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

Rongqian Wu,Youxin Ji,Mian Zhou,Shinya Higuchi,Weifeng Dong,Corrado P Marini,Thanjavur S Ravikumar,Ping Wang

doi:10.2119/molmed.2008.00092

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.

Highlights

Sepsis remains a critical problem, leading to significant morbidity and mortality even in the modern era of critical care management [1,2,3,4]
We have recently demonstrated that early administration of rat AM in combination with human AMBP-1 attenuates tissue injury, inhibits inflammatory responses, and reduces mortality in a rat cecal ligation and puncture (CLP) model of sepsis [14,15]
AM was originally isolated from a human pheochromocytoma because of its ability to increase cyclic adenosine

Summary

Introduction

Sepsis remains a critical problem, leading to significant morbidity and mortality even in the modern era of critical care management [1,2,3,4]. Sepsis is the second leading cause of death among patients in noncoronary intensive care units (ICU), and the 10th leading cause of death overall in the United States [5,6,7,8]. Evidence indicates that in the United States alone, more than 750,000 people develop sepsis each year, with an overall mortality of 28.6% [9]. The total cost of treating septic patients is even higher today. Given the intensive and prolonged care necessary to treat patients with sepsis, the economic burden is profound. There is an urgent unmet medical need for an effective novel therapy for septic patients

Methods

Results

Conclusion