The Impact of Atypical MAPK p38 Signaling in Inflammatory Disease Progression in the Mouse Lung

Abstract ID 100841 Poster Board 161 Mitogen-activated protein kinase (MAPK) p38 is a critical mediator of vascular disruption/edema and inflammatory signaling associated with acute lung injury (ALI) and is a desirable therapeutic target. However, p38-directed therapeutics have largely failed in the clinic due to the ubiquitous role of p38 activity. An atypical p38 activation pathway has recently been discovered that selectively regulates pathological signaling, but the role of this underexplored pathway has not been investigated in pulmonary function. Atypical p38 signaling in the vasculature rapidly induces the production of inflammatory cytokine expression, vascular disruption, and macrophage recruitment. Our goal is to understand the impact of atypical p38 signaling in the murine lungs during ALI. We hypothesized that atypical p38 activation plays a key role in propagating vascular disruption, alveolar damage, and pulmonary inflammatory responses in ALI. To explore this hypothesis, we utilized systemic Tab1KI C57BL6 mice compared with wild-type C57BL6 mice, and two models to induce ALI 1) lipopolysaccharide (LPS)-induced injury, or 2) Influenza A-induced injury. We predicted that blockade of atypical p38 signaling would significantly reduce pulmonary edema in vivo and establish a role in endothelial barrier dysregulation, cytokine production, and immune recruitment. Hematoxylin and eosin (H&E) staining revealed that Tab1KI mice display protection after LPS and Influenza infection. Tab1KI mice displayed differential gene expression of inflammatory markers, as well as suppressed inflammatory protein expression and disrupted phosphorylation via immunoblotting. We also assessed viral titers in influenza-infected lung homogenate to examine how atypical p38 affects viral replication. These studies will provide important innovative insight into the role of atypical p38 signaling in driving pulmonary inflammation and vascular dysregulation/edema, both major contributors to morbidity in patients with ALI. Georgia CTSA TL1 TR002382, UL1TR002378 NIH R03AI171967-01