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

Andrea Polito (1, 2) , Romain Sonneville (3, 4) , Céline Guidoux (3) , Lucinda Barrett (5) , Odile Viltart (6) , Virginie Mattot (7) , Shidasp Siami (1, 2) , Geoffroy Lorin de la Grandmaison (8) , Fabrice Chrétien (4) , Mervyn Singer (5) , Françoise Gray (3) , Djillali Annane (1, 2) , Jean-Philippe Brouland (3) , Tarek Sharshar (1, 2)

1 Service médical des soins intensifs [CHU Raymond Poincaré]
2 LARENES - Laboratoire d'étude de la réponse neuroendocrine au Sepsis
3 Hôpital Lariboisière-Fernand-Widal [APHP]
4 Histopathologie humaine et Modèles animaux
5 UCL - University College of London [London]
6 IBLI - Institut de biologie de Lille - IBL
7 U837 INSERM - IRCL - Institut pour la Recherche sur le Cancer de Lille
8 Hôpital Raymond Poincaré [AP-HP]

Context 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. Objective 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. Methods 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. Results 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. Conclusion 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.

Mots clés: Adrenocorticotropic Hormone; Animals; Arginine Vasopressin; Corticotropin-Releasing Hormone; Disease Models; Animal; Humans; Immunohistochemistry; In Situ Hybridization; Nitric Oxide Synthase Type II; RNA; Messenger; Rats; Receptors; Vasopressin; Shock; Septic

Domaines: Sciences cognitives

Andrea Polito, Romain Sonneville, Céline Guidoux, Lucinda Barrett, Odile Viltart, et al.. Changes in CRH and ACTH synthesis during experimental and human septic shock. PLoS ONE, 2011, PLOS ONE, 6 (11), pp.e25905. ⟨10.1371/journal.pone.0025905⟩. ⟨hal-04474888⟩