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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00147004.

Figure 1. PVN of patients who died from non-septic causes (A–C–E) or septic shock (B–D–F).

CRH mRNA (A–B) and AVP mRNA (C–D) labelling after in situ hybridization expression did not differ between the two groups. iNOS (E–F) expression after immunohistochemistry (ABC peroxidase/DAB) was higher in septic shock patients.

Figure 2. PVN of sham (A–D–G), septic (B–E–H) and septic with early death (septic ED) (C–F–I) rats.

Expression of CRH mRNA (A–B–C) and iNOS (G–H–I) after immunohistochemistry (ABC peroxidase/DAB) was greater in septic ED rats. AVP mRNA (D–E–F) expression after in situ hybridization did not differ between the three groups.

Figure 3. Ante-hypophysis of patients who died from non-septic causes (A–C–E) or septic shock (B–D–F).

Labelling of CRHR1 (A–B) and V1b receptor (C–D) after immunohistochemistry (ABC peroxidase/DAB) did not vary among the two groups. ACTH (E–F) immunostaining (ABC peroxidase/DAB) was decreased in septic shock patients.

Figure 4. Ante-hypophysis of sham (A–D–G), septic (B–E–H) and septic with early death (septic ED) (C–F–I) rats.

Labelling of CRHR1 (A–B–C) and V1b receptor (D–E–F) after immunohistochemistry (ABC peroxidase/DAB) did not vary among the three groups. ACTH (G–H–I) immunostaining (ABC peroxidase/DAB) was decreased in septic ED.