Pulmonary infection following skin injury delays wound healing through suppression of IL-1 and chemokine production

Abstract

Abstract Individuals who are hospitalized with traumatic injuries are susceptible to pneumonia. The effect of lung infection on the course of wound healing is not well understood in this setting. To begin to understand this, we examined data from patients who had received laparotomies and found that those who developed pneumonia experienced higher rates wound dehiscence compared to those without pneumonia. Based on this finding and the known role for the innate immune system in responding to injuries and infections, we hypothesized that the immune system cannot meet the demands of competing inflammatory insults in the skin and lungs, leading to impairment of one or both responses. To test this, we established two murine models of post-injury lung infection in which mice are wounded by the dorsal subcutaneous implantation of polyvinyl alcohol (PVA) sponges or by tail skin excision, then infected intranasally with Klebsiella oxytoca. In these models, the presence of a wound did not alter the response to pulmonary infection. In contrast, pulmonary infection delayed the closure tail skin wounds. Pulmonary infection also led to rapid suppression of IL-1beta and chemokine levels, as well as decreased leukocyte accumulation, in PVA sponge wounds. The impaired wound healing observed in infected mice could be rescued by the addition of IL-1beta or the chemokines CCL2 and CXCL1 to the wound bed; however, these treatments caused a delay in bacterial clearance in the lungs. These data suggest that the immune response is not fully equipped to respond to disparate and competing inflammatory insults, which could have implications beyond the setting of post-injury pneumonia. Supported by grants from NIH (NIES T32-ES7272, NIGMS COBRE Award P20GM10935, and NHLBI R01HL126887), Defense Advanced Research Projects Agency (DARPA), and Brown University (Dean’s Areas of Emerging New Science Award and Carney Institute Innovation Awards)