Peritoneal cavity lavage reduces the presence of mitochondrial damage associated molecular patterns in open abdomen patients

Abstract

Background Mitochondrial damage-associated molecular patterns (mtDAMPs), such as mitochondrial DNA and N-formylated peptides, are endogenous molecules released from tissue after traumatic injury. mtDAMPs are potent activators of the innate immune system. They have similarities with bacteria, which allow mtDAMPs to interact with the same pattern recognition receptors and mediate the development of Systemic Inflammatory Response Syndrome (SIRS). Current recommendations for management of an open abdomen include returning to the operating room every 48 hours for peritoneal cavity lavage until definitive procedure. These patients are often critically ill and develop SIRS. We hypothesized that mitochondrial DAMPs are present in the peritoneal cavity fluid in this setting, and that they accumulate in the interval between washouts. Methods We conducted a prospective pilot study of critically ill adult patients undergoing open abdomen management in the Surgical and Trauma ICUs. Peritoneal fluid was collected daily from 10 open abdomen patients. Specimens were analyzed via qPCR for mitochondrial DNA (mtDNA), via enzyme immunoassay for DNAse activity and via Western blot analysis for the ND6 subunit of the NADH: ubiquinone oxidoreductase, an N-formylated peptide. Results We observed a reduction in the expression of ND6 the day following lavage of the peritoneal cavity, that was statistically different from the days with no lavage (% change in ND6 expression, Post-Op from washout: −50±11 vs. No Washout day: 42±9, p<0.05). Contrary to expectation, the mtDNA levels remained relatively constant from sample to sample. We then hypothesized that DNAse present in the effluent may be degrading mtDNA. Conclusions These results indicate the peritoneal cavity irrigation reduces the presence of mitochondrial DAMPs in the open abdomen. It is possible that, increased frequency of peritoneal cavity lavage may lead to decreased systemic absorption of mtDAMPs, and thereby reducing the risk of SIRS. Level of Evidence Prospective study, Case Series, level V Study Type Prognostic

A Randomized Controlled Trial on Intra-Abdominal Irrigation during Emergency Trauma Laparotomy; Time for Yet Another Paradigm Shift

“…It is also possible that a larger amount of irrigation negates the possible benefits of the intervention through a yet unknown mechanism. While there is experimental evidence of at least one benefit to the use of irrigation in trauma victims [39], our results strongly suggest an upper limit of 5L for the effluent. This has relevance for today's practice, since epidemiological evidence exist for the current use of Intraoperative Peritoneal Lavage for this indication in surgical practice [41][42][43][44][45][46][47][48][49][50].…”

“…During the last decade of the twentieth century (and in some more recent literature [25][26][27][28][29][30][31][32]) animal and other experimental studies began addressing the question of which fluid and how much [8,[25][26][27][33][34][35][36][37][38][39][40]. It was during this period that the potential adverse effects of the use of abdominal washouts were described: upregulation of pro-inflammatory mediators, damage to peritoneal mesothelial cells and polymorphonuclear neutrophil membranes, promotion of postoperative adhesions, documented instances of bacterial translocation, failure to effectively decrease peritoneal bacterial counts, and potential adverse effects on final hemostasis (through technical or chemical issues) [7,33].…”

Mitochondria-Derived Damage-Associated Molecular Patterns in Sepsis: From Bench to Bedside

“…They have also observed that contraction of the trachea and bronchi caused by NFPs is concentration-dependent. Martinez-Quinones et al hypothesized that increased frequency of peritoneal cavity lavage may reduce the risk of SIRS via decreasing the levels of mtDAMPs according to their pilot study [21]. Based on Martinez's finding, we suggest that more studies are needed to determine the role of extracellular NFPs in SIRS and their possible clinical applications.…”

“…The elimination of mtDNA may be an effective means to improve the immune function of patients with sepsis. Martinez-Quinones et al [21] observed in the pilot study that abdominal cavity irrigation could reduce the concentration of ND6 (a kind of mtDAMPs) in peritoneal fluid of open abdomen patients. However, peritoneal lavage does not reduce the level of mtDNA in the abdominal cavity.…”

The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies

“…This hypothesis of extracellular accumulation of cf-mtDNA prior to its detection in circulation is also supported by the observation of Martinez-Quinones et al in patients who underwent open abdominal surgery. Peritoneal lavage was associated with lower plasma mtDNA concentrations [ 33 ]. This demonstrates surgical reduction of extracellular mtDNA load prior to its entry into circulation and raises the possibility of timely mtDNA removal as a potential therapy.…”