Fas Ligand Released by Activated Monocytes Causes Apoptosis of Lung Epithelial Cells in Human Acute Lung Injury Model in Vitro

Abstract

Acute lung injury (ALI) is defined as an inflammatory lung condition that is mediated by the interplay between inflammatory cells such as phagocytes, in particular macrophages and neutrophils, and non-immune cells such as alveolar epithelial cells. 1,2) Because the overall risk of mortality for ALI or acute respiratory distress syndrome (ARDS) patients remains unacceptably high, an improved understanding of the pathophysiology is needed to reduce mortality through the development of treatments that will be additive or synergistic with mechanical ventilation strategies using low tidal volumes.3) Recently, the several investigators have proposed that lung epithelial cell death occurs not only through necrotic processes, such as through ischemic change or direct disruption, but also by apoptotic processes. 1,4,5) Apoptosis, a form of programmed cell death characterized by nuclear condensation and endonuclease-mediated DNA fragmentation, is essential to tissue development and preservation of cell membrane integrity. Apoptosis also appears to be important in the pathophysiology of some diseases. [6][7][8][9] The Fas-Fas ligand (FasL) system comprises an important mechanism for regulating apoptotic cell death. The Fas antigen (CD95, APO-1) belongs to a conserved family of membrane receptors known as the tumor necrosis factor (TNF) receptor family, 10) and is expressed on various cells and tissues, including thymus, liver, heart, and lung. FasL is a type II integral membrane protein of the TNF family.11) Membranebound FasL is cleaved by specific matrix metalloproteinases to produce its soluble form.12) Although expression of FasL was originally thought to be limited to cytotoxic T cells, it also has been found in other types of cells.11) Polymorphonuclear neutrophils (PMN) release soluble FasL, which can induce apoptosis in certain Fas bearing cell types, including PMN themselves. 13,14) High levels of preformed FasL are found in the intracellular compartment, and stimulation of monocytic cells by phytohaemagglutinin or superantigen gives rise to the rapid release of soluble FasL. 15)Binding of FasL to Fas antigen causes apoptosis in Fas antigen-bearing cells via an apoptotic pathway that is dependent on the initiator caspase-8.16) Cross-linking of the extracellular domains of Fas by FasL results in Fas trimerization and intracellular recruitment of the adapter molecule Fas-associated death domain protein (FADD) to the receptor cluster. Recruitment is facilitated by homotypic interaction between death domains located in Fas and FADD. Receptorbound FADD oligomerizes and utilizes a second domain, the death effector domain, to recruit procaspase-8, forming the Fas/FADD/procaspase-8 complex known as the death-inducing signaling-complex (DISC).17,18) DISC catalyzes the proteolytic conversion of procaspase-8 into active caspase-8, which activates the downstream effector caspases, triggering cell death. Apoptosis also occurs via a mitochondria-mediated process, which begins with mitochondrial permeability transition, followed...

Resolvin D1 reduces deterioration of tight junction proteins by upregulating HO-1 in LPS-induced mice

“…Studies have shown that ALI is associated with increased cell death in humans, 38 while apoptosis inhibitors showed increased survival rodent models of ALI. 5,39 HO-1-mediated degradation of heme also releases CO.…”

Analysis of cytotoxicity induced by proinflammatory cytokines in the human alveolar epithelial cell line A549

“…In addition, cytomix showed the most prominent increase in level of cleaved cytokeratin 18. In addition to IFN-γ, to explore a more appropriate combination of inflammatory mediators, cytotoxicity of other inflammatory mediators, such as Fas ligand, IL-6, or high-mobility group box 1 (HMGB1), was also investigated because these mediators have been reported to play significant roles in sepsis (14,21,23). With contrast to IFN-γ, however, Fas ligand, IL-6, or HMGB1 failed to show cytotoxicity in A549 cells, either alone or in combination with IL-1β/TNFγ, up to 100 ng/mL ( Figure S1) (http://www.biosciencetrends.…”

“…Then, to clarify the cytotoxic signaling pathways responsible for alveolar epithelial cell injury, various agents with antiinflammatory or antioxidative properties were screened for cytoprotective effects in an in vitro acute lung injury model (9,(14)(15)(16)(17).…”

3-Oxoolean-12-en-27-oic Acid Isolated from Aceriphyllum rossii Induces Caspase-8-Dependent Apoptosis in Human Promyelocytic Leukemia HL-60 Cells

“…7,8) The second pathway regulates the apoptotic cascade via a convergence of signaling at mitochondria, such as, those signals mediated by Bcl-2 family proteins. This pathway involves altered mitochondrial membrane potentials, the release of cytochrome c into the cytosol, and the activation of procaspase-9, which is followed by the activations of effector caspases like caspase-3 and -7.…”

“…6) Furthermore, interaction between Fas and FasL induces apoptotic cell death and altered levels of Fas/FasL expression have been implicated in the pathogenesis of diseases associated with immune regulation. 7,8) The second pathway regulates the apoptotic cascade via a convergence of signaling at mitochondria, such as, those signals mediated by Bcl-2 family proteins. This pathway involves altered mitochondrial membrane potentials, the release of cytochrome c into the cytosol, and the activation of procaspase-9, which is followed by the activations of effector caspases like caspase-3 and -7.…”