Activated platelets trigger injurious NET formation in a model of VILI. In a murine model of VILI, high-pressure mechanical ventilation activates platelets, leading to heterodimerization of CXCL4 and CCL5 as well as expression of a β₂-integrin ligand. Simultaneous binding of the CXCL4/CCL5 heterodimer and β₂-integrin ligand to the GPCR and Mac-1, respectively, trigger pulmonary NET formation, leading to NET-mediated lung injury. MKEY, a peptide that blocks the CXCL4/CCL5 heterodimerization, and an anti-Mac-1 blocking antibody inhibit NET formation and significantly ameliorate lung injury in this model of sterile inflammation.