American journal of physiology. Cell physiology
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Am. J. Physiol., Cell Physiol. · Jul 2013
NLRP3 deletion protects from hyperoxia-induced acute lung injury.
Inspiration of a high concentration of oxygen, a therapy for acute lung injury (ALI), could unexpectedly lead to reactive oxygen species (ROS) production and hyperoxia-induced acute lung injury (HALI). Nucleotide-binding domain and leucine-rich repeat PYD-containing protein 3 (NLRP3) senses the ROS, triggering inflammasome activation and interleukin-1β (IL-1β) production and secretion. However, the role of NLRP3 inflammasome in HALI is unclear. ⋯ Hyperoxia-induced recruitment of inflammatory cells and elevation of IL-1β, TNFα, macrophage inflammatory protein-2, and monocyte chemoattractant protein-1 were attenuated in NLRP3(-/-) mice. NLRP3 deletion decreased lung epithelial cell death and caspase-3 levels and a suppressed NF-κB levels compared with WT controls. Taken together, this research demonstrates for the first time that NLRP3-deficient mice have suppressed inflammatory response and blunted lung epithelial cell apoptosis to HALI.
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Am. J. Physiol., Cell Physiol. · Jul 2013
A differential role of macrophage TRPM2 channels in Ca²⁺ signaling and cell death in early responses to H₂O₂.
Reactive oxygen species such as H₂O₂ elevates the cytosolic Ca²⁺ concentration ([Ca²⁺]c) and causes cell death via poly(ADPR) polymerase (PARP) activation, which also represents the primary mechanism by which H₂O₂ activate the transient receptor potential melastatin-related 2 (TRPM2) channel as a Ca²⁺-permeable channel present in the plasma membrane or an intracellular Ca²⁺-release channel. The present study aimed to define the contribution and mechanisms of the TRPM2 channels in macrophage cells in mediating Ca²⁺ signaling and cell death during initial response to H₂O₂, using mouse peritoneal macrophage, RAW264.7, and differentiated THP-1 cells. H₂O₂ evoked robust increases in the [Ca²⁺]c, and such Ca²⁺ responses were significantly greater at body temperature than room temperature. ⋯ H₂O₂ reduced macrophage cell viability in a duration- and concentration-dependent manner. H₂O₂-induced cell death was significantly attenuated by pretreatment with PJ-34 and TRPM2 channel deficiency but remained significant and persistent. Taken together, these results show that the TRPM2 channel in macrophage cells functions as a cell surface Ca²⁺-permeable channel that mediates Ca²⁺ influx and constitutes the principal Ca²⁺ signaling mechanism but has a limited, albeit significant, role in cell death during early exposure to H₂O₂.