Suppression of alveolar macrophage apoptosis prolongs survival of rats and mice with Pneumocystis pneumonia

Mark E. Lasbury, Pamela J. Durant, Chad A. Ray, Dennis Tschang, Reto Schwendener, Chao Hung Lee

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

The number of alveolar macrophages is decreased in patients or animals with Pneumocystis pneumonia (Pep). This loss of alveolar macrophages is in part due to apoptosis caused by Pneumocystis infection. The mechanism of apoptosis induction is unknown. Cell-free bronchoalveolar lavage fluids from Pneumocystis-infected rats or mice have the ability to induce apoptosis in normal alveolar macrophages. To characterize the mechanisms by which apoptosis proceeds in alveolar macrophages during Pep, specific caspase inhibitors are tested for their ability to suppress the apoptosis. In vitro induction of apoptosis can be inhibited by the caspase-9 inhibitor (Z-LEHD-FMK) but not by the inhibitor to caspase-8 or -10. The caspase-9 inhibitor can also inhibit apoptosis of alveolar macrophages in vivo when it is intranasally instilled into dexamethasone-immunosuppressed, Pneumocystis-infected rats or L3T4 cell-depleted, Pneumocystis-infected mice. The number of alveolar macrophages rebounds in caspase-9 inhibitor-treated Pep animals. Phagocytic activity of alveolar macrophages in treated animals is also recovered, and organism burden in these animals is reduced. Administration of caspase-9 inhibitor also clears the exudate that normally fills the alveoli during Pep and decreases lung inflammation. Furthermore, caspase-9-treated Pep animals survive for the entire 70-day period of the study, whereas nontreated Pep animals die 40-60 days after initiation of infection. Depletion of recovered alveolar macrophages by intranasal administration of clodronate-containing liposomes in caspase-9 inhibitor-treated animals abrogates the effects of the inhibitor. Together, these results indicate that immunomodulation of the host response may be an alternative to current treatments for Pep.

Original languageEnglish (US)
Pages (from-to)6443-6453
Number of pages11
JournalJournal of Immunology
Volume176
Issue number11
DOIs
StatePublished - Jun 1 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Lasbury, M. E., Durant, P. J., Ray, C. A., Tschang, D., Schwendener, R., & Lee, C. H. (2006). Suppression of alveolar macrophage apoptosis prolongs survival of rats and mice with Pneumocystis pneumonia. Journal of Immunology, 176(11), 6443-6453. https://doi.org/10.4049/jimmunol.176.11.6443