Mitochondrial damage-associated molecular patterns released by abdominal trauma suppress pulmonary immune responses.

Trauma is the sixth leading cause of death worldwide, and is a serious public health problem with major social and economic costs. Local injury initiates an inflammatory cascade leading to local inflammation. More extensive injury can lead to systemic inflammation. Simultaneously though, immune-suppression develops and enhances the risk of infection in severely injured patients (1). Thus trauma patients are at high risk of infection both because physical barriers to tissue inoculation are disrupted and because of impaired host defense against bacterial inoculation (2,3) Thus infection is a leading cause of death after trauma. (2) Blunt chest trauma is common and is an important contributor to 10% to 30% of adult trauma deaths. (4) Chest trauma is commonly accompanied by injury to other organ systems. Abdominal trauma is frequently associated with chest trauma, and is an important factor affecting mortality. (5) Pneumonia is the most common infection complicating chest trauma and is highly related to mortality. (6) Furthermore, pneumonia is the most common infectious complication in multiple trauma patients as a whole with an incidence reaching 30% after severe trauma. (7) Despite the critical association between chest trauma and chest infections in the trauma population, no basic biologic mechanisms have been advanced to explain the association of injury with pneumonia or the high morbidity and mortality of pneumonia after major trauma. Rather, associated findings like ‘splinting’ and ‘failure to breathe deeply’ have been causally implicated without rigorous scientific support. Our previous studies have shown that cellular disruption by trauma releases mitochondrial debris (MTD) into the circulation that is rich in damage associated molecular patterns (DAMPs). These mitochondrial DAMPs show evolutionarily conserved similarities to bacterial Pathogen Associated Molecular Patterns (PAMPs). Thus they can initiate inflammation by signaling through innate immune pathways that create a sepsis-like state. (8–10) Sepsis however, does not necessarily lead directly to lung injury. (11) Another important phenomena we have observed is that is that MTD released by injured tissues attracts neutrophils. This is mediated at least in part by formyl peptides (FP) that act on formyl peptide receptors like FPR1. (10,12) Formyl peptides are typical of bacteria, but are also found in mitochondria. In addition to being neutrophil chemoattractants FP activate mononuclear cells releasing further chemokines and lipid chemoattractants. (13) We hypothesized that MTD released by injured tissue could suppress pulmonary immune responses by diverting neutrophils from the lung and or altering PMN function, thus potentially leaving the lung susceptible to infection