Acute lung injury (ALI) and airway hyperresponsiveness are common characteristics of systemic inflammatory response syndrome (SIRS) and sepsis. N-Formyl peptides are molecules present only in mitochondria (F-MIT) and resemble those expressed in bacteria (F-MLP). We observed that after trauma, F-MIT released from damaged cells activate the innate immune system leading to cardiovascular collapse. Therefore, we hypothesized that F-MIT activates formyl peptide receptor and induces ALI, including airway constriction. Trachea, bronchus and bronchiole from Wistar rats (12 weeks) were cleaned and cut in segments (2-3 mm) to assess airway responsiveness. F-MIT (10-30μM) induced concentration-dependent contraction, and FPR-2 antagonist (WRW4, 10μM), but not FPR-1 antagonist (cyclosporine H, 1μM), decreased this response [maximum response (%KCl) trachea, F-MIT: 60±5 vs. F-MIT+WRW4: 33±6*; bronchus, F-MIT: 67±8 vs. F-MIT+WRW4: 34±2*; bronchiole, F-MIT: 25±8 vs. F-MIT+WRW4: 10±2, *p<0.05]. Basophil depletion (compound 48/80, 25μg/ml) also decreased F-MIT-induced contraction. In another experiment, rats were challenged with F-MIT or non-formylated peptide intratracheally (0.02 mg/rat). Six hours after F-MIT, but not non-formylated peptide treatment, we observed the presence of elastase in lungs and an increased expression of inducible nitric oxide synthase (iNOS) and cell division control protein 42 (CDC42, a protein involved in actin polymerization) in all airway segments. In conclusion, F-MIT via FPR-2 activation, lead to lung injury and airway contraction through mediators released from basophils and actin polymerization. Therefore, F-MIT could be a putative target to treat ALI in trauma-induced SIRS. Support: NIH; AHA, CNPq