Bleomycin stimulates lung epithelial cells to release neutrophil and monocyte chemotactic activities

Abstract

stimulates lung epithelial cells to release neutrophil and monocyte chemotactic activities. Am. J. Physiol. 276 (Lung Cell. Mol. Physiol. 20): L941-L950, 1999.-Although bleomycin, an antineoplastic drug, is used in the treatment of a variety of tumors, the mechanisms of bleomycin-induced lung injury and fibrosis are not fully elucidated. We postulated that bleomycin might stimulate A549 cells, a type II pneumocyte cell line, to release neutrophil and monocyte chemotactic activities (NCA and MCA, respectively). To test this hypothesis, A549 cell supernatant fluids were harvested and evaluated for NCA and MCA. A549 cell supernatant fluids showed NCA and MCA in response to bleomycin in a dose-and time-dependent manner (P Ͻ 0.05). Checkerboard analysis revealed that both NCA and MCA were predominantly chemotactic. Partial characterization of the released NCA and MCA showed that the activities were partially heat labile, trypsin digested, and predominantly ethyl acetate extractable. Lipoxygenase inhibitors and cycloheximide inhibited the release of chemotactic activities significantly. Molecular-sieve column chromatography revealed that the released activities were heterogeneous. However, lowmolecular-weight activity was prominent. Leukotriene B 4receptor antagonist, anti-interleukin-8, anti-granulocyte colony-stimulating factor, and anti-monocyte chemoattractant protein-1 antibodies attenuated the chemotactic activities. Immunoreactive leukotriene B 4 receptor, interleukin-8, granulocyte colony-stimulating factor, and monocyte chemoattractant protein-1 significantly increased in supernatant fluids in response to bleomycin. These data demonstrate that bleomycin stimulates type II epithelial cells to release chemotactic activities and plays a role in inflammatory cell recruitment into the lung.

Cigarette smoke exposure potentiates bleomycin-induced lung fibrosis in guinea pigs

“…Furthermore, TGF-␤1-producing eosinophils were predominantly localized within areas of active fibrosis in bleomycin-induced lung injury (52). It has been suggested that fibroblasts and alveolar epithelial cells may modulate eosinophil recruitment into the lung in this experimental model (38). The presence of eosinophils in the lungs of patients with pulmonary fibrosis has been correlated with poor prognosis or resistance to therapy (5).…”

Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice

“…Although BLM may directly cause epithelial structural damage, 26 its principal mode of action in leading to IPF-like pathology seems to be via endogenous mediators of inflammation, fibrosis and proliferation. The BLMinduced lung injury in experimental models causes an extensive inflammatory background, sometimes with elective centrolobular localization.…”

Effects of a leukotriene B4 receptor antagonist on bleomycin-induced pulmonary fibrosis

“…ONO-4057 (5-(2-(2-carboxyethyl)-(6-(4-methoxyphenyl)-5E-hexenyl) oxyphenoxy) valeric acid) (ONO Pharmaceutical, Osaka, Japan) is a nonselective BLTR antagonist that predominantly antagonises BLT1 and has been reported to [9,13]. We also focused on the effects of ONO-4057 on prostaglandin (PG)E 2 , active transforming growth factor (TGF)-b1, interleukin (IL)-4, IL-6, IL-13 and interferon (IFN)-c levels in BALF and on TGF-b expression in lung tissue in pulmonary fibrosis, because these mediators have been found to be strongly associated with the pathogenesis of pulmonary fibrosis [14][15][16].…”