Epidermal growth factor receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but attenuates lung fibrosis in response to radiation injury in rats.

BACKGROUND: Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been reported to be associated with interstitial lung disorders, and their high incidence and mortality have become a matter of great concern, especially in Japan. In this study, we investigated the effect of gefitinib on different phases of radiation-induced lung disorders in an experimental model. METHODS: The thoraxes of Wistar rats were irradiated on day 1 with a single X-ray dose of 20 Gy, and gefitinib (50 mg/kg/day) was orally administered from day 1 to 14. The rat lungs were harvested on days 15 and 57 and the bronchoalveolar lavage (BAL) was performed. RESULTS: Gefitinib treatment increased the infiltration of inflammatory cells, which produced more pro-inflammatory cytokines (IL-6, IL-1ß), in the lungs of the irradiated rats on days 15 and 57, while gefitinib treatment reduced collagen content of the lungs in irradiated rats and decreased proliferation and EGFR expression in the lung fibroblasts from irradiated rats on day 57. CONCLUSIONS: In irradiated rats, gefitinib treatment augmented lung inflammation, including inflammatory cell infiltration and pro-inflammatory cytokine expression, while gefitinib treatment attenuated fibrotic lung remodeling due to the inhibition of lung fibroblast proliferation.

Bestatin, an inhibitor for aminopeptidases, modulates the production of cytokines and chemokines by activated monocytes and macrophages.

The aim of this study was to clarify the effect of bestatin, an aminopeptidase inhibitor, on the production of cytokines from peripheral blood monocytes and alveolar macrophages (AM). Human monocytes isolated from peripheral blood of healthy volunteers were incubated with or without lipopolysaccharide (LPS) in the presence or absence of bestatin. AM obtained from patients with sarcoidosis were incubated in the presence or absence of bestatin. The concentration of cytokines in the culture supernatant was determined by enzyme-linked immunosorbent assay. The expression of mRNA was determined by reverse transcription polymerase chain reaction. Bestatin suppressed the production and expression of proinflammatory cytokines and chemokines, interleukin (IL)-6, CXCL8/IL-8, CCL3/macrophage inflammatory protein (MIP)-1alpha by LPS-stimulated monocytes. The mean percentage of the inhibition of IL-6, CXCL8/IL-8, CCL3/MIP-1alpha by bestatin at a concentration of 50 microg/mL was 71.2%, 29.7% and 61.0%, respectively. On the other hand, bestatin increased the production and mRNA expression of IL-10 by LPS-stimulated monocytes. The treatment with bestatin significantly inhibited the production of IL-6 and CXCL8/IL-8 by AM from patients with sarcoidosis. The data presented here indicate that bestatin suppresses the production of the pro-inflammatory cytokines and stimulates the anti-inflammatory cytokine by activated human monocytes. This study suggests that bestatin may be useful as an anti-inflammatory agent in various inflammatory diseases.

Observations on the occurrence of exacerbations in clinical course of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic disease that is characterized by an undulating course of exacerbations and remissions, and a major determinant of long-term prognosis is organ damage consequent to tissue injury that accompanies disease activity and toxicity of therapy. In this study, we evaluated which patients with SLE will develop an exacerbation and whether factors can be identified to predict the development of an exacerbation. Fifty-seven SLE patients (52 females) were included in this study. The exacerbation of SLE was found in 15 patients (26.3%). A relatively increased incidence of an exacerbation was found in younger SLE patients. An increased percentage of patients who had lupus nephritis at the time of diagnosis of SLE was found in patients with a subsequent exacerbation when compared with that in those without it. Increased incidence of an exacerbation was observed in patients who had decreased number of WBC and platelets, decreased level of C3 and CH50, and the presence positivity of anti-Sm antibodies at the time of the diagnosis. This study suggests that age, renal involvement, and the presence of decreased number of WBC and platelets, decreased level of complements anti-Sm antibodies are predictors of exacerbation.