Laparoscopic Ventral Hernia Repair Postoperative Complications in End Stage Renal Disease Patients.

Background: The prevalence of patients with end stage renal disease (ESRD) requiring general surgical procedures is increasing. Our aim was to explore the effect of ESRD on patients undergoing elective laparoscopic ventral hernia repair. Methods: The American College of Surgeons National Surgical Quality Improvement Program (2010-2015) database was used to identify patients who underwent elective laparoscopic ventral hernia repair. Multivariable analysis was performed adjusting for risk variables including age, gender, race, comorbidity status, body mass index ≥ 35, and presence of ESRD. Results: A total of 8,789 patients undergoing elective laparoscopic ventral hernia repair were identified. Sixty-four patients (0.73%) had ESRD. ESRD was identified as an independent risk factor for postoperative pneumonia (odds ration [OR] 6.91, p = 0.00363), sepsis (OR 18.58, p = 0.000286), and length of stay (IRR 1.63, 95% confidence interval 1.19 - 2.27, p = 0.0036). Conclusions: ESRD patients undergoing elective laparoscopic ventral hernia repair had an increased risk of postoperative pneumonia, sepsis, and length of stay. Clinicians should be cognizant of these risks when performing elective operations on ESRD patients.

Extracellular CIRP Induces Inflammation in Alveolar Type II Cells via TREM-1.

Extracellular cold-inducible RNA-binding protein (eCIRP) induces acute lung injury (ALI) in sepsis. Triggering receptor expressed on myeloid cells-1 (TREM-1) serves as a receptor for eCIRP to induce inflammation in macrophages and neutrophils. The effect of eCIRP on alveolar epithelial cells (AECs) remains unknown. We hypothesize that eCIRP induces inflammation in AECs through TREM-1. AECs were isolated from C57BL/6 mice and freshly isolated AECs were characterized as alveolar type II (ATII) cells by staining AECs with EpCAM, surfactant protein-C (SP-C), and T1 alpha (T1α) antibodies. AECs were stimulated with recombinant murine (rm) CIRP and assessed for TREM-1 by flow cytometry. ATII cells from WT and TREM-1-/- mice were stimulated with rmCIRP and assessed for interleukin-6 (IL-6) and chemokine (C-X-C motif) ligand 2 (CXCL2) in the culture supernatants. ATII cells from WT mice were pretreated with vehicle (PBS), M3 (TREM-1 antagonist), and LP17 (TREM-1 antagonist) and then after stimulating the cells with rmCIRP, IL-6 and CXCL2 levels in the culture supernatants were assessed. All of the freshly isolated AECs were ATII cells as they expressed EpCAM and SP-C, but not T1α (ATI cells marker). Treatment of ATII cells with rmCIRP significantly increased TREM-1 expression by 56% compared to PBS-treated ATII cells. Stimulation of WT ATII cells with rmCIRP increased IL-6 and CXCL2 expression, while the expression of IL-6 and CXCL2 in TREM-1-/- ATII cells were reduced by 14 and 23%, respectively. Pretreatment of ATII cells with M3 and LP17 significantly decreased the expression of IL-6 by 30 and 47%, respectively, and CXCL2 by 27 and 34%, respectively, compared to vehicle treated ATII cells after stimulation with rmCIRP. Thus, eCIRP induces inflammation in ATII cells via TREM-1 which implicates a novel pathophysiology of eCIRP-induced ALI and directs a possible therapeutic approach targeting eCIRP-TREM-1 interaction to attenuate ALI.

An extracellular cold-inducible RNA-binding protein-derived small peptide targeting triggering receptor expressed on myeloid cells-1 attenuates hemorrhagic shock.

BACKGROUND: Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern, which is released into the circulation after hemorrhagic shock (HS). Recently, we discovered that triggering receptor expressed on myeloid cells-1 (TREM-1) serves as a new receptor of eCIRP to exaggerate inflammation. Here, we hypothesize that by inhibiting the interaction between eCIRP and TREM-1 with the use of a novel short peptide derived from human eCIRP known as M3, we can inhibit the inflammatory response and acute lung injury in HS. METHODS: Hemorrhagic shock was induced using C57BL/6 mice by cannulating both femoral arteries. One femoral artery was used for removal of blood while the other was used for continuous monitoring of mean arterial blood pressure. The mean arterial pressure of 25 mm Hg to 30 mm Hg was maintained for 90 minutes, followed by a resuscitation phase of 30 minutes with 1 mL of normal saline. The treatment group was given 10 mg/kg of M3 during the resuscitation phase. Four hours after resuscitation, serum and lungs were collected and analyzed for various injury and inflammatory markers by using colorimetry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. RESULTS: There was an increase in the serum levels of tissue injury markers (alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) as well as cytokines (TNF-α and IL-6) when comparing the vehicle group versus the sham group. This increase was significantly inhibited in the M3-treated group. The mRNA expression of proinflammatory cytokines TNF-α, IL-6, and IL-1ß and the chemokines MIP-2 and KC in lungs was significantly increased in the vehicle-treated HS mice, while their expression was significantly decreased in M3-treated HS mice. Finally, M3 treatment significantly decreased the lung injury score compared with vehicle-treated HS mice. CONCLUSION: The novel eCIRP-derived TREM-1 antagonist (M3) can be a potential therapeutic adjunct in the management of hemorrhagic shock.

Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis.

Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently discovered damage-associated molecular pattern. Understanding the precise mechanism by which it exacerbates inflammation is essential. Here we identified that eCIRP is a new biologically active endogenous ligand of triggering receptor expressed on myeloid cells-1 (TREM-1), fueling inflammation in sepsis. Surface plasmon resonance revealed a strong binding affinity between eCIRP and TREM-1, and fluorescence resonance energy transfer assay confirmed eCIRP's interaction with TREM-1 in macrophages. Targeting TREM-1 by its siRNA or a decoy peptide, LP17, or by using TREM-1-/- mice dramatically reduced eCIRP-induced inflammation. We developed a potentially novel 7-aa peptide derived from human eCIRP, M3, which blocked the interaction of TREM-1 and eCIRP. M3 suppressed inflammation induced by eCIRP or agonist TREM-1 antibody cross-linking in murine macrophages or human peripheral blood monocytes. M3 also inhibited eCIRP-induced systemic inflammation and tissue injury. Treatment with M3 further protected mice from sepsis, improved acute lung injury, and increased survival. Thus, we have discovered a potentially novel TREM-1 ligand and developed a new peptide, M3, to block eCIRP-TREM-1 interaction and improve outcomes in sepsis.

Extracellular microRNA 130b-3p inhibits eCIRP-induced inflammation.

Although microRNAs regulate mRNA expression intracellularly, they are often released into the circulation in inflammatory diseases. During sepsis, secreted extracellular cold-inducible RNA-binding protein (eCIRP) acts as a damage-associated molecular pattern (DAMP), inducing tissue damage by elevating inflammatory cytokines and chemokines. Here, we report that the circulating microRNA 130b-3p inhibits eCIRP-mediated sterile and cecal ligation and puncture (CLP)-induced non-sterile inflammation. We find that levels of miR-130b-3p are increased in the serum of septic mice and patients and that it strongly interacts with recombinant murine (rm) CIRP in vitro and with eCIRP in the serum of septic mice in vivo. Combining a miR-130b-3p mimic with rmCIRP significantly decreases TNF-α release by macrophages compared to only rmCIRP-treated cells. This combined treatment also dose-dependently decreases the affinity of rmCIRP with its receptor TLR4/MD2. Finally, injection of a miR-130b-3p mimic significantly reduces rmCIRP- or CLP-induced systemic inflammation and acute lung injury in mice. These data show that extracellular miR-130b-3p functions as a novel endogenous inhibitor of eCIRP and point to an innovative therapeutic approach to treat inflammatory diseases.

DAMPs and NETs in Sepsis.

Sepsis is a deadly inflammatory syndrome caused by an exaggerated immune response to infection. Much has been focused on host response to pathogens mediated through the interaction of pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs). PRRs are also activated by host nuclear, mitochondrial, and cytosolic proteins, known as damage-associated molecular patterns (DAMPs) that are released from cells during sepsis. Some well described members of the DAMP family are extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), histones, and adenosine triphosphate (ATP). DAMPs are released from the cell through inflammasome activation or passively following cell death. Similarly, neutrophil extracellular traps (NETs) are released from neutrophils during inflammation. NETs are webs of extracellular DNA decorated with histones, myeloperoxidase, and elastase. Although NETs contribute to pathogen clearance, excessive NET formation promotes inflammation and tissue damage in sepsis. Here, we review DAMPs and NETs and their crosstalk in sepsis with respect to their sources, activation, release, and function. A clear grasp of DAMPs, NETs and their interaction is crucial for the understanding of the pathophysiology of sepsis and for the development of novel sepsis therapeutics.

An iliac-appendiceal fistula causing gastrointestinal bleeding.

Aortoenteric fistulas are an uncommon cause of gastrointestinal bleeding, and iliac-appendiceal fistulas are an even rarer cause. We describe a case of an iliac-appendiceal fistula in a patient who presented several months after aortic reconstruction with gastrointestinal bleeding. An extensive workup revealed that the source of bleeding was localized to the appendiceal orifice. The patient underwent an appendectomy with a two-stage procedure involving the iliac graft for definitive repair and ultimately recovered well. Despite the rarity of aortoenteric and iliac-appendiceal fistulas causing gastrointestinal bleeding, keeping a high index of suspicion in patients with a prior vascular repair can prevent death.