Aquaporin 5 as a Target for Prophylactic Countermeasures for Pulmonary Hyperbaric Oxygen Toxicity
Abstract
PROBLEM: Exposure to high O2 causes pulmonary oxygen toxicity (POT).MISSION RELEVANCE: The impaired pulmonary function reduces performance, and toxicity can lead to serious illness or even death. PHYSIOLOGY: Divers and submariners can experience a high alveolar O2partial pressure (PAO2), leading to exaggerated O2 uptake from alveolar air into alveolar type I cells (ATICs) and then into pulmonary capillary endothelial cells (PCECs). In both cell types, a high intracellular O2 concentration ([O2]i) leads to oxidative damage. Understanding the pathophysiology and developing prophylactic countermeasures has been a high priority for Undersea Medicine. SOLUTION: Leverage newly discovered and characterized gas-channel physiology to identify new targets for adjuvant therapies. Aquaporin 5 (AQP5) is highly expressed in the apical (air-facing) membrane of ATICs. AQP5 has the highest-known CO2 permeability and is likely to conduct O2 as well. AQP1 is highly expressed in PCECs and conducts CO2 and O2.HYPOTHESIS: AQP5 mediates a substantial fraction ofO2 uptake into ATICs, and AQP1 does the same for PCECs. At high PAO2, the genetic deletion of AQP5 and/or AQP1 will reduce oxidative damage to ATICs and/or PCECs while maintaining sufficient O2 uptake for exercise. The genetic deletions, by lowing arterial PO2, may also protect the brain and other organs. LONG-TERM GOALS: This pilot project is part of a long-term plan to mitigate acute pulmonary (and perhaps CNS) oxygen toxicity in divers and submariners through development of drugs, identification of biomarkers, or extension of dive tables. Oxygen concentration is a limiting factor in Navy diving operations and disabled-submarine scenarios. APPROACH: In a model of normobaric O2 toxicity, we will determine if AQP5-knockout (KO), AQP1-KO, or double-knockout (dKO) mice experience less oxygen toxicity#based on markers of ATIC and PCEC integrity or inflammation#than their wild-type (WT) counterparts. SIGNIFICANCE: The proposed work would establish a genetic proof of principle that a reduction in AQP5 and/or AQP1 activity would be an effective countermeasure POT, and pave the way to the development of AQP inhibitors for testing in swine and humans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 24, 2023
- Source ID
- N000142312555
Entities
People
- Walter Boron
Organizations
- Case Western Reserve University
- Office of Naval Research
- United States Navy