tests. The diagnosis of IPF and PE in the other patients was based on the pathological findings of autopsied lungs in addition to clinical findings. All patients showed PE mainly in the upper lobes and IPF in the lower lobes. In all patients, in addition to all known causes of pulmonary fibrosis, the possibilities that chronic or recurrent infections in PE induced pulmonary fibrosis and that IPF produced emphysematous changes were carefully excluded by medical records and pathological findings. It is not clear whether the occurrence of emphysema and pulmonary fibrosis in these cases is coincidental, or whether the two diseases are linked by a common pathogenetic pathway.

Aged↗
PubMed1992

[A case of pulmonary fibrosis in which inhibition of pulmonary vasoconstriction was detected using DSA pulmonary wedge angiography].

A 65-year-old man was admitted to our hospital complaining of productive cough and dyspnea on exertion. X-ray films and CT scan of the chest disclosed diffuse reticular shadows, especially in the bilateral lower lung fields. Blood gas analysis showed severe hypoxemia. Pulmonary function test disclosed severe restrictive pattern. From these findings, the patient was thought to have pulmonary fibrosis. Right heart catheterization showed pulmonary hypertension. To evaluate the pulmonary vascular bed, we performed DSA pulmonary wedge angiography. The pulmonary capillary phase stained homogeneously in normal subjects. However, in the present case, filling of the right pulmonary A9 was incomplete and capillary bed staining was decreased under room air condition. After breathing 5 L/min oxygen for 20 min., the A9 was filled well and capillary bed staining was increased. We consider that this change was induced by inhibition of hypoxic pulmonary vasoconstriction (HPV) by oxygen. DSA pulmonary wedge angiography was useful for visual evaluation of HPV.

Aged↗
PubMed1985

Immunological involvement in pulmonary fibrosis induced by peplomycin.

Pulmonary fibrosis in mice induced by peplomycin (PEP) was suppressed by administration of anti-inflammatory agents such as prednisolone and D-penicillamine during or after the administration of PEP. Pulmonary fibrosis was also suppressed by administration of cyclophosphamide, an immunosuppressive antitumor agent before, during or after the administration of PEP. The pulmonary fibrosis in athymic nude mice induced by PEP was less than that in normal mice. The low response in the nude mice was enhanced by transfer of thymocytes to the same level as that in the normal mice. This suggests that the immune system, especially thymus-dependent immunity, is involved in the pulmonary fibrosis induced by PEP.

Animals↗
PubMed1987

High dose continuous infusion of bleomycin in mice: a new model for drug-induced pulmonary fibrosis.

Bleomycin (BLM) produces pulmonary fibrosis in mice when given as a single intratracheal injection, a single i.v. injection or multiple s.c. injections. All of these models are associated with significant disadvantages including a variable distribution of lesions, high mortality or a requirement for multiple procedures. We have developed a convenient method of BLM treatment that avoids these difficulties and yields extensive, reproducible pulmonary fibrosis in mice. Osmotic minipumps containing BLM (100 mg/kg) were implanted s.c. in C57Bl/6 mice and the drug was delivered as a continuous s.c. infusion over 1 week. No mortality occurred over the first 5 weeks after pump placement whereas i.v. BLM (80 mg/kg) produced 50% mortality within 2 weeks. BLM given by pump infusion produced a greater increase (P less than .05) in lung hydroxyproline after 6 weeks (70%) than a similar total dose given as multiple s.c. injections (40%). Lungs from pump-treated mice showed confluent subpleural fibrosis involving almost 50% of the pleural surface and evidence of subpleural alveolar collapse. Mice receiving i.v. or s.c. injections showed involvement of only 10 to 15% of the pleural surface. BALB/c mice were resistant to pulmonary fibrosis after pump implantation, indicating a murine strain difference in pulmonary responsiveness to BLM administered by constant infusion. This superior model for drug-induced pulmonary fibrosis uses a single procedure and provides an extensive, reproducible lung lesion. Additionally, our studies suggest that dysfunction of the pulmonary epithelium may play an important role in progressive pulmonary disease after BLM treatment.

Animals↗
PubMed1979

Morphologic-physiologic correlates of the severity of fibrosis and degree of cellularity in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of lung parenchyma characterized by a chronic inflammatory cellular infiltration and varying degrees of interstitial fibrosis. Current data indicate that the severity of fibrosis and the degree of cellularity determine, in part, the prognosis of IPF and the response to therapy. Whereas lung biopsy gives the best assessement of fibrosis and cellularity, physiologic studies are used to stage and monitor the disease process. To determine which physiologic studies correlate best with severity of fibrosis and degree of cellularity, these parameters were graded in lung biopsies of 23 patients with IPF and compared with a variety of physiologic studies. Although vital capacity, total lung capacity, and diffusing capacity are commonly used as objective monitors of the disease process, none of these parameters correlated with either the severity of fibrosis or the degree of cellularity in biopsy specimens. In contrast, almost all parameters of lung distensibility correlated with the morphologic assessment of degree of fibrosis; compliance had the best correlation. Parameters of distensibility, however, correlated poorly with the degree of cellularity. In comparison, gas exchange during exercise correlated with both morphologic parameters; the exercise-induced changes in arterial oxygen pressure per liter of oxygen consumed had a high correlation with the degree of fibrosis (r = 0.89; P less than 0.001) and correlated to a lesser extent with the degree of cellularity (r = 0.56; P = 0.009). In contrast, neither the resting arterial oxygen tension nor the arterial oxygen tension at maximal exercise correlated with the morphologic assessment of degree of fibrosis or the degree of cellularity. These morphologic-physiologic comparisons suggest that (a) lung volumes and diffusing capacity are poor monitors of both the degree of fibrosis and the degree of cellularity; (b) the fibrotic process contributes, at least in part, to parameters of lung distensibility, and both fibrosis and cellularity contribute to gas exchange alterations during exercise; and (c) parameters of lung distensibility and exercise-induced gas exchange alterations may be useful in staging the severity of disease in IPF.

Adult↗
PubMed2005

Natural killer T (NKT) cells attenuate bleomycin-induced pulmonary fibrosis by producing interferon-gamma.

Pulmonary fibrosis is a progressive illness characterized by interstitial fibrosis. Although the precise mechanism for pulmonary fibrosis is not completely understood, an immune response involving interferon (IFN)-gamma appears to play a role. Therefore, we examined the functional roles of natural killer T (NKT) cells, which produce IFN-gamma and interleukin-4 on activation, in bleomycin-induced pulmonary fibrosis. In NKT cell-deficient mice, pulmonary fibrosis was worse in terms of histology, hydroxyproline levels, and mortality than in control mice. The transforming growth factor (TGF)-beta1 levels were higher in the lung after injecting bleomycin, and blockade of TGF-beta1 by neutralizing monoclonal antibody attenuated the pulmonary fibrosis in CD1d-/- mice. In contrast, the production of IFN-gamma was reduced in lungs from CD1d-/- mice. Moreover, the adoptive transfer of NKT cells into CD1d-/- mice increased IFN-gamma and reduced TGF-beta1 production, attenuating pulmonary fibrosis. An in vitro assay demonstrated that IFN-gamma was involved in suppressing TGF-beta1 production in cells collected from bronchoalveolar lavage. The adoptive transfer of NKT cells from IFN-gamma-/- mice did not reverse pulmonary fibrosis or TGF-beta1 production in lungs of CD1d-/- mice whereas NKT cells from B6 control mice attenuated fibrosis and reduced TGF-beta1 production. In conclusion, IFN-gamma-producing NKT cells play a novel anti-fibrotic role in pulmonary fibrosis by regulating TGF-beta1 production.

Adoptive Transfer↗
PubMed2003

Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis.

Derangement in pulmonary surfactant or its components and alveolar collapse are common findings in idiopathic pulmonary fibrosis (IPF). Surfactant proteins play important roles in innate host defense and normal function of the lung. We examined associations between IPF and genetic polymorphic variants of surfactant proteins, SP-A1, SP-A2, SP-B, SP-C, and SP-D. One SP-A1 (6A(4)) allele and single nucleotide polymorphisms (SNPs) that characterize the 6A(4) allele, and one SP-B (B1580_C) were found with higher frequency ( P</=0.01) in nonsmoker and smoker IPF ( n=84) subgroups, respectively, compared with healthy controls ( n=194). To explore whether a tryptophan (present in 6A(4)) or an arginine (present in other SP-A1 alleles and in all SP-A2 alleles) at amino acid 219 alters protein behavior, two truncated proteins that varied only at amino acid 219 were oxidized by exposure to ozone. Differences in the absorption spectra (310-350 nm) between the two truncated recombinant SP-A proteins were observed both before and after protein oxidation, suggesting allele-specific aggregation differences attributable to amino acid 219. The SP-B SNP B1580_C (odds ratio:7.63; confidence interval:1.64-35.4; P</=0.01), to be a risk factor for IPF smokers, has also been shown to be a risk factor for other pulmonary diseases. The SP-C and SP-D SNPs and SP-B-linked microsatellite markers studied did not associate with IPF. These findings indicate that surfactant protein variants may serve as markers to identify subgroups of patients at risk, and we speculate that these contribute to IPF pathogenesis.

Adult↗
PubMed1998

Pulmonary function tests and CT scan in the management of idiopathic pulmonary fibrosis.

Relationships between pulmonary function testing and high-resolution computed tomography (HRCT) were studied in 39 untreated patients with idiopathic pulmonary fibrosis (IPF) at diagnosis, 23 of whom were followed during 7.5 +/- 0.3 mo (mean +/- SEM). At diagnosis, the extent of overall lung involvement in the HRCT scans showed a moderate but significant correlation only with FVC (r = -0.46, p = 0. 003) and DLCO (r = -0.40, p = 0.03). The extent of ground glass pattern also correlated with FVC (r = -0.58, p = 0.0001). Arterial PO2 at peak exercise (n = 13 patients) showed a significant association with the extent of both ground-glass pattern and overall lung involvement in HRCT (r = -0.60, p = 0.02; and r = -0.64, p = 0. 01, respectively). On multivariate analysis a significant independent correlation between the global disease extent in HRCT and both FVC and DLCO was observed. Changes over time in the total extent of the disease evaluated with HRCT scans were also related to those observed in DLCO and in FVC (r = -0.57, p = 0.01, and r = -0. 51, p = 0.01, respectively). The present study suggests that FVC and DLCO are the physiological variables that best reflect the global extent of disease in IPF and thus may provide significant information for the assessment of the disease's progression.

Aged↗
PubMed2006

Proapoptotic Bid is required for pulmonary fibrosis.

The molecular mechanisms of pulmonary fibrosis are poorly understood. Previous reports indicate that activation of TGF-beta1 is essential for the development of pulmonary fibrosis. Here, we report that the proapoptotic Bcl-2 family member Bid is required for the development of pulmonary fibrosis after the intratracheal instillation of bleomycin. Mice lacking Bid exhibited significantly less pulmonary fibrosis in response to bleomycin compared with WT mice. The attenuation in pulmonary fibrosis was observed despite similar levels of inflammation, lung injury, and active TGF-beta1 in bronchoalveolar lavage fluid 5 days after the administration of bleomycin in mice lacking Bid and in WT controls. Bleomycin induced similar levels cell death in vitro in alveolar epithelial cells isolated from WT and bid(-/-) mice. By contrast, alveolar epithelial cells from bid(-/-) mice were resistant to TGF-beta1-induced cell death. These results indicate that Bcl-2 family members are critical regulators for the development of pulmonary fibrosis downstream of TGF-beta1 activation.

Animals↗
PubMed2002

Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans.

Pulmonary fibrosis is a progressive and largely untreatable group of disorders that affects up to 100,000 people on any given day in the United States. To elucidate the molecular mechanisms that lead to end-stage human pulmonary fibrosis we analyzed samples from patients with histologically proven pulmonary fibrosis (usual interstitial pneumonia) by using oligonucleotide microarrays. Gene expression patterns clearly distinguished normal from fibrotic lungs. Many of the genes that were significantly increased in fibrotic lungs encoded proteins associated with extracellular matrix formation and degradation and proteins expressed in smooth muscle. Using a combined set of scoring systems we determined that matrilysin (matrix metalloproteinase 7), a metalloprotease not previously associated with pulmonary fibrosis, was the most informative increased gene in our data set. Immunohistochemisry demonstrated increased expression of matrilysin protein in fibrotic lungs. Furthermore, matrilysin knockout mice were dramatically protected from pulmonary fibrosis in response to intratracheal bleomycin. Our results identify matrilysin as a mediator of pulmonary fibrosis and a potential therapeutic target. They also illustrate the power of global gene expression analysis of human tissue samples to identify molecular pathways involved in clinical disease.

Animals↗
PubMed1999

[The clinical study of pulmonary emphysema with pulmonary fibrosis].

OBJECTIVE: Emphysema and interstitial pulmonary fibrosis are two different diseases in clinical manifestation and pathology, but it was noticed that there were cases diagnosed as pulmonary emphysema and pulmonary fibrosis. It is necessary to study the relationship between the clinical aspects of these cases. METHODS: 11 patients with emphysema and pulmonary fibrosis were found in the past five years. Clinical symptoms, radiographic features, arterial blood-gas, lung function testing and computed tomography of the chest were analyzed. RESULTS: These patients had a long history of cigarette-smoking. Their clinical features are those of both emphysema and pulmonary fibrosis. CONCLUSIONS: Although emphysema and interstitial pulmonary fibrosis are two different diseases, they could coexist in some patients. Their clinical features do not like either of the two diseases. HRCT is an important method for discovering the coexistance of pulmonary emphysema and interstitial fibrosis.

Diagnosis, Differential↗
PubMed2002

Evaluation and management of pulmonary fibrosis in scleroderma.

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.

Bronchoalveolar Lavage Fluid↗
PubMed1991

[A study on the inhibition effect of tetrandrine on the pingyangmycinum induced pulmonary fibrosis].

A model of pulmonary fibrosis caused by a single intratracheal injection 0.1 mg pingyangmycinum in mice was reported. The effect of tetrandrine, a herbal powder, 50 mg/kg time, on the pathological development of pulmonary fibrosis, and the activity of superoxide dismutase (SOD), angiotensin converting enzyme (ACE), quantity of hydroxyproline (HYP) in this mice model were investigated. We also contrast tetrandrine with cortisol. The result showed that tetrandrine may inhibit the formation and development of pulmonary fibrosis. On the other hand, tetrandrine and cortisol may increase the activity of SOD of lung tissue, reduce the quantity of HYP of lung tissue and decrease the activity of serum ACE.

Alkaloids↗