Abstract 262: Mitochondrial N-formyl Peptides Lead to Sepsis-like Symptoms via Basophil Activation
Traumatic injury may lead to bacteria-induced systemic inflammation (sepsis). However, 15% of trauma patients present sepsis-like symptoms in the absence of infection. In these patients, it is possible that fragments from mitochondria (damage-associated molecular patterns) from traumatized tissue act to initiate an inflammatory response. Previously, we have demonstrated that infusion of mitochondrial N-formyl peptides (F-MIT) leads to exacerbated vasodilatation and hypotension via formly-preptide receptor (FPR) activation and inducible nitric oxide release. However, the cell type mediating this effect was not determined. We hypothesized that F-MIT induces sepsis-like symptoms, include hypotension, via basophil activation. Male Wistar rats (12-weeks old, n=5-8) were cannulated (femoral artery and vein) for blood pressure recordings and drug infusion. To analyze organ damage, the lungs were collected and stained with H&E. F-MIT infusion (0.02 mg/rat/i.v.) induced severe lung injury (edema, neuthrophil infiltration and alveolar thickening) (4-fold vs. control) and vascular leakage in aorta (+34%) and mesenteric resistance arteries (+66%). Moreover, F-MIT infusion increased body temperature (Control: 36±0.09 vs. F-MIT: 37±0.28 °C, *p<0.05) and reduced bleeding time (Control: 89±8 vs. F-MIT: 33±11 seconds, *p<0.05). Since F-MIT induced vascular leakage, rats were treated with histamine 2 receptor antagonist, cimetidine (50 mg/kg/i.v.) prior F-MIT infusion. As expected, F-MIT (0.02 mg/rat) induced hypotension [Control: 82±3 vs. F-MIT: 60±4 mmHg, *p<0.05]. However, cimetidine treatment abolished this response (Control: 75±1 vs. F-MIT infusion: 70±4 mmHg). Interesting, F-MIT had no effect on blood pressure in animals treated with anti-asialo GM1 antiserum (0.2 ml/i.p.) for depletion of basophils. Neither neutrophil nor mast cell depletion blocked F-MIT-induced hypotension (p>0.05). These data suggest that F-MIT, via basophil activation, leads to histamine release, vascular leakage and hypotension, associated to organ damage, fever, blood clotting. Thus, F-MIT may be the link between SIRS and cardiovascular collapse in sterile trauma patients.
Author Disclosures: C.F. Wenceslau: None. C.G. McCarthy: None. S. Goulopoulou: None. T. Szasz: None. R. Webb: None.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).
- © 2014 by American Heart Association, Inc.