Hypothermia protects against ventilator-induced lung injury by limiting gasdermin D activation and NET formation

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B827
Abstract ID: 5173

Presenting Author:
Vanessa Borges , Post Doctoral Scientist at Cedars-Sinai Med. Ctr.

Abstract:

Although mechanical ventilation (MV) is a critical intervention to acute respiratory distress syndrome (ARDS), it can trigger an IL-1β-associated complication known as ventilator-induced acute lung injury (ALI). In mice, we found that LPS and high-volume ventilation, LPS-HVV, leads to hypoxemia with albumin leakage, IL-1β release, neutrophil migration and neutrophil extracellular traps (NET) formation in alveoli. DNase I treatment prevented ALI development, indicating that NET are required for LPS-HVV-induced ALI. Furthermore, IL-1R1^-/- LPS-HVV mice did not develop hypoxemia and had lower NET levels in the alveoli, indicating that IL-1R1 signaling plays a role in NET formation. Indeed, IL-1β enhanced NET induction by ionomycin. Therapeutic hypothermia (TH) is known to reduce the release of inflammatory mediators, including IL-1β. Accordingly, we investigated the potential of TH to modulate ALI. In LPS-HVV mice, TH (32 ºC body temperature) prevented hypoxemia development, reducing albumin leakage, IL-1β release, GSDMD concentration and NET formation. We also observed that LPS-primed macrophages stimulated at 32ºC with ATP or nigericin have reduced IL-1β release and inhibited gasdermin D (GSDMD) cleavage. Furthermore, neutrophils stimulated with ionomycin at 32ºC formed fewer NETs.  Thus, hypothermia is an important modulating factor for the expression and activation of GSDMD in NLRP3 inflammasome activation, IL-1β release and NET formation, preventing LPS-HVV-induced ALI.