title: Enhanced enzymatic degradation of tryptophan by indoleamine 2,3-dioxygenase contributes to the tryptophan-deficient state seen after major trauma.
abstract: Decreased lymphocyte proliferation, lymphopenia, immunodepression, and opportunistic infections are common after major trauma. Early alimentation in these patients corrects lymphopenia, enhances immunity, and reduces the incidence of infections, but the underlying mechanisms are poorly understood. Tryptophan is essential for the production and function of rapidly proliferating cells such as lymphocytes. Tryptophan is enzymatically degraded by indoleamine 2,3-dioxygenase (IDO), whose activity is solely dependent on expression of interferon-gamma (IFN-gamma). Because increased expression of IFN-gamma has been reported in trauma patients, we investigated whether enhanced IDO-mediated tryptophan degradation is associated with lymphopenia and poor outcomes after major trauma. The incidence of bacteremic sepsis (BS), adult respiratory distress syndrome (ARDS), multiple organ dysfunction/failure syndromes (MODS/MOF), and death was prospectively documented in 22 trauma patients with a mean ISS of 24.9 +/- 2.2. Sequential blood samples were obtained from admission through postinjury day 10. Five patients developed BS, three of whom developed ARDS; two of the three ARDS patients developed MOF and died on day 10. Trauma patients had significantly lower tryptophan levels (days 1-10), higher kynurenine:tryptophan ratios (days 1-2), and fewer lymphocytes (days 1-4) than healthy volunteers (P < 0.05). Although patients with poor outcomes (i.e., BS, ARDS, MOF, and death) had significantly lower tryptophan levels and greater lymphopenia on several days after injury, the sample size was too small to draw any definitive conclusions. These data indicate that decreased plasma tryptophan levels and lymphopenia typically occur after major trauma. A concomitant increase in kynurenine suggests that the observed tryptophan deficiency is caused, in part, by IDO-mediated tryptophan degradation.
authors.affiliation: Department of Surgery, M. L. King, Jr./Drew Medical Center, Los Angeles, California, USA. kathpellegrin@aol.com
authors.forename: Katharina
authors.initials: K
authors.lastname: Pellegrin
authors.forename: Gabriele
authors.initials: G
authors.lastname: Neurauter
authors.forename: Barbara
authors.initials: B
authors.lastname: Wirleitner
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Fleming
authors.forename: Verlyn M
authors.initials: VM
authors.lastname: Peterson
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fuchs
mesh_terms: D000293:Adolescent; D000328:Adult; D016470:Bacteremia / Q000097:blood / Q000209:etiology; D016022:Case-Control Studies; D002648:Child; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000378:metabolism; D007737:Kynurenine / Q000097:blood; D008231:Lymphopenia / Q000209:etiology; D008297:Male; D009102:Multiple Organ Failure / Q000097:blood / Q000209:etiology; D011379:Prognosis; D011446:Prospective Studies; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000209:etiology; D018805:Sepsis / Q000097:blood / Q000209:etiology; D014364:Tryptophan / Q000097:blood* / Q000172:deficiency*; D014366:Tryptophan Oxygenase / Q000378:metabolism*; D014947:Wounds and Injuries / Q000097:blood* / Q000150:complications
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase