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A1864 - Effects of Ursolic Acid on Acute Lung Injury Induced Diaphragm Dysfunction Effects of Ursolic Acid on Acute Lung Injury Induced Diaphragm Dysfunction
Author Block: L. P. Callahan, E. A. Schroder, L. Wang, G. S. Supinski; Pulmonary, Critical Care and Sleep Medicine, University of Kentucky, Lexington, KY, United States.
Rationale: Acute lung injury (ALI) is an important cause of critical illness and need for mechanical ventilation. Moreover, it is now recognized that diaphragm and limb muscle weakness acquired during critical illness is a significant form of organ failure and contributes to acute and long term morbidity and mortality. We recently showed that ALI is a major cause of diaphragm weakness, inducing marked derangements in diaphragm specific force generation, fatiguability, mitochondrial dysfunction, and atrophy. Unfortunately, there are no treatments for critical illness induced diaphragm dysfunction. Interestingly, recent work suggests that ursolic acid, a naturally occurring pentacyclic acid present in apple peels, improves muscle force generation, activates mitochondrial biogenesis, and restores muscle mass. Objective: The purpose of the present study was to test the hypothesis that administration of ursolic acid would improve ALI-induced diaphragm dysfunction. Methods: Three groups of CD1 mice (n=4-6/group) were studied: controls (injected intratracheally with saline), ALI (injected intratracheally with lipopolysaccharide, 10 mg/kg, and ALI + urosolic acid (200 mg/kg twice daily, intraperitoneally). Three days post-intratracheal injections, diaphragm specific force generating capacity, fatiguability, mitochondrial function and mass were measured. Results: Administration of ursolic acid did not improve diaphragm specific force generation in ALI (maximum force generation was 29.0 ± 1.3 N/cm2, 17.3 ± 1.5 N/cm2, and 18.4 ± 2.0 N/cm2 for controls, ALI, and ALI + ursolic acid groups). Moreover, ALI-induced diaphragm fatiguability did not recover with administration of ursolic acid. Ursolic acid administration also did not increase ALI-induced reductions in diaphragm mitochondrial function (State 3 rates averaged 549 ± 15, 341.7 ± 15, 365 ± 24 natoms O/min/mg mitochondrial protein, respectively, for control, ALI, and ALI + ursolic acid treated groups). In addition, ALI-induced reductions in diaphragm mass were not restored with ursolic acid administration. Conclusions: While ursolic acid is an emerging neutraceutical with reported beneficial effects on skeletal muscle function in a variety of diseases, our results indicate that ursolic acid does not improve ALI-induced diaphragm weakness. One potential explanation for our results is that mechanisms by which ursolic acid exerts its beneficial effects do not play a role in ALI-induced diaphragm dysfunction. Accordingly, additional work is required to identify safe and easily translatable agents which can improve diaphragm dysfunction produced by ALI. Such therapies are likely to improve acute and long term morbidity and mortality due to critical illness acquired diaphragm weakness.