Reversing Established Sepsis in Rats with Human Vasoactive Hormone Adrenomedullin and its Binding Protein

Abstract

We recently demonstrated that early administration of rat adrenomedullin (AM), a vasoactive peptide, in combination with its binding protein (human AMBP-1) produces various beneficial effects in sepsis. Human AM is a 52-amino acid peptide, but rat AM differs from human AM, having only 50 amino acid residues, with two amino acid deletions and six substitutions. It remains unknown whether a combination of human AM and human AMBP-1 (AM/AMBP-1) is also beneficial in sepsis and, if so, whether human AM/AMBP-1 reverses established sepsis in rats. To test the effects of human AM/AMBP-1, we induced sepsis in male adult rats by cecal ligation and puncture (CLP). At 10 h after CLP (i.e., severe sepsis), human AM (12-48 microg/kg body weight) was administered in combination with human AMBP-1 (40-160 microg/kg body weight). Vehicle-treated animals received a nonspecific human plasma protein (albumin). Blood and intestinal samples were collected at 20 h for various measurements. In additional groups of septic animals, the gangrenous cecum was surgically excised at 20 h after CLP. The 10-day survival was recorded. Our results showed that tissue injury, as evidenced by increased levels of transaminases and lactate, was present at 20 h after CLP. Proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 were significantly elevated. Gut barrier dysfunction, manifested by increased mucosal permeability to hydrophilic macromolecules and increased bacterial translocation to mesenteric lymph nodes, also occurred at 20 h after CLP. Administration of human AM/AMBP-1 in established sepsis markedly attenuated tissue injury, reduced proinflammatory cytokine levels, ameliorated intestinal-barrier dysfunction, and improved the survival rate from 47% to 67%-80%. Thus, human AM/AMBP-1 can be further developed as a safe and effective therapy for patients with established sepsis.

Inhibition of lipogenesis reduces inflammation and organ injury in sepsis

“…However, one of the phenotypical characteristics of sepsis is the exaggerated inflammatory response and that compounds that can attenuate this effect has shown to be protective in sepsis. We have previously shown protective effects of several such compounds in animal models of sepsis and other organ injury indications [34–36]. It can also be argued that the administration of C75 4 h after CLP can be considered as early treatment and that later time points would have been suitable for testing the therapeutic potential of C75.…”

Milk fat globule epidermal growth factor-factor 8 mitigates inflammation and tissue injury after hemorrhagic shock in experimental animals

“…It has been shown to be a “bridging” molecule between professional phagocytes and apoptotic cells, by binding to specific regions on both cell populations 11 . We have previously demonstrated that the administration of recombinant murine MFG-E8 (rmMFG-E8) successfully attenuated multiple markers of organ injury during severe sepsis, as well as increasing apoptotic cell clearance and lessening acute lung injury after intestinal ischemia and reperfusion 12–16 . Recently, we used our recombinant human analogue of MFG-E8 (rhMFG-E8), and confirmed that it also provides multiple beneficial effects in severe sepsis 17,18 .…”

Transcriptomic analysis of peritoneal cells in a mouse model of sepsis: confirmatory and novel results in early and late sepsis

“…Adrenomedullin is a member of the calcitonin peptide superfamily, and is a reliable early prognostic marker of sepsis in humans [27,28], with a prognostic accuracy similar to the APACHEII score and procalcitonin expression [29,30]. Besides being a potent vasodilating agent, adrenomedullin is an immune-modulating and antibacterial mediator and a potential therapeutic target for sepsis [31]. In abdominal sepsis, adrenomedullin stabilizes the gut barrier function [32].…”