Protection against lung damage in reduced-size liver transplantation.
OBJECTIVE
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.


METHODS
Randomized and controlled animals study.


METHODS
Experimental laboratory.


METHODS
Male Sprague-Dawley rats.


METHODS
Lung damage was evaluated in ROLT with or without preconditioning. Nitric oxide and interleukin (IL)-1 actions were altered pharmacologically.


RESULTS
IL-1, tumor necrosis factor (TNF)-alpha, 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-1alpha 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-1alpha and lung damage, reduced systemic sTNFR2 and increased free TNF levels. These injurious effects were avoided when IL-1 action was inhibited.


CONCLUSIONS
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.
Hepatology Unit, Investigaciones Biomédicas de Barcelona August Pi i Sunyer, Consejo Superior de Investigaciones Científicas (IDIBAPS-CSIC), Barcelona, Spain.
Rosa
R
Franco-Gou
Joan
J
Roselló-Catafau
Carmen
C
Peralta
D000818:Animals; D000068800:Etanercept; D007074:Immunoglobulin G / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D019194:Ischemic Preconditioning; D016031:Liver Transplantation; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007074:Immunoglobulin G; D007375:Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000068800:Etanercept