Figure 6. Two-hit theory of initiation of multiple organ dysfunction (MOD). The initial trauma to a tissue or organ is considered the initial event. Reactive oxygen species (ROS), lipid peroxidation, released Ca²⁺ from the endoplasmic reticulum (ER) and liberated cytokines are proposed to mediate cell death reactions in initially affected cells as well as in neighbouring cells and tissue that may or may not have been initially affected by the traumatic stress. The "second hit" is thought to be initiated by activation of inflammatory cells and genesis of cell debris or secondary infections and endotoxaemia. Uncontrolled systemic inflammatory responses (SIRS) and immunological dissonance then initiates MOD in localised tissues and organs, and globally throughout the body. See text for further discussion.