A Critical Role for P2X7 Receptor–Induced VCAM-1 Shedding and Neutrophil Infiltration during Acute Lung Injury

Abstract

Pulmonary neutrophils are the initial inflammatory cells that are recruited during lung injury and are crucial for innate immunity. However, pathological recruitment of neutrophils results in lung injury. The objective of this study is to determine whether the novel neutrophil chemoattractant, soluble VCAM-1 (sVCAM-1), recruits pathological levels of neutrophils to injury sites and amplifies lung inflammation during acute lung injury. The mice with P2X7 receptor deficiency, or treated with a P2X7 receptor inhibitor or anti-VCAM-1 antibodies were subjected to a clinically relevant two-hit LPS and mechanical ventilation-induced acute lung injury. Neutrophil infiltration and lung inflammation were measured. Neutrophil chemotactic activities were determined by a chemotaxis assay. VCAM-1 shedding and signaling pathways were assessed in isolated lung epithelial cells. Antibody neutralization of sVCAM-1 or deficiency or antagonism of P2X7R reduced neutrophil infiltration and proinflammatory cytokine levels. The ligands for sVCAM-1 were increased during acute lung injury. sVCAM-1 had neutrophil chemotactic activities and activated alveolar macrophages. VCAM-1 is released into the alveolar airspace from alveolar epithelial type I cells through P2X7 receptor-mediated activation of the metalloproteinase ADAM-17. In conclusion,sVCAM-1 is a novel chemoattractant for neutrophils and an activator for alveolar macrophages. Targeting sVCAM-1 provides a therapeutic intervention that could block pathological neutrophil recruitment, without interfering with the physiological recruitment of neutrophils, thus avoiding the impairment of host defenses.

Induced Pluripotent Stem Cells Regulate Triggering Receptor Expressed on Myeloid Cell-1 Expression and the p38 Mitogen-Activated Protein Kinase Pathway in Endotoxin-Induced Acute Lung Injury

“…VCAM‐1 also mediates the chemotactic activities of neutrophils and activates alveolar macrophages . In the present study, a high concentration of VCAM‐1 was detected in BALF following LPS induction of ALI, and this result is consistent with the observation that blocking of alveolar VCAM‐1 activity is protective in ALI . The p38 MAPK pathway has also been shown to play a critical role in regulating VCAM‐1 expression .…”

Interleukin-1β is a potential therapeutic target for periodontitis: a narrative review

“…38 An antagonist of the P2X7 receptor, AZ106006120, reduces neutrophil infiltration and the secretion of pro-inflammatory cytokines in a mouse model of acute lung injury. 151 Several P2X7 antagonists are in clinical trials for inflammatory or pain-related diseases. Unfortunately, AstraZeneca's AZD-9056 and Pfizer's CE-224,535 failed in phase II clinical trials.…”

Frontline Science: Macrophage-derived exosomes promote neutrophil necroptosis following hemorrhagic shock

“…PMNs are the most abundant circulating leukocytes in humans and play important roles in the innate immune response through rapid recruitment into sites of infection and injury . However, overproduction of hydrolytic enzymes and ROS by PMN have been considered major causes of PMN‐mediated damage to local surrounding tissues . PMN apoptosis, a form of regulated noninflammatory cell death, has been reported as an effective approach to control the number of local PMNs, thereby facilitating a negative‐feedback mechanism for inflammation and promoting its resolution .…”

“…5 However, overproduction of hydrolytic enzymes and ROS by PMN have been considered major causes of PMN-mediated damage to local surrounding tissues. 6 PMN apoptosis, a form of regulated noninflammatory cell death, has been reported as an effective approach to control the number of local PMNs, thereby facilitating a negative-feedback mechanism for inflammation and promoting its resolution. 7 However, emerging evidence has shown that other types of regulated inflammatory PMN death may also occur during inflammation, which can exaggerate inflammation through release of DAMPs.…”