Hemorrhagic Shock/Resuscitation Reduces the M2 Phenotype of Alveolar Macrophages: A Potential Mechanism Contributing to Increased LPS-Induced Lung Injury

ABSTRACTMajor hemorrhage is a significant contributor to the morbidity and mortality resulting from traumatic injury. In addition to its role in in early mortality, hemorrhagic shock followed by resuscitation (HS/R) is known to initiate immunological events which contribute to the development of organ dysfunction. The pathogenesis of acute lung injury following HS/R involves macrophage activation. Recent studies have shown that macrophage function may in part be regulated by polarization towards classical M1 pro-inflammatory cells or alternatively activated anti-inflammatory M2 cells. We hypothesized that alteration in the M1/M2 phenotypic balance of alveolar macrophages in the lung may contribute to a pro-inflammatory state following HS/R. Using a murine model, we show that HS/R causes a rapid reduction in surface CD206 and CD36, markers of M2 cells, as well as in CD206 mRNA. M1 markers including surface CD80 and TNFα and iNOS mRNA were increased, albeit in a somewhat delayed time course. The prostaglandin 5-deoxyDelta12,14 prostaglandin J2 (15d-PGJ2), known to polarize cells towards M2, restored levels of M2 macrophages towards control and prevented lung injury, as assessed by bronchoalveolar protein content. Adoptive cell transfer of in vitro M2 polarized macrophages also reduced lung inflammation/injury following hemorrhagic shock. Together, these studies demonstrate that HS/R increases M1/M2 ratio, predominantly by lowering M2 cells, and thus enhances the proinflammatory state. Various strategies aimed at promoting M2 polarization may lessen the magnitude of inflammation and injury. This represents a novel approach to the prevention/treatment of lung injury in critically ill trauma patients.