Characterization of Atypical p38 signaling in Acute Lung Injury

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Mitogen-activated protein kinase (MAPK) p38 is a critical mediator of vascular disruption/edema and inflammatory signaling associated with acute lung injury (ALI), acute respiratory distress syndrome (ARDS). However, p38 directed therapeutics have failed in the clinic due to the physiologically ubiquitous role of p38 activity in all tissues. Thus, there is an essential need to explore alternative mechanisms that selectively regulate pathological p38 signaling pathways. An understudied atypical p38 activation pathway has recently been discovered that selectively regulates pathological signaling induced via a direct p38 interaction with the adaptor protein TAB1, independent from classical p38 activation by MKK3/6. The role of this underexplored pathway in pulmonary function has not been investigated, representing a major gap in our molecular knowledge of ALI/ARDS. P38 signaling is known to regulate inflammatory cytokine expression, vascular dysfunction, macrophage and neutrophil activation and recruitment, enhancing the progression of pulmonary damage. Atypical p38 signaling in the vasculature rapidly induces production of inflammatory cytokine expression and blood vessel leakage, and macrophage recruitment. The goal of these studies is to understand the physiological impact that atypical MAPK p38 signaling has in pulmonary vasculature during the initial stages of LPS induced acute lung injury, and its contribution to pulmonary damage. Our central hypothesis disruption, alveolar damage, is that atypical p38 activation plays a key role in propagating vascular and pulmonary inflammatory responses in acute lung injury. From this hypothesis we propose two specific aims: 1) Characterize the contribution of atypical p38 signaling to pulmonary edema/vascular dysregulation, 2) Characterize atypical p38 pro-inflammatory responses in ALI. We will also use an acute lung injury (ALI) model using lipopolysaccharide (LPS) in a systemic TAB1-KI mouse verses wild-type mouse and a cell-penetrating inhibitor peptide which can block atypical p38 signaling. We predict that blockade of atypical p38 signaling will significantly reduce pulmonary edema in vivo and establish a critical role in endothelial barrier dysregulation in vitro and in vivo. Furthermore, we predict that these studies will demonstrate a clear role for atypical p38 signaling in cytokine expression, leading to activation and recruitment of neutrophils and macrophages. Critically, these studies will be the first to define the role of atypical p38 signaling in acute lung injury and provide essential foundational evidence for further more detailed studies into pulmonary atypical p38 signaling. Furthermore, these studies will demonstrate the future therapeutic potential for selectively inhibiting atypical p38 signaling in vascular and pulmonary inflammatory diseases.