Am J Respir Cell Mol Biol. 2024 Apr 10. doi: 10.1165/rcmb.2023-0451OC. Online ahead of print.

ABSTRACT

Extreme heat caused by climate change is increasing transmission of infectious diseases resulting in a sharp rise in heat-related illness and mortality. Understanding mechanistic link between heat, inflammation and disease is thus important for public health. Thermal hyperpnea, and consequent respiratory alkalosis is crucial in febrile seizures and convulsions induced by heat stress in humans. Here we address what causes thermal hyperpnea in neonates and how is it affected by inflammation. TRPV1, a heat-activated channel is sensitized by inflammation and modulates breathing, and thus may play a key role. To investigate whether inflammatory sensitization of TRPV1 modifies neonatal ventilatory responses to heat stress, leading to respiratory alkalosis and an increased susceptibility to hyperthermic seizures we treated neonatal rats with bacterial lipopolysaccharide, and breathing, arterial pH, in-vitro vagus nerve activity, and seizure susceptibility were assessed during heat stress in the presence or absence of a TRPV1 antagonist (AMG-9810) or shRNA-mediated TRPV1 suppression. Lipopolysaccharide-induced inflammatory preconditioning lowered the threshold temperature and latency of hyperthermic seizures. This was accompanied by increased tidal volume, minute ventilation, expired CO2, and arterial pH (alkalosis). Lipopolysaccharide exposure also elevated vagal spiking and intracellular calcium levels in response to hyperthermia. TRPV1 inhibition with AMG-9810 or shRNA reduced the lipopolysaccharide-induced susceptibility to hyperthermic seizures and altered the breathing pattern to fast shallow breaths (tachypnea), making each breath less efficient and restoring arterial pH. These results indicate that inflammation exacerbates thermal hyperpnea-induced respiratory alkalosis associated with increased susceptibility to hyperthermic seizures, primarily mediated by TRPV1 localized to vagus neurons.

PMID:38597725 | DOI:10.1165/rcmb.2023-0451OC