Depletion of resident alveolar macrophages does not prevent Fas-mediated lung injury in mice

Abstract

Activation of the Fas/Fas ligand (FasL) system in the lungs results in a form of injury characterized by alveolar epithelial apoptosis and neutrophilic inflammation. Studies in vitro show that Fas activation induces apoptosis in alveolar epithelial cells and cytokine production in alveolar macrophages. The main goal of this study was to determine the contribution of alveolar macrophages to Fas-induced lung inflammation in mice, by depleting alveolar macrophages using clodronate-containing liposomes. Liposomes containing clodronate or PBS were instilled by intratracheal instillation. After 24 h, the mice received intratracheal instillations of the Fas-activating monoclonal antibody Jo2 or an isotype control antibody and were studied 18 h later. The Jo2 MAb induced increases in bronchoalveolar lavage fluid (BALF) total neutrophils, lung caspase-3 activity, and BALF total protein and worsened histological lung injury in the macrophage-depleted mice. Studies in vitro showed that Fas activation induced the release of the cytokine KC in a mouse lung epithelial cell line, MLE-12. These results suggest that the lung inflammatory response to Fas activation is not primarily dependent on resident alveolar macrophages and may instead depend on cytokine release by alveolar epithelial cells.

Monocytes Control Second-Phase Neutrophil Emigration in Established Lipopolysaccharide-induced Murine Lung Injury

“…In keeping with previous studies in rodents (36,37), prior compartmental depletion of resident AMs did not reduce experimental pulmonary inflammation ( Figure E3). …”

CD40 amplifies Fas-mediated apoptosis: a mechanism contributing to emphysema

“…Surface expression of CD40 on pulmonary dendritic cells has been reported to be increased by smoke inhalation in mice (11). However, Matute et al (4,25) reported that, in acute lung injury, Fas directly affects alveolar cells, not via myeloid cells such as alveolar macrophages. Indeed, we did not detect increased numbers of apoptotic immune cells in lungs of our mouse models.…”

Divergent Effects of Neutrophils on Fas-Induced Pulmonary Inflammation, Apoptosis, and Lung Damage

“…Fas-induced lung injury requires Fas-expression on nonmyeloid cells of the lung [120], emphasizing the role of lung epithelial cell dependent mediator release, and apoptosis. In the absence of resident AM, Fasinduced lung damage was worsened [21], displayed by significantly increased BAL protein concentration and lung histology. Furthermore, depletion of AM increased lung damage and inflammation following non-lethal unilateral lung contusion in mice [109].…”

“…Among the discussed signal transduction pathways nuclear factor-kappa B (NF-B) [145], extracellular signal regulated kinase 1/2 (ERK 1/2), and mitogen-activated protein kinase p38 (p38 MAPK) [141] have been suggested to be involved. The observation of a marked inflammatory response in the absence of alveolar macrophages [21,152] is important because it suggests that other cell types in the lung can promote inflammation in response to Fas. An important role of neutrophils in Fas-induced inflammation has been suggested and was part of this study.…”