THE RELATIONSHIP BETWEEN ARGINASE, NOS, AND ADMA TO ACUTE LUNG INJURY IN SEPSIS

Linda Sousse¹, C.Jonkam, M.D. ², D.Traber, Ph.D. ², L.Traber, R.N.², D.Herndon, M.D. ³, and P. Enkhbaatar, M.D., Ph.D.²

¹Departments of Pathology and ²Anesthesiology, UTMB, ³Shriner’s Burn Hospital for Children

Background: More than 750,000 patients in the United States develop sepsis annually. Previously, we have demonstrated variant arginase activity that is dependent on the nature of the causative agent such as Pseudomonas aeruginosa (PA) or Methicillin-resistant Staphylococcus aureus (MRSA). Objective: We hypothesize that asymmetrical dimethyl-arginine (ADMA) causes a decrease in nitric oxide (NO) production, increasing arginine availability and resulting in increased arginase activity in PA sepsis. Methods: Ewes were operatively prepared and randomized after a 7-day recovery period into control, MRSA, and PA groups (n=6). Injury consisted of instillation of 2-5 x 10<sup>11 CFU of live MRSA or PA into the airway; animals were sacrificed after 24 hours. In addition, groups of C57Bl/6J, iNOS and nNOS knockout mice (n=8) were nasally inoculated with 2-5 x 10<sup>5 CFU of live MRSA or PA and were sacrificed after 8 hours. Results: PA induced a more severe lung injury compared to MRSA (PaO₂/FiO₂: 319 ± 82 vs 205 ± 72). PA-treated sheep had a larger increase in arginase activity compared to MRSA-treated sheep (1.55 ± 0.16 uM urea/uG protein vs 1.33 ± 0.11) and had significantly higher ADMA (1.79 uM ± 0.14 vs 1.30 ± 0.28, p<0.05). PA-treated sheep had significantly lower plasma NOx compared to MRSA-treated sheep. iNOS knockout mice treated with PA vs MRSA had significantly higher arginase activity (10.96 ± 1.43 vs 4.18 ± 0.32, p<0.05). nNOS knockout mice treated with PA had significantly higher arginase activity as well (14.12 ± 1.48 vs 5.07 ± 0.59, p<0.05). Conclusions: The results strongly suggest that the severity of acute lung injury in PA sepsis is due to the increased activity of ADMA and arginase. Treatment strategies for PA and MRSA should consider their different host responses. For possible therapeutic intervention, effects of arginase inhibitors should be tested.

(Supported by Shriners Hospitals for Children, No.8541)