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. 2001 Jan;158(1):153-61.
doi: 10.1016/S0002-9440(10)63953-3.

Fas (CD95) induces alveolar epithelial cell apoptosis in vivo: implications for acute pulmonary inflammation

G Matute-Bello  1 , R K Winn, M Jonas, E Y Chi, T R Martin, W C Liles
Affiliations

Fas (CD95) induces alveolar epithelial cell apoptosis in vivo: implications for acute pulmonary inflammation

G Matute-Bello et al. Am J Pathol. 2001 Jan.

Abstract

Activation of the Fas/FasL system induces apoptosis of susceptible cells, but may also lead to nuclear factor kappaB activation. Our goal was to determine whether local Fas activation produces acute lung injury by inducing alveolar epithelial cell apoptosis and by generating local inflammatory responses. Normal mice (C57BL/6) and mice deficient in Fas (lpr) were treated by intranasal instillation of the Fas-activating monoclonal antibody (mAb) Jo2 or an irrelevant control mAb, and studied 6 or 24 hours later using bronchoalveolar lavage (BAL), histopathology, DNA nick-end-labeling assays, and electron microscopy. Normal mice treated with mAb Jo2 had significant increases in BAL protein at 6 hours, and BAL neutrophils at 24 hours, as compared to lpr mice and to mice treated with the irrelevant mAb. Neutrophil recruitment was preceded by increased mRNA expression for tumor necrosis factor-alpha, macrophage inflammatory protein-1alpha, macrophage inflammatory protein-2, macrophage chemotactic protein-1, and interleukin-6, but not interferon-gamma, transforming growth factor-ss, RANTES, eotaxin, or IP-10. Lung sections from Jo2-treated normal mice showed neutrophilic infiltrates, alveolar septal thickening, hemorrhage, and terminal dUTP nick-end-labeling-positive cells in the alveolar septae and airspaces. Type II pneumocyte apoptosis was confirmed by electron microscopy. Fas activation in vivo results in acute alveolar epithelial injury and lung inflammation, and may be important in the pathogenesis of acute lung injury.

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Figures

Figure 1.
Figure 1.
Total BAL protein at 6 hours (A) or 24 hours (B) after the intranasal administration of either an irrelevant control mAb or the Fas-activating mAb Jo2. C57, wild-type mice; lpr, Fas-deficient mice. Data are shown as means ± SEM.
Figure 2.
Figure 2.
Total BAL PMN at 6 hours (A) or 24 hours (B) after the intranasal administration of either an irrelevant control mAb or the Fas-activating mAb Jo2. C57, wild-type mice; lpr, Fas-deficient mice. Data are shown as means ± SEM.
Figure 3.
Figure 3.
RPA analysis of cytokine mRNA expression in the lungs of mice, 6 hours after the intranasal administration of the mAb Jo2. RPA analysis was performed as described in the Methods section. Results are expressed as relative mRNA expression (mean ± SEM), which represents normalized Jo2-induced expression (n = 3 mice)/normalized control expression (n = 3 mice) for each cytokine. *, Value significantly greater than control (P < 0.05). **, Value significantly less than control (P < 0.05).
Figure 4.
Figure 4.
Histopathological lung injury score for C57 mice 24 hours after receiving either an irrelevant control mAb (n = 7) or the Fas-activating mAb Jo2 (n = 6). The score represents the average of two independent investigators who read each H&E-stained slide in a blinded manner. The categories used to generate the score were alveolar septal congestion, alveolar hemorrhage, intra-alveolar fibrin deposition, and intra-alveolar infiltrates (see text for further explanation). *, P < 0.01.
Figure 5.
Figure 5.
H&E preparation and DNA nick-end-labeling assay from consecutive sections of the caudal lung lobe of a wild-type mouse 24 hours after intranasal instillation of Fas activating mAb Jo2. The H&E preparation shows inflammatory infiltrates and areas of hemorrhage [original magnifications: ×100 (a); ×400 (b)]. The DNA nick-end-labeling assay shows positive cells in the inflammatory exudate [original magnification, ×100 (c)] and in the alveolar walls (arrows) [original magnification, ×400 (d)]. Negative controls for the DNA nick-end-labeling assay are shown in e and f.
Figure 6.
Figure 6.
H&E preparation and DNA end-nick-labeling assay from consecutive sections of the caudal lung lobe of a wild-type mouse 24 hours after intranasal instillation of an irrelevant control mAb. The H&E preparation shows normal lung architecture [original magnifications, ×100 (a); ×400 (b)], whereas the DNA nick-end-labeling assay shows no positive cells [original magnifications, ×100 (c); × 160 (d)]. Negative controls for the DNA nick-end-labeling assay are shown in e (original magnification, ×100) and f (original magnification, ×160).
Figure 7.
Figure 7.
Electron micrographs from the lungs of a wild-type mouse 24 hours after intranasal instillation of Fas activating mAb Jo2, showing alveolar type II cells with very electron dense cytoplasm, and swollen mitochondria (M) with irregular cristae. In b the nuclear chromatin is condensed at the periphery of the nucleus. Some of the lamellar bodies (LB) are degranulating (arrows). N nucleus. Original magnification, ×13,500.
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