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PubMed1991

Zirconium compound-induced pulmonary fibrosis.

Despite suspicion that inhalation of zirconium should be capable of causing human pulmonary disease, documentation of zirconium pneumoconiosis in humans has been lacking. We studied a likely case of zirconium compound-induced pulmonary fibrosis. The diagnosis was based on the following: (1) a history of gradual increase in symptoms and slowly progressing pulmonary fibrosis by chest roentgenogram compatible with a pneumoconiosis; (2) an appropriate history of exposure and a latency period of about 15 years before the onset of dyspnea and of roentgenographic changes; (3) analysis of open lung biopsy material revealing end-stage fibrosis and honeycombing, a moderate number of birefringent particles, and extremely high levels of a variety of zirconium compounds; and (4) no other potential cause of fibrosis. We conclude that zirconium should be considered a likely cause of pneumoconiosis and that appropriate precautions should be taken in the workplace.

Humans↗
PubMed1986

Concentration, biosynthesis and degradation of collagen in idiopathic pulmonary fibrosis.

Despite several studies both in vitro and in vivo, the pathogenesis of pulmonary fibrosis is unclear and some findings related to the biochemistry of collagen are controversial. Collagen metabolism was studied in 11 patients with idiopathic pulmonary fibrosis and in six control subjects. There was an increase in collagen concentration (mean 327 (SD 76) compared with control values of 185 (18) micrograms/mg dry weight, p less than 0.001), normal values for biosynthesis (mean 2.2% (0.8%) v 2.08% (0.5%), and a noteworthy decrease in collagenolytic activity (mean 0.07 (0.04) v 0.23 (0.04) micrograms of collagen degraded per mg of collagen incubated, p less than 0.001). These results suggest that an alteration in enzymatic breakdown of collagen plays an important role in the maintenance and progression of interstitial fibrosis in this disease.

Adult↗
PubMed2000

Involvement of Epstein-Barr virus latent membrane protein 1 in disease progression in patients with idiopathic pulmonary fibrosis.

BACKGROUND: The role of Epstein-Barr virus (EBV) in idiopathic pulmonary fibrosis (IPF) is uncertain. A study was undertaken to detect the virus in IPF as well as to clarify the influence of EBV on the clinical features of the disease. METHODS: Twenty nine lung specimens were obtained from patients with IPF, as well as five specimens from patients with systemic sclerosis with pulmonary fibrosis (SSc) and 15 specimens from controls. EBV DNA and EBV latent membrane protein 1 (LMP1) were detected using the PCR method and immunohistochemical analysis, respectively. RESULTS: EBV DNA was detected in 24 of 25 patients with IPF (96%), in all five patients with SSc (100%), and in 10 of 14 controls (71%). The detection ratio was significantly higher in patients with IPF than in controls (p = 0.047, odds ratio (OR) = 9.60, 95% confidence interval (CI) 0.9 to 96.9). Immunohistochemical analysis revealed that cuboidal epithelial cells were positively stained with anti-LMP1 antibody in nine of the 29 lung specimens from IPF patients. In contrast, neither the patients with SSc nor the control subjects showed positive staining. In the follow up periods LMP1 positive patients with IPF died more frequently from respiratory failure than LMP1 negative patients (4/9 versus 1/20; p = 0.022, OR = 15.20, 95% CI 1. 3 to 168.0). CONCLUSIONS: EBV LMP1 positivity may be associated with more rapid disease progression in IPF.

Adult↗
PubMed1992

Morphometric analysis of airways in idiopathic pulmonary fibrosis patients with mucous hypersecretion.

Five idiopathic pulmonary fibrosis (IPF) patients with sputum since the initial period of the disease (IPF SP+, more than 15 ml/day) were compared with five IPF patients without sputum throughout the course of the disease (IPF SP-) and four control subjects without pulmonary disease matched for age and sex. No significant differences in the duration of symptoms, pulmonary functions, or glucocorticoid therapy were observed between the two IPF groups. Autopsied lungs fixed by immersion into formaldehyde were used for morphometry by digitizing computer. The volume proportion of glands to bronchial wall thickness (gland%), volume proportion of goblet cells to total epithelial layer (goblet%), and luminal mucous volume were measured in central and peripheral airways. The gland percentage in the central airways of the IPF SP+ group was 18 +/- 1% (mean +/- SE), which was significantly greater than 7 +/- 0.6% of the IPF SP- group (p less than 0.001), similar to the 6 +/- 1% of control subjects. Luminal mucous volume in the peripheral airways of the IPF SP+ group was 11 +/- 2%, which was significantly greater than 3 +/- 1% of the IPF SP- group (p less than 0.05) or 0.6 +/- 0.3% of the control subjects (p less than 0.01). Furthermore, luminal mucous volume in both the central and peripheral airways significantly correlated with gland% (p less than 0.01, each). No significant difference in other parameters such as goblet% and cell infiltration between the IPF SP+ group and IPF SP- group was observed. These findings suggest that IPF with hypersecretion is associated with mucous glandular hypertrophy and the accumulation of mucus in the airways.

Aged↗
PubMedDate not supplied

Idiopathic pulmonary fibrosis: newer concepts and management strategies.

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with the histologic appearance of usual interstitial pneumonia (UIP) on lung biopsy. It is characterized by progresive dyspnea, worsening of pulmonary function and radiographically, by patchy subpleural interstitial infiltrates with minimal ground glass appearance predominantly affecting the lung bases. The etiology is unknown and no therapy has been clearly shown to prolong survival. The diagnosis, which earlier was difficult to establish, is now based on guidelines of American Thoracic Society. Newer insight into its etiopathogenesis, particularly the mechanisms involved including T helper 1 (Th1) and T helper 2 (Th2) types of responses occurring after the initial and repetitive lung insults and the ineffectiveness of conventional modes of therapy has prompted clinicians worldwide to look for alternative modes of therapy. Conventional therapy for this disorder has been steroids and immunosuppressives. Immunomodulators (Interferon gamma 1b) and antioxidants (Glutathione and its precursor N-acetyl cysteine) are promising results in this, otherwise, uniformly fatal condition.

Humans↗
PubMedDate not supplied

Cytokines and pulmonary fibrosis.

In the past several years, significant progress in many aspects of pulmonary fibrosis research has been made. Among them, the finding that a variety of cytokines play important roles in the complex process appears most intriguing. These cytokines include at least transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), platelet-derived growth factor, fibroblast growth factors, (TGF-alpha), interleukin-1, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 alpha. These cytokines have been demonstrated to be produced at the sites of active fibrosis where they appear to be expressed by activated inflammatory cells, such as macrophages and eosinophils. More interestingly, other noninflammatory lung cells including mesenchymal cells, such as myofibroblasts, and epithelial cells, have been found to be significant sources as well, albeit in most instances at somewhat different time points than those by inflammatory cells. Study of the individual cytokines in vitro has revealed a variety of potential roles for these cytokines in the regulation of the fibrotic process in vivo, including chemoattractant, mitogenic activities for fibroblasts, stimulation of extracellular matrix and alpha-smooth muscle actin gene expression, alteration of the contractile phenotype of fibroblasts and regulation of diverse functions of lung inflammatory and epithelial cells which can further impact on the fibrotic process by autocrine and paracrine mechanisms. Of these cytokines, it appears that TGF-beta is probably the most important cytokine in terms of the direct stimulation of lung matrix expression which typifies fibrosis. Recently however, there is accumulating evidence to indicate that the situation is much more complex than any one single cytokine being solely responsible for the fibrotic response. The concept of complex lung cytokine networks, orchestrated by a few key cytokines, such as TNF-alpha, being responsible for this response has received strong support from recent studies. This means that it is the balance of positive (profibrogenic) and negative (antifibrogenic) forces generated from interaction among the various cytokines constituting these networks, which may finally determine the outcome of lung injury and inflammation. The importance of these cytokines also suggests new potential targets for designing new therapies for progressive pulmonary fibrosis, and perhaps their utility in prognostication as well.

Animals↗
PubMed1983

Bleomycin-induced pulmonary fibrosis in hamsters. An alveolar macrophage product increases fibroblast prostaglandin E2 and cyclic adenosine monophosphate and suppresses fibroblast proliferation and collagen production.

Bleomycin-induced pulmonary fibrosis in hamsters is associated with collagen accumulation that results from increased lung collagen synthesis rates. However, 1-2 wk after intratracheal instillation of bleomycin, lung collagen synthesis rates decline toward control values. To evaluate the potential role of the bronchoalveolar macrophage in regulating lung collagen production, we studied the effects of macrophages from normal and bleomycin-treated hamsters upon fibroblasts in vitro. We observed: (a) Medium from macrophage cultures decreased fibroblast [3H]thymidine incorporation and nondialyzable [3H]hydroxyproline production in a dose-dependent manner. Fibroblast cell counts were decreased in exposed cultures, and fibroblast viability was unchanged. Procollagen prolyl hydroxylation and prolyl-transfer RNA-specific activity were not altered by macrophage medium; this indicates that [3H]hydroxyproline reflects collagen production rate under the experimental conditions. (b) The suppressive effect of macrophage medium was selective for collagen since collagen production decreased more than noncollagen protein production. (c) Medium from bleomycin-treated hamster macrophages suppressed fibroblast proliferation and collagen production to a greater degree than medium from normal hamster macrophages. (d) Fibroblast suppression by macrophage medium was associated with increased fibroblast endogenous prostaglandin E2 production and intracellular cyclic AMP (cAMP). (e) Incubation of fibroblasts with indomethacin before exposure completely inhibited prostaglandin E2 production and increases in cAMP, and eliminated suppression of fibroblast proliferation and collagen production. The macrophage-derived suppressive factor has an apparent molecular weight of 20,000-30,000 and is heat stable. It does not appear to be species restricted since both hamster and human lung fibroblasts are similarly suppressed. It is at least in part preformed in macrophages obtained by lavage, but its production can also be stimulated in vitro. We concluded that alveolar macrophages release a product that stimulates endogenous fibroblast prostaglandin E2 production and cAMP formation with resultant suppression of fibroblast proliferation and collagen production. Enhanced release of suppressive factor by macrophages during a time when lung collagen production is declining in bleomycin-induced pulmonary fibrosis suggests that macrophages may limit collagen accumulation in pulmonary fibrosis.

Animals↗
PubMed1999

Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats.

The proliferation of myofibroblasts is a central feature of pulmonary fibrosis. In this study we have used tyrosine kinase inhibitors of the tyrphostin class to specifically block autophosphorylation of the platelet-derived growth factor receptor (PDGF-R) or epidermal growth factor receptor (EGF-R). AG1296 specifically inhibited autophosphorylation of PDGF-R and blocked PDGF-stimulated [3H]thymidine uptake by rat lung myofibroblasts in vitro. AG1478 was demonstrated as a selective blocker of EGF-R autophosphorylation and inhibited EGF-stimulated DNA synthesis in vitro. In a rat model of pulmonary fibrosis caused by intratracheal instillation of vanadium pentoxide (V2O5), intraperitoneal delivery of 50 mg/kg AG1296 or AG1478 in dimethylsulfoxide 1 hour before V2O5 instillation and again 2 days after instillation reduced the number of epithelial and mesenchymal cells incorporating bromodeoxyuridine (Brdu) by approximately 50% at 3 and 6 days after instillation. V2O5 instillation increased lung hydroxyproline fivefold 15 days after instillation, and AG1296 was more than 90% effective in preventing the increase in hydroxyproline, whereas AG1478 caused a 50% to 60% decrease in V2O5-stimulated hydroxyproline accumulation. These data provide evidence that PDGF and EGF receptor ligands are potent mitogens for collagen-producing mesenchymal cells during pulmonary fibrogenesis, and targeting tyrosine kinase receptors could offer a strategy for the treatment of fibrotic lung diseases.

Animals↗
PubMed1994

[A case of pulmonary fibrosis associated with CMV inclusion body].

A 71-year-old woman admitted to our hospital with complaints of progressive dyspnea on exertion and weight loss. Roentgenological examination demonstrated peripheral pulmonary fibrosis and a mediastinal tumor suggesting thymoma. The pathological findings of transbronchial lung biopsy (TBLB) confirmed pulmonary fibrosis. Moreover, cytomegalic inclusion bodies in TBLB and a high titer of serum CMV IgG antibody suggested pulmonary CMV infection. It is considered that pulmonary fibrosis and CMV infection were coexistent in this patient.

Aged↗
PubMed1980

[Alveolar septal changes in idiopathic pulmonary fibrosis (author's transl)].

To clarify the mechanism of the disturbance of alveolar gas exchange in idiopathic pulmonary fibrosis, various pulmonary function tests were performed on 7 patients with the disease, of which 5 were defined histo-pathologically and 2 clinically. On 4 of all patients, detailed comparative studies of histopathological findings to pulmonary functions were carried out additionally. As the results, marked decreases of total lung capacity, pulmonary diffusing capacity (DLco) and Pao2 were observed. On exercise, the improvement of DLco or physiologic dead space (VD/VT) was hardly seen, while AaDO2 increased markedly. Ventilation (VA), perfusion (Q), and VA/Q ratio examined by 133Xe scintigram distributed more evenly over the entire lung fields than controls. These may suggest that the disturbance of alveolar gas exchange is mainly due to the elongation of the distance for diffusion in the membrane.

Aged↗
PubMed2000

Increased expression of epimorphin in bleomycin-induced pulmonary fibrosis in mice.

Epimorphin was originally identified as a mesenchymal, cell surface-associated protein that modulates epithelial morphogenesis in embryonic organs, whereas pulmonary fibrosis is a process of wound healing, which in part mimics the process of fetal lung development. We investigated the temporal and spatial changes in the distribution of epimorphin protein and expression of its messenger RNA (mRNA) in bleomycin-induced pulmonary fibrosis in mice. Immunohistochemical analysis showed that low levels of epimorphin were present in the bronchiolar, alveolar, and vascular walls of normal adult lungs. However, from Day 7 until Day 28 after bleomycin treatment, increasing levels of epimorphin immunoreactivity were detected in the mesenchymal cells and in the extracellular matrix within intra-alveolar fibrotic lesions. Moreover, Northern blots showed corresponding increases in epimorphin mRNA expression. Re-epithelialization of epimorphin-rich intra-alveolar fibrosis was complete by Day 28 after bleomycin, and by Day 56, epimorphin immunoreactivity had declined. In situ hybridization and confocal microscopic studies confirmed expression of epimorphin mRNA by mesenchymal cells situated within early fibrotic lesions, whereas immunoelectron microscopy localized the epimorphin to the endoplasmic reticulum of the mesenchymal cells and to the basement membrane and collagen fibrils in the area. These results suggest that epimorphin may contribute to the remodeling of pulmonary fibrosis via epithelial-mesenchymal interactions.

Animals↗
PubMed2005

[Respiratory failure and pulmonary fibrosis as a late side-effect after chemotherapy-induced by oxygen administration].

Pulmonary fibrosis (PF) may develop following successful chemotherapy for malignancy, even if such therapy is not combined with radiotherapy. Bleomycin, which is known to induce acute pneumonitis and lung fibrosis, is especially associated with chemotherapy-induced PF, and bleomycin-induced pulmonary fibrosis can occur more than five years after such therapy. Additionally, supplemental oxygen therapy can trigger the onset of pneumonitis and lethal PF in patients who have previously received bleomycin therapy. Careful assessment of lung function via spiroergometry and arterial blood gas analysis during exercise are required if the administration of supplemental oxygen is considered. Two case reports reveal the potential lethal risk of oxygen for patients who have been treated with bleomycin: (1) a patient with successfully resected and treated basal tongue carcinoma and (2) a patient in remission after being treated for non-Hodgkin lymphoma. Single and double lung transplantation is the only therapeutic option for patients with severe, oxygen-induced PF and should be included as an indication for lung transplantation. Early recognition of pulmonary diffusion abnormalities and establishing a risk profile, as well as consequent monitoring of pulmonary function, may help to avoid or at least reduce the risk of PF induced by oxygen therapy when administered to patients who have previously been given bleomycin.

Adult↗
PubMed1999

An increase in hyaluronan by lung fibroblasts: a biomarker for intensity and activity of interstitial pulmonary fibrosis?

The purpose of the present study was to clarify the roles of hyaluronan (HA) production of lung fibroblasts in the pathogenesis of pulmonary fibrosis. Quantitative and comparative assessments of the HA levels in bronchoalveolar lavage fluid (BALF) and lung fibroblast-conditioned media (F-CM) were made at various stages during the development of bleomycin-induced pulmonary fibrosis in rats. In bleomycin-treated animals, the HA levels in F-CM increased significantly (P < 0.01) on day 1 after bleomycin treatment, peaked on day 3, and then gradually declined and returned to control values on days 14-28. The HA concentrations of BALF in the bleomycin group were significantly increased (P < 0.01) on day 3, were maximal on day 7, and thereafter gradually decreased, remaining significantly above normal values (P < 0.01) on day 14, but returning to control values by day 28. In the bleomycin group, the HA levels both in BALF and in F-CM were significantly correlated with the cell components in BALF and there was a significant correlation between the HA concentration in BALF and in the F-CM. Lung fibroblasts were activated and produced increased HA which resulted in excessive accumulation of HA in the lung in the early stage of pulmonary fibrosis; the increased HA synthesis of lung fibroblasts and enhanced HA concentrations of BALF might reflect the intensity of alveolitis and the disease activity.

Animals↗
PubMed2000

Early molecular and cellular events of oxidant-induced pulmonary fibrosis in rats.

To evaluate the early molecular events of oxidant-induced pulmonary fibrosis, rats were continuously exposed to 0.4 ppm ozone and 7 ppm nitrogen dioxide. The early responses to the combined gases could be divided into three phases. Acute pulmonary inflammation indicated by an increase in pulmonary edema as well as an influx of neutrophils into the airspaces first occurred on days 1 to 3 of the exposure. The pulmonary inflammation was reversed by day 8, and no biochemical or morphologic aspects of tissue responses were detected from days 15 to 45, suggesting that rats adapted to the stimuli during that period. Pulmonary fibrosis could be detected by an increase in the biomarker of lung collagen content at day 60 and by histopathologic evaluation by day 90. Enhanced expression of macrophage inflammatory protein-2 was observed only at day 1, whereas the pulmonary expression of transforming growth factor-beta was upregulated on days 60 and 90 of the exposure. Macrophage expressions of interleukin-1beta and interleukin-6 were enhanced during acute pulmonary inflammation; however, macrophage expression of tumor necrosis factor-alpha was elevated at both day 1 and days 60-90. Activation of nuclear factor-kappa B and increased expression of thioredoxin in the lungs was also observed at day 1 and days 60-90. The expression of antioxidant enzymes, such as manganeous superoxide dismutase and glutathione peroxidase, was not altered during exposure. These results indicate that macrophage activation and the expression of macrophage-derived cytokines may play an important role in the early pulmonary responses against the combined gases.

Administration, Inhalation↗
PubMed1993

Antibodies to collagen in patients with idiopathic pulmonary fibrosis.

STUDY OBJECTIVE: The pathogenesis of idiopathic pulmonary fibrosis (IPF) is uncertain. This investigation was undertaken to determine if antibodies to human native collagens and their chains are present in the serum of the patients with IPF and to examine their relationship with clinical factors. MATERIALS: Serum specimens were obtained from 45 subjects. The subjects were separated into three distinct groups: group 1 consisted of 16 patients with IPF; group 2a, 9 patients with pulmonary fibrotic scars from previous tuberculosis were examined as a control group; group 2b, 20 normal individuals matched by age and sex. The collagen antigens used in this study consisted of four genetically distinct types, I, II, III, IV and their corresponding chains alpha 1(I) + alpha 2(I), alpha 1(II), and alpha 1(III). METHODS: a passive microhemagglutination assay was used to test the antibody activity in the sera of both patients and controls. Titration was performed in microtiter plastic plates, using 0.5 percent cell suspension. The specificity of anticollagen antibodies was then tested using an absorption serum technique with native collagens and their chains. Hemagglutination enhancement and inhibition tests, as well as chromatography, were used to determine the type of antibodies. RESULTS: Thirteen of 16 (81 percent) patients with IPF (group 1) had antibodies against at least one type of native collagen or one type of collagen chain in titers up to 1:512. Twelve patients exhibited anticollagen antibodies with titers above 1:16. By contrast, only 2 of 9 (22 percent) subjects with fibrotic scars (group 2a) and 3 of 20 (15 percent) normal subjects (group 2b) had antibody activity in titers up to 1:8. The differences between group 1 and group 2a and 2b were statistically significant, (p < 0.05 and p < 0.001, respectively). There was an inverse, statistically significant correlation between duration of the disease (IPF) and antibody activity. The correlation coefficient between duration of the disease and titers of antibodies to type III collagen (native and/or chain) was higher than the correlation coefficient between duration of the disease and titers to collagen I. The enhancement and inhibition of agglutination tests, as well as the chromatography, showed that the agglutination factors were antibodies of IgG and IgM classes. The antibody absorption test revealed that the anticollagen antibodies were specific for each collagen and its chain and there was no cross-reaction. CONCLUSION: This study suggests that the anticollagen antibodies could be a marker of IPF activity and may perpetuate the lung tissue inflammation. It is still unclear if the autoimmunity of the collagen participates in the pathogenesis of IPF or the presence of the anticollagen antibodies is simply an epiphenomenon.

Adult↗
PubMed1998

Detection of anti-cytokeratin 8 antibody in the serum of patients with cryptogenic fibrosing alveolitis and pulmonary fibrosis associated with collagen vascular disorders.

BACKGROUND: It has been suggested that the humoral immune system plays a role in the pathogenesis of cryptogenic fibrosing alveolitis (CFA). Although circulating autoantibodies to lung protein(s) have been suggested, none of the lung proteins have been characterised. The purpose of this study was to determine the antigen to which the serum from patients with pulmonary fibrosis reacted. METHODS: The anti-A549 cell antibody was characterised in a patient with CFA using Western immunoblotting and immunohistochemical staining of A549 cells. As we identified that one of the antibodies against A549 cells was anti-cytokeratin 8, the expression of mRNA of cytokeratin 8 in A549 cells was evaluated. In addition, we attempted to establish an enzyme linked immunosorbent assay to measure the levels of anti-cytokeratin 8 antibody in the serum of patients with CFA and pulmonary fibrosis associated with collagen vascular disorders (PF-CVD). RESULTS: Initially two anti-A549 cell antibodies were detected in the serum of patients with pulmonary fibrosis, one of which was characterised as anticytokeratin 8 antibody by Western immunoblotting. We were able to establish an ELISA to measure anti-cytokeratin 8 antibody and found significantly higher levels in patients with CFA and PF-CVD than in normal volunteers, patients with sarcoidosis, pneumonia, and pulmonary emphysema. CONCLUSIONS: One of the anti-A549 cell antibodies in the serum of patients with CFA was against cytokeratin 8. The serum levels of anti-cytokeratin 8 antibody were increased in patients with CFA and PF-CVD. These results suggest that anticytokeratin 8 antibody may be involved in the process of lung injury in pulmonary fibrosis.

Adult↗