Mitochondrial-derived N-formyl peptides: novel links between trauma, vascular collapse and sepsis

Abstract

Sepsis is a major cause of mortality and morbidity in trauma patients despite aggressive treatment. Traumatic injury may trigger infective or non-infective systemic inflammatory response syndrome (SIRS) and sepsis. Sepsis and SIRS are accompanied by an inability to regulate the inflammatory response but the cause of this perturbation is still unknown. The major pathophysiological characteristic of sepsis is the vascular collapse (i.e., loss of control of vascular tone); however, at the cellular level the final mediator of extreme vasodilatation has yet to be identified. After trauma, cellular injury releases endogenous damage-associated molecular patterns (DAMPs) that activate the innate immune system. Mitochondrial DAMPs express at least two molecular signatures, N-formyl peptides and mitochondrial DNA that act on formyl peptide receptors (FPRs) and Toll-like receptor 9, respectively. N-Formyl peptides are potent immunocyte activators and, once released in the circulation, they induce modulation of vascular tone by cellular mechanisms that are not completely understood. We have observed that N-formyl peptides from bacterial (FMLP) and mitochondrial (FMIT) sources induce FPR-mediated vasodilatation in resistance arteries. Accordingly, we propose that tissue and cellular trauma induces the release of N-formyl peptides from mitochondria triggering inflammation and vascular collapse via activation of FPR and contributing to the development of sepsis. The proposed hypothesis provides clinically significant information linking trauma, mitochondrial N-formyl peptides and inflammation to vascular collapse and sepsis. If our hypothesis is true, it may lead to new strategies in the management of sepsis that can help clinicians effectively manage non-infectious and infectious inflammatory responses.

Fig. 1.

Representative image of the formyl peptide receptor (FPR) total protein expression in mesenteric resistance arteries (A) and heart (B) from non-treated Wistar rats. To obtain this data, Western blot technique was performed.

Fig. 2.

Representative tracing of formyl peptide from bacteria (FMLP)-induced relaxation in isolated resistance arteries (third order mesenteric arteries) from Wistar rats. The segments were initially contracted with phenylephrine (PE, 10 μM). Subsequently, FMLP (N-formyl–methionyl–leucyl–phenylalanine, 10 or 30 μM) was added in the absence or presence of cyclosporin H (FRP antagonist: CsH, 1 μM). As shown in (A), both concentrations of FMLP (10 or 30 μM) induced relaxation, and the pre-incubation with CsH inhibited this response (B). Wire myograph was used to analyze vascular function.

Fig. 3.

N-formyl peptides from mitochondria (FMIT) and from bacteria trigger inflammation and vascular dysfunction via formyl peptide receptor (FPR) activation, contributing to the loss of control of vascular tone and to the development of sepsis.

Fig. 4.

Representative tracing of formyl peptide mitochondrial (FMIT)-induced relaxation in resistance arteries (third order mesenteric arteries) from Wistar rats. The segments were initially contracted with phenylephrine (PE, 3 μM). Subsequently, FMIT (formyl–methionine–methionine–tyrosine–alanine–leucine–phenylalanine, 10 or 30 μM) was added in the absence or presence of cyclosporin H (FRP antagonist: CsH, 1 μM). As shown in (A), both concentrations of FMIT (10 or 30 μM) induced relaxation and the pre-incubation with CsH inhibited this response (B). Wire myograph was used to analyze vascular function.