Reversing established sepsis in rats with human vasoactive hormone adrenomedullin and its binding protein.
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.
Wu
Rongqian
R
The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, United States of America.
Higuchi
Shinya
S
Dong
Weifeng
W
Ji
Youxin
Y
Zhou
Mian
M
Marini
Corrado P
CP
Ravikumar
Thanjavur S
TS
Wang
Ping
P
D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D016207:Cytokines / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D053607:Adrenomedullin; D017242:Complement Factor H; D016207:Cytokines; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C507862:ADM protein, human; C493495:CFH protein, human