It is well established that cyclic nucleotides function as canonical second messengers. In the lung, these nucleotides exert regulatory influences on a host of cell processes, including endothelial cell barrier permeability. Previous reports demonstrated that Pseudomonas aeruginosa injects host cells with an effector protein, ExoY, the enzymatic activity of which increases cytosolic cAMP, leading to microtubule destabilization and endothelial barrier disruption. Kyle Adam Morrow and colleagues at the University of South Alabama have now published a study showing that inoculation with ExoY caused differential generation of cyclic nucleotides in macro- and microvascular lung endothelial cells (ECs). They found that ExoY increased both purine and pyrimidine cyclic nucleotides, with cGMP exhibiting the largest change. The increase in cyclic nucleotides temporally correlated with endothelial cell monolayer barrier disruption. Intriguingly, the ExoY-induced cyclic nucleotide signature differed in macrovascular and microvascular ECs; in macrovascular ECs ExoY induced a faster and more robust increase in cyclic nucleotides, including cAMP (which was not increased in microvascular ECs), resulting in earlier and more profound barrier disruption. Based on the fact that microvascular ECs are more likely to encounter this bacterium but are apparently more resistant, it is tempting to speculate that pulmonary microvascular ECs have developed host-protective mechanisms to help mitigate the effects of Pseudomonas aeruginosa.
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