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This study examined the effect of ischemic preconditioning on pulmonary damage associated with reduced-size orthotopic liver transplantation (ROLT) and attempted to identify the underlying protective mechanisms.Randomized and controlled animals study.Experimental laboratory.Male Sprague-Dawley rats.Lung damage was evaluated in ROLT with or without preconditioning. Nitric oxide and interleukin (IL)-1 actions were altered pharmacologically.IL-1, tumor necrosis factor (TNF)-α, soluble TNF receptors (sTNFR), and inflammatory response in lung were measured after ROLT. Our results indicate the involvement of IL-1 in the lung damage following ROLT. Ischemic preconditioning, mediated by nitric oxide, reduced IL-1 release and protected against lung damage. Nitric oxide synthesis inhibition in the preconditioned group led to increased IL-1 levels and increased lung damage following ROLT, whereas the addition of IL-1 receptor antagonist protected against the injurious effects of nitric oxide inhibition. In addition, nitric oxide pretreatment gave similar results in terms of IL-1α and lung protection to those found in preconditioning. The benefits to the lung attributable to IL-1 inhibition might be linked to the effect of this cytokine on sTNFR, an endogenous mechanism that modulates systemic TNF actions. In fact, strategies aimed at inhibiting IL-1 action, including IL-1 receptor antagonist, ischemic preconditioning, and nitric oxide donor, increased systemic sTNFR2 and decreased free TNF, following ROLT. Similarly, nitric oxide synthesis inhibition in the preconditioned group, which increased IL-1α and lung damage, reduced systemic sTNFR2 and increased free TNF levels. These injurious effects were avoided when IL-1 action was inhibited.Ischemic preconditioning and pharmacologic strategies that simulate its benefits protected against lung damage in an experimental model of ROLT. Our results also suggest a potential relationship between nitric oxide, IL-1, and TNF/sTNF in the benefits of preconditioning on the lung damage associated with ROLT.