Changes in CRH and ACTH synthesis during experimental and human septic shock

• Published in: PloS one 2011-11, Vol.6 (11), p.e25905
• Main Authors: Polito, Andrea, Sonneville, Romain, Guidoux, Céline, Barrett, Lucinda, Viltart, Odile, Mattot, Virginie, Siami, Shidasp, Lorin de la Grandmaison, Geoffroy, Chrétien, Fabrice, Singer, Mervyn, Gray, Françoise, Annane, Djillali, Brouland, Jean-Philippe, Sharshar, Tarek
• Format: Article
• Language: English
• Subjects: Adrenal glands; Adrenocorticotropic hormone; Adrenocorticotropic Hormone - biosynthesis; Adrenocorticotropic Hormone - genetics; Analysis; Animals; Arginine Vasopressin - metabolism; Argipressin receptors; Brain; Carbon monoxide; Cognitive science; Corticotropin; Corticotropin-releasing hormone; Corticotropin-Releasing Hormone - biosynthesis; Corticotropin-Releasing Hormone - genetics; Cytokines; Disease Models, Animal; Drug dosages; Epidemiology; Feces; Gene expression; Hematology; Histopathology; Hormones; Humans; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Intensive care; Laboratories; Medical research; Medicine; mRNA; Nervous system; Neurons; Neuropathology; Nitric oxide; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Pathology; Patients; Peritonitis; Rats; Receptors; Receptors, Vasopressin - metabolism; RNA; RNA, Messenger - genetics; Rodents; Sepsis; Septic shock; Shock, Septic - metabolism; Studies; Synthesis; Vasopressin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0025905

The mechanisms of septic shock-associated adrenal insufficiency remain unclear. This study aimed at investigating the synthesis of corticotropin-releasing hormone (CRH) and vasopressin (AVP) by parvocellular neurons and the antehypophyseal expression of ACTH in human septic shock and in an experimental model of sepsis. To test the hypothesis that ACTH secretion is decreased secondarily to alteration of CRH or AVP synthesis, we undertook a neuropathological study of the antehypophyseal system in patients who had died from septic shock and rats with experimental faecal peritonitis. Brains obtained in 9 septic shock patients were compared to 10 nonseptic patients (controls). Parvocellular expression of AVP and CRH mRNA were evaluated by in situ hybridization. Antehypophyseal expression of ACTH, vasopressin V1b and CRH R1 receptors and parvocellular expression of iNOS in the PVN were evaluated by immunohistochemistry. The same experiments were carried out in a fecal peritonitis-induced model of sepsis. Data from septic rats with (n = 6) or without (n = 10) early death were compared to sham-operated (n = 8) animals. In patients and rats, septic shock was associated with a decreased expression of ACTH, unchanged expression of V1B receptor, CRHR1 and AVP mRNA, and increased expression of parvocellular iNOS compared to controls. Septic shock was also characterized by an increased expression of CRH mRNA in rats but not in patients, who notably had a greater duration of septic shock. The present study suggests that in humans and in rats, septic shock is associated with decreased ACTH synthesis that is not compensated by its two natural secretagogues, AVP and CRH. One underlying mechanism might be increased expression of iNOS in hypothalamic parvocellular neurons.