The discovery of potent endogenous danger signals released from injured/necrotic cells clearly adds to our understanding of the pathogenesis of “sterile inflammation,” as well as SIRS when tissue injury is sufficient to produce systemic inflammation. Alarmins represent nothing less than the proximal endogenous mediators linking cell necrosis and the inflammatory response generated by tissue injury. The identification of alarmins from mitochondria that are ancient bacteria sheltered inside of cells makes a lot of sense. Mitochondria have retained throughout the evolution some molecules of their bacterial ascent that, when found extracellularly, can be recognized as “non-self” by cells from the immune system. Other alarmins, such as ATP, also are strictly intracellular molecules that when found extracellularly will be sensed as a “danger molecule,” meaning for the immune system: “rupture of plasma cell membrane and tissue injury.” Although extracellular ATP does not seem to be capable of mediating a great deal of inflammation, it is an important cofactor, an enhancer of the inflammatory reaction in response to mitochondrial danger molecules and to microbial-associated molecular patterns.
Given their proximal location in the inflammatory cascade during tissue inflammation, alarmins and alarmin-dependent pathways represent attractive targets to develop drugs aimed at dampening deleterious inflammatory reactions following (massive) tissue injury. Examples of such situations in critical care are: multiple trauma, ARDS, ventilator-induced lung injury, ischemia/reperfusion injury, and severe pancreatitis. Blocking alarmin-dependent pathways will certainly dampen neutrophil-dependent tissue injury. It also will decrease innate immune responses and possibly favor bacterial and yeast superinfections, because it will interfere with the recruitment and the activation of neutrophils. Phagocyte recruitment at the site of tissue injury also plays an important role for the removal of cell debris, the restitution of tissue integrity and healing. As with many modulators of the inflammation, finding the right dose of “anti-alarmins,” the proper route of administration, and the adequate time window will be key to develop successful novel drugs designed to combat SIRS and SIRS-induced organ dysfunction.