The calpain inhibitor calpeptin prevents bleomycin-induced pulmonary fibrosis in mice.

Pulmonary fibrosis is characterized by progressive worsening of pulmonary function leading to a high incidence of death. Currently, however, there has been little progress in therapeutic strategies for pulmonary fibrosis. There have been several reports on cytokines being associated with lung fibrosis, including interleukin (IL)-6 and transforming growth factor (TGF)-ß1. We reported recently that two substances (ATRA and thalidomide) have preventive effects on pulmonary fibrosis by inhibiting IL-6-dependent proliferation and TGF-ß1-dependent transdifferentiation of lung fibroblasts. Rheumatoid arthritis is a chronic autoimmune disorder, and its pathogenesis is also characterized by an association with several cytokines. It has been reported that calpain, a calcium-dependent intracellular cysteine protease, plays an important role in the progression of rheumatoid arthritis. In this study, we examined the preventive effect of Calpeptin, a calpain inhibitor, on bleomycin-induced pulmonary fibrosis. We performed histological examinations and quantitative measurements of IL-6, TGF-ß1, collagen type Iα1 and angiopoietin-1 in bleomycin-treated mouse lung tissues with or without the administration of Calpeptin. Calpeptin histologically ameliorated bleomycin-induced pulmonary fibrosis in mice. Calpeptin decreased the expression of IL-6, TGF-ß1, angiopoietin-1 and collagen type Iα1 mRNA in mouse lung tissues. In vitro studies disclosed that Calpeptin reduced (i) production of IL-6, TGF-ß1, angiopoietin-1 and collagen synthesis from lung fibroblasts; and (ii) both IL-6-dependent proliferation and angiopoietin-1-dependent migration of the cells, which could be the mechanism underlying the preventive effect of Calpeptin on pulmonary fibrosis. These data suggest the clinical use of Calpeptin for the prevention of pulmonary fibrosis.

A novel clinical role for angiopoietin-1 in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour associated with asbestos exposure that has only a limited response to conventional therapy; therefore, diagnosing MPM early is very important. We have previously reported that angiopoietin (Ang)-1 was correlated with bleomycin-induced pulmonary fibrosis. Here, we investigated the association of Ang-1 with the development of MPM cells, which originate from mesenchymal cells similar to lung fibroblasts, and demonstrated that Ang-1 stimulated the growth and migration of MPM cells in vitro. We also demonstrated that patients with MPM had significantly higher serum levels of Ang-1 in comparison to a population who had been exposed to asbestos but had not developed MPM. The patients with advanced-stage MPM showed higher levels of Ang-1 than the early-stage MPM patients and the Kaplan-Meier method revealed a significant correlation between serum Ang-1 levels and survival. We propose the possibility that Ang-1 plays an important role in MPM tumour growth and our data suggest that the serum concentration of Ang-1 could be useful as prognostic factor.

All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour of mesothelial origin associated with asbestos exposure. Because MPM has limited response to conventional chemotherapy and radiotherapy, the prognosis is very poor. Several researchers have reported that cytokines such as interleukin (IL)-6 play an important role in the growth of MPM. Previously, it was reported that all-trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-beta1 in experiments using lung fibroblasts. We investigated whether ATRA had an inhibitory effect on the cell growth of MPM, the origin of which was mesenchymal cells similar to lung fibroblasts, using a subcutaneous xenograft mouse model. We estimated the tumour growth and performed quantitative measurements of IL-6, TGF-beta1 and platelet-derived growth factor (PDGF) receptor (PDGFR)-beta mRNA levels both of cultured MPM cells and cells grown in mice with or without the administration of ATRA. ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-beta1, TGF-beta1 receptors and PDGFR-beta, and 2) TGF-beta1-dependent proliferation and PDGF-BB-dependent migration of MPM cells. These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM.

Pneumonitis associated with natural and recombinant interferon alfa therapy for chronic hepatitis C.

We report three cases of chronic hepatitis C (HC) with pneumonitis, suspected to be caused by natural and recombinant interferon (INF) alfa treatments. The patients were administered INF through intramuscular injection. All three patients developed acute respiratory failure (PaO2 < or = 60 mm Hg) with bilateral lung infiltration. One of the patient's condition improved after the cessation of INF treatment, without any other therapy. The other two patients were administered corticosteroids, and one patient's condition improved, while in the other patient the pneumonitis persisted, even after a high dose of corticosteroids. To our knowledge, these three cases are the first report of pneumonitis associated with INF alfa in patients with chronic HC.