L-arginine decreases alveolar macrophage proinflammatory monokine production during acute lung injury by a nitric oxide synthase-dependent mechanism.
BACKGROUND
Recent clinical reports indicate that inhaled nitric oxide (NO) reduces lung parenchymal inflammation during acute lung injury; however, the mechanism of its protective effects remains incompletely understood. We hypothesized that the provision of substrate for local NO production (L-arginine) would reduce alveolar macrophage proinflammatory monokine production during endotoxin (ETX)-induced acute lung injury. Our purposes were to (1) determine alveolar macrophage tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) production after ETX-induced acute lung injury; (2) determine the effect of L-arginine on alveolar macrophage TNFalpha and IL-1beta production in ETX-induced acute lung injury; and (3) determine whether L-arginine's effects on the alveolar macrophage are mediated by NO.


METHODS
Rats received ETX (0.5 mg/kg intraperitoneal (i.p.)) or vehicle, with or without (1) L-arginine supplementation (300 mg/kg i.p.) and (2) nitric oxide synthase inhibition (N(G)-monomethyl-L-arginine, 30 mg/kg i.p.). Four hours later, alveolar macrophage were harvested by bronchoalveolar lavage and incubated at 10(6) cells/mL + 1 microg/mL phorbol myristase acetate for 24 hours. Cell-free supernatants were collected and assayed (enzyme-linked immunosorbent assay) for TNFalpha and IL-1beta.


RESULTS
Sublethal ETX increased alveolar macrophage capacity to produce TNFalpha and IL-1beta (p < 0.05, analysis of variance and Bonferroni/Dunn). L-Arginine decreased alveolar macrophage TNFalpha and IL-1beta release during acute lung injury. Concurrent inhibition of nitric oxide synthase abrogated L-arginine's protective effects, suggesting that L-arginine's anti-inflammatory effects are mediated by NO.


CONCLUSIONS
(1) L-Arginine is an immunomodulating nutritional supplement; (2) L-arginine decreases alveolar macrophage proinflammatory monokine production during ETX-induced acute lung injury by a nitric oxide synthase-dependent mechanism; and (3) the provision of exogenous substrate for local NO production may reduce inflammation during acute lung injury.
Meldrum
D R
DR
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
McIntyre
R C
RC
Sheridan
B C
BC
Cleveland
J C
JC
Fullerton
D A
DA
Harken
A H
AH
D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004353:Drug Evaluation, Preclinical; D004731:Endotoxins / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000276:immunology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011292:Premedication; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D004731:Endotoxins; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase