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Item Inhibition of alveolar Na transport and LPS causes hypoxemia and pulmonary arterial vasoconstriction in ventilated rats(WILEY, 2016-01-01) Davieds, Bodo; Gross, Julian; Berger, Marc M.; Baloglu, Emel; Baertsch, Peter; Mairbaeurl, HeimoOxygen diffusion across the alveolar wall is compromised by low alveolar oxygen but also by pulmonary edema, and leads to hypoxemia and hypoxic pulmonary vasoconstriction (HPV). To test, whether inhibition of alveolar fluid reabsorption results in an increased pulmonary arterial pressure and whether this effect enhances HPV, we established a model, where anesthetized rats were ventilated with normoxic (21\% O-2) and hypoxic (13.5\% O-2) gas received aerosolized amiloride and lipopolisaccharide (LPS) to inhibit alveolar fluid reabsorption. Right ventricular systolic pressure (RVsP) was measured as an indicator of pulmonary arterial pressure. Oxygen pressure (PaO2) and saturation (SaO(2)) in femoral arterial blood served as indicator of oxygen diffusion across the alveolar wall. Aerosolized amiloride and bacterial LPS decreased PaO2 and SaO(2) and increased RVsP even when animals were ventilated with normoxic gas. Ventilation with hypoxic gas decreased PaO2 by 35 mmHg and increased RVsP by 10 mmHg. However, combining hypoxia with amiloride and LPS did not aggravate the decrease in PaO2 and SaO(2) and had no effect on the increase in RVsP relative to hypoxia alone. There was a direct relation between SaO(2) and PaO2 and the RVsP under all experimental conditions. Two hours but not 1 h exposure to aerosolized amiloride and LPS in normoxia as well as hypoxia increased the lung wet-to-dry-weight ratio indicating edema formation. Together these findings indicate that inhibition of alveolar reabsorption causes pulmonary edema, impairs oxygen diffusion across the alveolar wall, and leads to an increased pulmonary arterial pressure.Item The role of hypoxia-induced modulation of alveolar epithelial Na+- transport in hypoxemia at high altitude(2021-01-01) Baloglu, Emel; Nonnenmacher, Gabriel; Seleninova, Anna; Berg, Lena; Velineni, Kalpana; Ermis-Kaya, Ezgi; Mairbaeurl, HeimoReabsorption of excess alveolar fluid is driven by vectorial Na+-transport across alveolar epithelium, which protects from alveolar flooding and facilitates gas exchange. Hypoxia inhibits Na+-reabsorption in cultured cells and in-vivo by decreasing activity of epithelial Na+-channels (ENaC), which impairs alveolar fluid clearance. Inhibition also occurs during in-vivo hypoxia in humans and laboratory animals. Signaling mechanisms that inhibit alveolar reabsorption are poorly understood. Because cellular adaptation to hypoxia is regulated by hypoxia-inducible transcription factors (HIF), we tested whether HIFs are involved in decreasing Na+-transport in hypoxic alveolar epithelium. Expression of HIFs was suppressed in cultured rat primary alveolar epithelial cells (AEC) with shRNAs. Hypoxia (1.5\% O-2, 24 h) decreased amiloride-sensitive transepithelial Na+-transport, decreased the mRNA expression of alpha-, beta-, and gamma-ENaC subunits, and reduced the amount of alpha beta gamma-ENaC subunits in the apical plasma membrane. Silencing HIF-2 alpha partially prevented impaired fluid reabsorption in hypoxic rats and prevented the hypoxia-induced decrease in alpha- but not the beta gamma-subunits of ENaC protein expression resulting in a less active form of ENaC in hypoxic AEC. Inhibition of alveolar reabsorption also caused pulmonary vasoconstriction in ventilated rats. These results indicate that a HIF-2 alpha-dependent decrease in Na+-transport in hypoxic alveolar epithelium decreases alveolar reabsorption. Because susceptibles to high-altitude pulmonary edema (HAPE) have decreased Na+-transport even in normoxia, inhibition of alveolar reabsorption by hypoxia at high altitude might further impair alveolar gas exchange. Thus, aggravated hypoxemia might further enhance hypoxic pulmonary vasoconstriction and might subsequently cause HAPE.Item In Search of a Sensor: How Does CO2 Regulate Alveolar Ion Transport?(AMER THORACIC SOC, 2021-01-01) Baloglu, Emel; Mairbaurl, HeimoItem Hypoxia Aggravates Inhibition of Alveolar Epithelial Na-Transport by Lipopolysaccharide-Stimulation of Alveolar Macrophages(MDPI, 2022-01-01) Baloglu, Emel; Velineni, Kalpana; Ermis-Kaya, Ezgi; Mairbaeurl, HeimoInflammation and hypoxia impair alveolar barrier tightness, inhibit Na- and fluid reabsorption, and cause edema. We tested whether stimulated alveolar macrophages affect alveolar Na-transport and whether hypoxia aggravates the effects of inflammation, and tested for involved signaling pathways. Primary rat alveolar type II cells (rA2) were co-cultured with rat alveolar macrophages (NR8383) or treated with NR8383-conditioned media after stimulation with lipopolysaccharide (LPS