Mechanistic aspects of inducible nitric oxide synthase-induced lung injury in burn trauma

Abstract Introduction Although the beneficial effects of inducible nitric oxide synthase (iNOS) inhibition in acute lung injury secondary to cutaneous burn and smoke inhalation were previously demonstrated, the mechanistic aspects are not completely understood. The objective of the present study is to describe the mechanism(s) underlying these favourable effects. We hypothesised that iNOS inhibition prevents formation of excessive reactive nitrogen species and attenuates the activation of poly(ADP) (poly(adenosine diphosphate)) ribose polymerase, thus mitigating the severity of acute lung injury in sheep subjected to combined burn and smoke inhalation. Methods Adult ewes were chronically instrumented for a 24-h study and allocated to groups: sham: not injured, not treated, n = 6; control: injured, not treated, n = 6; and BBS-2: injured treated with iNOS dimerisation inhibitor BBS-2, n = 6. Control and BBS-2 groups received 40% total body surface area 3rd-degree cutaneous burn and cotton smoke insufflation into the lungs under isoflurane anaesthesia. Results Treatment with iNOS inhibitor BBS-2 significantly improved pulmonary gas exchange (partial pressure of oxygen in the blood/fraction of inspired oxygen ( Pa O2 / Fi O2 ) 409 ± 43 mmHg vs. 233 ± 50 mmHg in controls, p < 0.05) and reduced airway pressures (peak pressure 20 ± 1 cm H2 O vs. 28 ± 2 cm H2 O in controls, p < 0.05) and lung water content (lung wet-to-dry ratio 4.1 ± 0.3 vs. 5.2 ± 0.2 in controls, p < 0.05) 24 h after the burn and smoke injury. BBS-2 significantly reduced the increases in lung lymph nitrite/nitrate (10 ± 3 μM vs. 26 ± 6 μM in controls, p < 0.05) and 3-nitrotyrosine (109 ± 11 (densitometry value) vs. 151 ± 18 in controls, p < 0.05). Burn/smoke-induced increases in lung tissue nitrite/nitrate, poly(ADP)ribose polymerase, nuclear factor-κB (NF-κB) activity, myeloperoxidase activity and malondialdehyde formation and interleukin (IL)-8 expression were also attenuated with BBS-2. Conclusions The results provide strong evidence that BBS-2 ameliorated acute lung injury by inhibiting the inducible nitric oxide synthase/reactive nitrogen species/poly(ADP-ribose) polymerase (iNOS/RNS/PARP) pathway.