Apoptosis and epithelial injury in the lungs

Abstract

Epithelial injury is a critical event in the development of acute lung injury, but the mechanisms that cause death of the alveolar epithelium are not completely understood. Epithelial death occurs by necrosis and apoptosis; more information is needed about the balance between these two types of cell death in the lungs. Direct epithelial necrosis probably occurs in response to bacterial exotoxins and over-distension of alveolar units by mechanical ventilation. Apoptosis is a regulated form of cell death that is mediated by membrane death receptors and direct mitochondrial injury. Apoptosis pathways are activated in the lungs of patients with acute lung injury, in part by activation of the membrane Fas death receptor by soluble Fas ligand (sFasL), which accumulates in biologically active form at the onset of lung injury. Accumulating evidence in humans and experimental models links sFasL and Fas pathway with lung epithelial injury and fibrosis. New strategies to inhibit Fas-mediated epithelial apoptosis need to be developed in order to develop new ways to preserve epithelial function in patients who develop acute lung injury.

Figure 1.

Cellular pathways that mediate apoptosis. A family of death receptors can initiate apoptosis, and their relative importance depends on the cell type. Two major pathways are shown here: the Fas receptor pathway and the receptor-independent mitochondrial pathway. The various membrane receptors share some components of the signaling pathways shown. DcR3 is unique, however, as it is a truncated receptor that does not signal. The soluble form of DcR3 functions as a decoy receptor that blocks receptor/ligand-mediated apoptosis.

Figure 2.

Soluble Fas ligand concentrations (sFasL) measured by specific immunoassay in the bronchoalveolar lavage fluid of normal volunteers (Normal), patients at risk for ARDS because of either clinical sepsis or trauma (At risk), and patients with established ARDS (ARDS). The horizontal axis shows the day on which bronchoalveolar lavage was performed (from Reference 39).

Figure 3.

Interactions between the Fas-dependent apoptosis pathway and the TLR4 pathway that mediates cellular activation in response to bacterial lipopolysaccharide. FADD, Fas-associated death domain protein. The FADD protein shuttles back and forth between the Fas intracellular tail, where it promotes apoptosis, and the TLR4 adaptor protein, MyD88, where it antagonizes TLR4-dependent signaling.