The pathophysiology of musculoskeletal trauma and of skeletal muscle ischemia/reperfusion is summarized in Figure 3 . The oxygen deficit in major trauma, in conjunction with subsequent reperfusion of ischemic tissues has been recognized as a trigger of an intense inflammatory response that may cause damage both locally in the affected muscle and also in remote organs primary not involved in the ischemic insult [149] [150] [151] [152] . Complement activation and consumption represents a critical event in the early phase of limb ischemia/reperfusion (I/R) injury resulting in the release of potent complement fragments like C3a and C5a [150, 153, 154] . It has been suggested that binding of preexisting natural IgM antibodies to neoantigen expressed by hypoxic cells after interruption of the blood flow is responsible for the activation of the classical complement pathway that importantly contributes to skeletal muscle I/R injury [155] [156] [157] . This hypothesis is strengthened by the fact that mice genetically deficient of mature B and T cells and natural antibodies (Rag1 -/mice) show significant reductions of tissue damage in a model of hindlimb ischemia and reperfusion [155, 158] . Furthermore, muscle edema and secondary neutrophil accumulation in the lung, as signs of reperfusion injury, were attenuated in C1q -/and C4 -/mice deficient in central components of the classical complement pathway [159, 160] . Aside from the classical pathway, recent data indicate important involvement of the classical and the lectin pathway in skeletal muscle I/R injury [159, 161] . A protective effect was attributed to the complement regulatory molecules decay-accelerating factor (DAF/CD55), C1-INH, and soluble complement receptor type 1 (sCR1) after skeletal muscle reperfusion injury [162] [163] [164] . Moreover, a pivotal role of C5a in causing lung damage after hindlimb I/R was shown in an experimental study in rats [165] . In accordance with this observation, multiple markers of local and remote organ injury were markedly reduced in C5-deficient mice, and in mice treated with a neutralizing C5aR antagonist [74, [166] [167] [168] .