Suppression of alveolar macrophage apoptosis prolongs survival of rats and mice with pneumocystis pneumonia.
The number of alveolar macrophages is decreased in patients or animals with Pneumocystis pneumonia (Pcp). 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 Pcp, 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 Pcp 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 Pcp and decreases lung inflammation. Furthermore, caspase-9-treated Pcp animals survive for the entire 70-day period of the study, whereas nontreated Pcp 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 Pcp.
Lasbury
Mark E
ME
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. melasbur@iupui.edu
Durant
Pamela J
PJ
Ray
Chad A
CA
Tschang
Dennis
D
Schwendener
Reto
R
Lee
Chao-Hung
CH
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D053453:Caspase 9; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D007165:Immunosuppression Therapy; D016676:Macrophages, Alveolar / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D011020:Pneumonia, Pneumocystis / Q000201:enzymology / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D013997:Time Factors
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053453:Caspase 9