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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Exp+Med
2008 ; 205
(13
): 3065-77
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Lung epithelial apoptosis in influenza virus pneumonia: the role of
macrophage-expressed TNF-related apoptosis-inducing ligand
#MMPMID19064696
Herold S
; Steinmueller M
; von Wulffen W
; Cakarova L
; Pinto R
; Pleschka S
; Mack M
; Kuziel WA
; Corazza N
; Brunner T
; Seeger W
; Lohmeyer J
J Exp Med
2008[Dec]; 205
(13
): 3065-77
PMID19064696
show ga
Mononuclear phagocytes have been attributed a crucial role in the host defense
toward influenza virus (IV), but their contribution to influenza-induced lung
failure is incompletely understood. We demonstrate for the first time that
lung-recruited "exudate" macrophages significantly contribute to alveolar
epithelial cell (AEC) apoptosis by the release of tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL) in a murine model of influenza-induced
pneumonia. Using CC-chemokine receptor 2-deficient (CCR2(-/-)) mice characterized
by defective inflammatory macrophage recruitment, and blocking anti-CCR2
antibodies, we show that exudate macrophage accumulation in the lungs of
influenza-infected mice is associated with pronounced AEC apoptosis and increased
lung leakage and mortality. Among several proapoptotic mediators analyzed, TRAIL
messenger RNA was found to be markedly up-regulated in alveolar exudate
macrophages as compared with peripheral blood monocytes. Moreover, among the
different alveolar-recruited leukocyte subsets, TRAIL protein was predominantly
expressed on macrophages. Finally, abrogation of TRAIL signaling in exudate
macrophages resulted in significantly reduced AEC apoptosis, attenuated lung
leakage, and increased survival upon IV infection. Collectively, these findings
demonstrate a key role for exudate macrophages in the induction of alveolar
leakage and mortality in IV pneumonia. Epithelial cell apoptosis induced by
TRAIL-expressing macrophages is identified as a major underlying mechanism.