Extracellular polycation signalling in alveolar and systemic inflammation

Critically ill patients with pneumonia often have impaired neutrophil function and disruption of alveolar-capillary barrier integrity.

During inflammation, excessive polycation generation activates the calcium-sensing receptor (CaSR), which can potentially compromise neutrophil function and barrier integrity.

My over-arching hypothesis is that, during critical illness, CaSR, activated by polycations, mediates impairment of neutrophil, alveolar epithelial and pulmonary endothelial function, leading to reduced bacterial clearance and disruption of alveolar-capillary barrier.

To test the hypothesis, I shall use a range of complementary methods to (a) assess the effect of positive and negative allosteric CaSR modulators and polycations on a range of functions in neutrophils and monocytes from critically ill patients at high risk of developing nosocomial infection; (b) isolate human primary alveolar epithelial cells and culture primary human pulmonary microvascular endothelial cells, and assess the effect of CaSR modulators on barrier function, inflammatory signatures, and antimicrobial functions; (c) perform the first temporal assessment of CaSR expression (and effect of CaSR inhibition) in extravasated neutrophils and alveolar macrophages from human healthy volunteers receiving inhaled lipopolysaccharide (LPS) or control; and (d) create neutrophil-specific CaSR knockout mice, assessing the influence of neutrophil CaSR on the natural history of acute pulmonary infection, inflammation, and alveolar-capillary barrier disruption.