Lung endothelium, tau, and amyloids in health and disease

Abstract

Lung endothelium in the arteries, capillaries, and veins are heterogeneous in structure and function. Lung capillaries in particular represent a unique vascular niche, with a thin yet highly restrictive alveolar-capillary barrier that optimizes gas exchange. Capillary endothelium surveys the blood while simultaneously interpreting cues initiated within the alveolus and communicated via immediately adjacent type I and type II epithelial cells, fibroblasts, and pericytes. This cell-cell communication is necessary to coordinate the immune response to lower respiratory tract infection. Recent discoveries identify an important role for the microtubule associated protein tau that is expressed in lung capillary endothelia in the host-pathogen interaction. This endothelial tau stabilizes microtubules necessary for barrier integrity, yet infection drives production of cytotoxic tau variants that are released into the airways and circulation, where they contribute to end-organ dysfunction. Similarly, beta amyloid is produced during infection. Beta amyloid has antimicrobial activity, but during infection it can acquire cytotoxic activity that is deleterious to the host. The production and function of these cytotoxic tau and amyloid variants are the subject of this review. Lung-derived cytotoxic tau and amyloid variants are a recently discovered mechanism of end-organ dysfunction, including neurocognitive dysfunction, during and in the aftermath of infection.

Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19

“…Second, while our data suggest the transcriptomic changes in microglia we observe in patients with COVID-19 are induced by TNF-α and other cytokines, we cannot infer causality from these observational data. As an alternative hypothesis, tissue hypoxia resulting from COVID-19-induced vascular injury could account for inflammatory activation of microglia through HIF-1α (31,(70)(71)(72)(73), or cognitive dysfunction may result from other lung-derived damage-associated molecular patterns, neurotoxic agents, or pro-inflammatory molecules (74)(75)(76). Third, the administration of corticosteroids in our observational cohort was not randomized and did not include a placebo control.…”

Tau and Aβ42 in lavage fluid of pneumonia patients are associated with end-organ dysfunction: A prospective exploratory study

“…We have recently identified a novel host response to pneumonia that may contribute to end-organ dysfunction and offers a novel therapeutic target. Pneumonia elicits production of cytotoxic tau and amyloids within the lung; these cytotoxins are heat and protease stable, are transmissible between cells and animals, consistent with prion disease, and are sufficient to injure naïve organs, including the lung, heart, and brain [13][14][15][16][17]. While these prior studies demonstrated that pneumonia initiates a proteinopathy of the lung, this principle has not been tested in a controlled patient cohort.…”

“…Finally, HBSS washes from extra-corporeal membrane oxygenation oxygenators of infected patients, but not uninfected patients, contain tau and amyloids that are toxic to naïve animals [16]. While these results illustrate the contribution of infection-elicited cytotoxic tau and amyloids to end-organ dysfunction in pre-clinical animal models [15], the infectious proteinopathy hypothesis has not been tested in a prospective clinical study.…”

“…Recently, we have discovered that pneumonia elicits lung endothelial production of cytotoxic tau and amyloids [13,14] and reviewed in [15]. These lung-derived cytotoxins are similar to those found in the brain [16,17].…”

“…Bacterial pneumonia is a common cause of end-organ dysfunction. Our prior pre-clinical studies have suggested that tau and Aβ 42 may contribute to acute and long-term morbidity and mortality in critically ill patients [13][14][15][16][17]. Therefore, we designed a prospective, exploratory observational study to determine whether bacterial pneumonia elicits release of tau and Aβ 42 in the bronchoalveolar lavage fluid and whether the presence of tau and Aβ 42 portends end-organ dysfunction.…”