Lung capillary endothelial tau expression promotes alveolar-capillary barrier integrity following <i>Pseudomonas aeruginosa</i> pneumonia

Lung capillary endothelium expresses the microtubule associated protein tau, important for microtubule stabilization. Four tau isoforms are expressed in lung capillaries, including the 0N4R, 1N4R, 2N4R, and Big Tau isoforms (N denotes amino terminal inserts, whereas R denotes microtubule binding repeats). The physiological function(s) of these isoforms in endothelium is poorly understood. Here, we hypothesized that endothelial tau expression contributes to integrity of the alveolar-capillary membrane following Pseudomonas aeruginosa pneumonia. To test this hypothesis, pulmonary perfusion pressures and permeability were measured in isolated perfused lungs of wild type and tau knockout (KO; B6.129S4(Cg)- Mapt tm1(EGFP/Klt /J) mice, over a range of perfusion rates, in both anterograde and retrograde flow orientations. Lung vascular pressures, weight gain, and filtration coefficients were similar in the lungs of both groups, although the lungs from wild type mice tended to withstand higher perfusion rates before succumbing to edema, consistent with improved alveolar-capillary barrier integrity at baseline. Mice were infected with intratracheal Pseudomonas aeruginosa (PA103 exoUexoT::Tc pUCP exoY; 5x10 5 CFU). Forty-eight hours later, non-invasive pulmonary ultrasound was performed to assess for the presence of B lines prior to examination of the lung vascular pressures and permeability. B lines were present in both wild type and KO lungs. Although pulmonary vascular pressures were similar in both groups, filtration coefficient was higher in the KO lungs, indicating endogenously expressed endothelial tau preserves alveolar-capillary barrier integrity during infection. To assess whether expression of the 1N4R tau is sufficient to confer protection to the endothelial barrier, adeno-associated virus 2 (AAV2) with tropism for lung capillary endothelium was engineered for expression of either enhanced green fluorescence protein (EGFP) or the 1N4R tau. AAV2s were injected into the tail vein of KO mice, and in three weeks Pseudomonas aeruginosa was introduced into the airways. Forty-eight hours later, lung vascular pressures and permeability were assessed. Tau was detected in the lung and circulation following AAV2-1N4R rescue to lung capillaries, whereas it was absent following delivery of AAV2-EGFP. Lungs from KO mice accommodated similar flow rates, whether they received AAV2-EGFP or AAV2-1N4R tau. However, even though lung vascular pressures were similar among the groups, filtration coefficient was lower in the lungs of animals expressing 1N4R tau than EGFP in the capillaries. Taken together, these data indicate that lung endothelial tau expression improves alveolar-capillary barrier integrity during Pseudomonas aeruginosa pneumonia. HL66299 (T.S.), HL167997 (T.S.), HL148069 (T.S.), HL140182 (M.T.L.), NS135147 (A.R.N.) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.