Alveolar macrophage apoptosis and TNFf-α, but not p53, expression correlate with murine response to bleomycin

Luis A. Ortiz, Kryztof Moroz, Jing Yao Liu, Gary W. Hoyle, Timothy Hammond, Raymond F. Hamilton, Andrij Holian, William Banks, Arnold R. Brody, Mitchell Friedman

Research output: Contribution to journalArticlepeer-review

Abstract

Apoptosis is considered to be a protective mechanism that limits lung injury. However, apoptosis might contribute to the inflammatory burden present in the injured lung. The exposure of mice to bleomycin (BLM) is a well-established model for the study of lung injury. BLM exposure induces DNA damage and enhances tumor necrosis factor (TNF)-α expression in the lung. To evaluate the importance of alveolar macrophage (AM) apoptosis in the pathogenesis of lung injury, we exposed BLM-sensitive (C57BL/6) and BLM- resistant (BALB/c) mice to BLM (120 mg/kg) and studied the induction of apoptosis [by light-microscopy changes (2, 8, 12, 24, 48, and 72 h) and annexin V uptake by flow cytometry (24 h)], the secretion of TNF-α (measured by ELISA), and the expression of p53 (by immunoblotting) in AM retrieved from these mice. BLM, but not vehicle, induced apoptosis in AM from both murine strains. The numbers of apoptotic AM were significantly greater (P < 0.001) in C57BL/6 mice (52.9%) compared with BALB/c mice (40.8%) as demonstrated by annexin V uptake. BLM induction of apoptosis in AM was preceded by an increased secretion of TNF-α in C57BL/6 but not in BALB/c mice. Furthermore, double TNF-α receptor-deficient mice, developed on a C57BL/6 background, demonstrated significantly (P < 0.001) lower numbers of apoptotic AM compared with C57BL/6 and BALB/c mice. BLM also enhanced p53 expression in AM from both murine strains. However, p53-deficient mice developed BLM-induced lung injury, exhibited similar lung cell proliferation (measured as proliferating cell nuclear antigen immunostaining), and accumulated similar amounts of lung hydroxyproline (65 ± 6.9 μg/lung) as did C57BL/6 (62 ± 6.5 μg/lung) mice. Therefore, AM apoptosis is occurring during BLM-induced lung injury in a manner that correlates with murine strain sensitivity to BLM. Furthermore, TNF-α secretion rather than p53 expression contributes to the difference in murine strain response to BLM.

Original languageEnglish
Pages (from-to)L1208-L1218
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume275
Issue number6 19-6
DOIs
StatePublished - 1998

Keywords

  • Strain susceptibility
  • Tumor necrosis factor

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