Plasma concentrations and anti-L-cytokine effects of alpha-melanocyte stimulating hormone in septic patients

Objectives: The aim of this research was to investigate endogenous concentr ations and anti-cytokine effects of the antiinflammatory peptide alpha-mela nocyte stimulating hormone (alpha-MSH) in patients with systemic inflammati on. The objectives were to determine the following: changes over time of pl asma alpha-MSH and relationship with patient outcome, correlation between p lasma alpha-MSH and tumor necrosis factor (TNF)-alpha plasma concentration and production in whole blood samples, and influences of alpha-MSH on produ ction of TNF-alpha and interleukin (II)-1 beta in whole blood samples stimu lated with lipopolysaccharide (LPs). Design: Prospective, nonrandomized, clinical study. Setting: Intensive care unit of a university hospital. Patients: A total of 21 patients with sepsis syndrome/septic shock and an e qual number of healthy volunteers. Interventions: Circulating alpha-MSH and TNF-alpha concentrations and TNF-a lpha production in supernatants of LPS (1 ng/ml)-stimulated whole blood wer e measured repeatedly. To determine whether alpha-MSH can modulate producti on of TNF-alpha and IL-1 beta, these cytokines were measured in whole blood samples stimulated with LPS (1 ng/ml) in the presence or absence of concen trations of the peptide. Measurements and Main Results: Plasma alpha-MSH was low in early samples an d gradually increased in patients who recovered but not in those who died. There was a negative correlation between plasma concentrations of alpha-MSH and TNF-alpha. In blood samples taken at early phases of sepsis syndrome, production of TNF-alpha was reduced relative to control values; such produc tion increased in patients who recovered but not in those who died. Additio n of alpha-MSH to LPS-stimulated whole blood samples inhibited production o f TNF-alpha and II-1 beta in a concentration-dependent manner. Conclusions: In patients with systemic inflammation, there are substantial changes over time in plasma concentrations of alpha-MSH that are reduced in early phases of the disease. Reduction of this endogenous modulator of inf lammation could be detrimental to the host. Addition of alpha-MSH to LPS-st imulated blood samples reduces production of cytokines involved in developm ent of septic syndrome. This inhibition by alpha-MSH, a peptide that is ben eficial in treatment of experimental models of sepsis, might therefore be u seful to treat sepsis syndrome in humans.