Endothelial Focal adhesion kinase maintains lung fluid balance and prevents cytokine storm

Abstract

Sepsis‐induced acute lung injury (ALI) results from inflammatory cell infiltration and protein‐rich edema formation. Since focal adhesion kinase (FAK) influences adherens junction formation required for establishing the endothelial barrier, we generated tamoxifen‐inducible endothelial (EC) FAK deficient transgenic mice (EC‐FAK−/−) to address whether FAK controls pulmonary fluid balance and inflammation. EC‐FAK deletion severely disrupts the lung vasculature and promotes pro‐inflammatory cytokine generation such that EC‐FAK−/− mice have increased mortality to endotoxin (LPS). FAK null lung ECs showed actin stress fiber formation, adherens junction disassembly and increased pro‐inflammatory cytokine levels, naming EC‐FAK as a central regulator of lung fluid balance and inflammation. Mechanistically, loss of FAK markedly altered the balance of small GTPases RhoA and Rac1; RhoA activity was significantly increased whereas Rac1 was decreased in FAK null ECs. FAK deletion also amplified p38MAPK activity, which is known to generate cytokines downstream of toll‐like receptors. We confirmed these findings using siRNA‐mediated FAK suppression in human pulmonary ECs. Moreover, EC‐FAK levels were decreased in lungs of patients diagnosed with lung disease and in mice following sepsis. Thus, upregulating endothelial‐FAK provides an unexpected mechanism for preventing cytokine storm and ALI.