Increased expression of D2 and increased expression of thyroid hormone transporters, as we observed in the prolonged critically ill rabbits, could theoretically lead to increased local T3 levels, explaining the suppressed TRH gene expression and the low circulating TSH levels. However, unexpectedly, MEK162 Sigma local T3 concentrations were not increased and even tended to be low and hypothalamic T4 content was significantly reduced in prolonged ill animals. Data on local levels of thyroid hormones in the hypothalamus during prolonged critical illness are scarce. A study by Arem and colleagues showed that the hypothalamus of patients who died after chronic severe illness contains less than half the concentration of T3 as compared with patients who died from an acute trauma [31], which is in line with our data.

There are two possible ways to interpret our findings. Because we measured iodothyronine concentrations in the entire hypothalamic block, we cannot exclude a dilution effect. Alternatively, local thyroid hormone content in the hypothalamus could indeed be low during prolonged critical illness. In that case, other mechanisms inferentially are responsible for reducing TRH gene expression during prolonged critical illness and the increased D2 and increased thyroid hormone transporter gene expression levels which we observed could reflect a compensatory response to a local hypothyroid state. Such a compensatory response would be in line with the upregulated D2 expression and activity documented in skeletal muscle of prolonged critically ill patients [32].

Some limitations of our study should be addressed. Our animal model of burn injury-induced critical illness may mirror only part of the complex entity of human critical illness, and thus extrapolating to the human situation or to other illnesses should be done with great caution. Secondly, we were only able to measure gene expression levels of thyroid hormone receptors and transporters. This does not necessarily reflect transporter activity levels.ConclusionsIn conclusion, although hypothalamic D2 mRNA and gene expression of the thyroid hormone transporters MCT10 and OATP1C1 were increased in our animal model of prolonged critical illness, we failed to detect an increase in local T3 levels. This suggests that the reduced hypothalamic TRH expression in our animal model of prolonged critical illness is not necessarily the exclusive result of feedback-inhibition by locally elevated T3 levels.

Other illness-related factors could Batimastat be inferred to suppress the TRH gene and the increased expression of thyroid hormone transporters (MCT10 and OATP1C1) and of D2 may reflect a compensatory response to a central hypothyroid state during prolonged critical illness.Key messages? D2 mRNA and expression of thyroid hormone transporters MCT10 and OATP1C1 is increased in the hypothalamus of prolonged critically ill rabbits.