Intratracheal instillation of neutrophils rescues bacterial overgrowth initiated by trauma damage-associated molecular patterns

Abstract

Background Nosocomial pneumonias are common in trauma patients and so interventions to prevent and treat nosocomial pneumonia may improve outcomes. Our prior work strongly suggests that tissue injury predisposes to infections like nosocomial pneumonia because mitochondrial debris (MTD) originating from injured cells contains damage-associated molecular patterns (DAMPs) that can reduce neutrophil (PMN) migration into the airway and diminish PMN function in response to bacterial inoculation of the airway. This suggested that putting exogenous “normal” PMN into the airway might be beneficial. Methods Post-injury pneumonia (PNA) commonly arises in two groups, early, community-acquired PNA (CAP) and later hospital-acquired PNA (HAP). Post-traumatic Early onset CAP and Late onset HAP were modeled in CD-1 mice using S. aureus (SA) or P. aeruginosa (PA) instilled intra-tracheal (i.t.) at clinically relevant times with or without extrapulmonary injuries mimicked by an intraperitoneal application of mitochondrial DAMPs. We applied bone-marrow derived PMN intratracheally to access bacterial clearance in the lung. Results BM-PMN instillation i.t. had no untoward clinical effects on recipient animals. In both the Early/CAP and Late/HAP models, clearance of the inoculum from the lung was suppressed by MTD and restored to uninjured levels by i.t. instillation of exogenous BM-PMN. Furthermore PMN instillation cleared the inoculum of P. aeruginosa that could not be cleared by uninjured mice. The instillation of PMN into the lung, even across strains (CD-1 vs. C57BL/6) had no injurious effect. Conclusion These initial studies suggest PMN instillation (i.t.) is worthy of further study as a potential adjunctive therapy aimed at decreasing the morbidity of lung infections in trauma patients. Moreover, PMN instillation (i.t.) may represent a unique means of preventing or treating pneumonia after serious injury that is completely independent of the need for antibiotic use.

Direct Airway Instillation of Neutrophils Overcomes Chemotactic Deficits Induced by Injury

“…3, B and D). We believe these findings lend further support to our prior suggestions (1,11) that FPR1 antagonists might play a role in the prevention of nosocomial pneumonias.…”

“…But studied empirically, airway instillation of PMN has not caused ALI in any of our studies. In fact, there is no damage to the recipient lung when PMN from mice either of the same or different strains were applied to the airway (11). Here, we instilled human PMN into the mouse airway, and found no evidence of acute lung injury in any of the recipients.…”

“…Here, we instilled human PMN into the mouse airway, and found no evidence of acute lung injury in any of the recipients. We examined BALF samples for protein increase as a sign of lung damage but found no evidence by PMN instillation (11). All the animals were healthy and active.…”

Formyl Peptide Receptor-1 Blockade Prevents Receptor Regulation by Mitochondrial Danger-Associated Molecular Patterns and Preserves Neutrophil Function After Trauma

“…We evaluated whether in vivo application of CsH after injury would affect bacterial clearance in lungs by using our established mouse injury model (14). Details can be found in Supplemental Digital Content 1.…”

Extracellular mitochondria drive CD8 T cell dysfunction in trauma by upregulating CD39

“…Lung infection studies were conducted as previously described 13. Briefly, S. aureus Rosenbach (ATCC 25923, Manassas, Virginia, USA) was used as the bacterial pathogen.…”