Protein carbonyl measurements show evidence of early oxidative stress in critically ill patients

Abstract

Our results provide evidence of oxidation occurring early in severe sepsis and major trauma patients, with protein carbonyl measurements providing a sensitive index of this process. High protein carbonyl concentrations in plasma as well as bronchial aspirates indicate that oxidation is not restricted to the lungs. The correlation between oxidative measures and myeloperoxidase concentrations in the lung indicates that neutrophil oxidants could be responsible for the injury.

Ceruloplasmin Is an Endogenous Inhibitor of Myeloperoxidase

“…However, when ceruloplasmin is overwhelmed by myeloperoxidase, as may occur in sepsis (71) or within the airways of children with cystic fibrosis (8), then it may be free to produce reactive oxygen species. Recently, increased mortality and a greater degree of protein oxidation were seen in Cp Ϫ/Ϫ mice in a model of inflammatory bowel disease compared with controls (72).…”

Transepithelial Migration of Neutrophils

“…Tissue injury due to oxidants is thought to be a key factor in the pathogenesis of ALI/ARDS (237), as levels of plasma (238) and lung (239-241) oxidants, likely of neutrophil origin (242), are increased in patients with ALI/ARDS and correlate with mortality (238). There are also data from clinical trials to suggest that antioxidant therapy may attenuate lung injury (243), although this data is inconclusive (244).…”

Serum Proteins Modified by Neutrophil-Derived Oxidants as Mediators of Neutrophil Stimulation

“…In recent years data have accumulated on the contribution of ROI to the development of various disease states, such as ARDS (16,21), atherosclerosis (17), chronic obstructive pulmonary disease (18), sepsis (24), or side effects of hemodialysis (20,29) and mAb treatment (19). The therapeutically used anti-CD3 mAb OKT3 strongly induces the neutrophil oxidative burst in a strictly IgG2a-dependent Fc␥R-mediated fashion (19).…”

“…The biological relevance of oxidative protein modification awaits future in vivo elucidation. However, it could be reflected by the recent discovery of highly elevated levels of oxidized proteins in various pathological conditions, including ARDS (26), sepsis, major trauma (24), uremia (63), asthma (23), bronchitis (22), and prematurity (25). On the basis of our results, we propose that oxidatively modified serum proteins may be not only a manifestation of collateral damage by PMN-derived ROI (10), but also proinflammatory mediators of neutrophil stimulation.…”

“…Moreover, ROI are implicated in the pathogenesis of a variety of conditions, such as adult respiratory distress syndrome (ARDS) (16), atherosclerosis (17), chronic obstructive pulmonary disease (18), and Ab therapy-and hemodialysis-associated side effects (19,20). Reduced plasma antioxidant status (21) and protein oxidation correlating with either PMN infiltration or tissue MPO content (22)(23)(24)(25)(26) was observed in patients suffering from inflammatory disorders. However, it is not known whether oxidized proteins are simply a consequence of increased ROI burden during inflammation or also contribute to neutrophil effector functions.…”