Septic acute lung injury (ALI) causes high morbidity and mortality in intensive care service as a result of biotrauma and dysfunction in the lungs and other organ systems. We hypothesized that surfactant and/or inhaled nitric oxide (iNO) may have different effects in modulation of inflammatory injury in septic ALI. Twenty-four healthy, 6-9 kg piglets were anesthetized, and intraperitoneally injected with Escherichia coli, followed by a low tidal volume ventilation until sepsis and ALI developed within 4-6 h. They were then randomly treated in groups (n=6 each) as: control (C), inhaled NO at 10 ppm (NO), surfactant at 100mg/kg (Surf), or both surfactant and iNO (SNO). A normal control group (N) was sham-injected and similarly ventilated. Over the 24 h of treatment period, both Surf, and SNO groups had significantly improved PaO2/FiO2, dynamic compliance and resistance of respiratory system. At 24h, the best alveolar aeration and least protein leakage, the lowest wet-to-dry lung weight ratio and lung injury score were found in SNO. Activity of nuclear factor kappa B (NF-kappaB) and myeloperoxidase, interleukin 8 mRNA expression and melondialdehyde were significantly increased, and IL-10 mRNA decreased, in lung tissue of the C group, but were significantly altered in the SNO group, and moderately altered in either NO or Surf group. We conclude that the effects of lung protection by surfactant and/or iNO in this model may be different in modulation of inflammatory cytokine mRNA expression and activity of NF-kappaB, and iNO did not have adverse effects.