AQP5 and AQP1 as Targets for Prophylactic Countermeasures for Pulmonary Hyperbaric Oxygen Toxicity
Abstract
Background. Gas transport across cell membranes is essential for life but also plays central roles in disease, especially pathology of importance to the Navy. Although the dogma had been that all gases cross all membranes merely by dissolving in membrane lipids, we now know that some biological membranes have a negligible permeability to dissolved gases, whereas some membrane proteinsnotably a subset of aquaporinscan conduct O2 and CO2. All AQPs are tetramers, and the four monomers surround a hydrophobic central pore that appears to be the main conduit for CO2 and O2 diffusion through these proteins.Problem. For divers or DISSUB submariners, exposure to high O2 can cause pulmonary oxygen toxicity (POT).Mission relevance. POT impairs pulmonary function, reduces performance, and can lead to serious illness or even death.Physiology. Divers and submariners can experience high alveolar O2 partial pressure, leading to exaggerated O2 uptake from alveolar air into alveolar type I cells (ATICs) and then into pulmonary capillary endothelial cells (PCECs). A high intracellular oxygen concentration leads to oxidative damage. Understanding the pathophysiology and developing prophylactic countermeasures is 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. It has the highest-known CO2 permeability of all AQPs, and is likely to be an excellent O2 channel as well. AQP1 is highly expressed in PCECs. Data from our MURI team indicate that AQP1 functions as an O2 channel in RBCs.Hypothesis. AQP5 mediates a substantial fraction of O2 uptake into ATIC, and AQP1 similarly contributes to O2 uptake by PCECs. At high alveolar PO2, the genetic deletion of AQP5 or AQP1 from mice will reduce oxidative damage to ATICs and PCECs, respectively. The reduced inflammation and water permeability also will reduce pulmonary edema.Long-term goals. Our long-term plan is to extend our AQP5 and AQP1 work to protect swine and eventually humans from acute lung and perhaps CNS injury in order to mitigate O2 toxicity in divers through the development of drugs, identification of biomarkers, or extension of dive tables. O2 concentration is a limiting factor in Navy diving operations and disabled-submarine scenarios.Objective. Test the genetic proof of principle that the absence of AQP5 or AQP1 is protective in a mouse model of POT. The Boron Lab will generate and ship to Dr. Claude Piantadosi of Duke University the following: wild-type (WT) mice, knockout (KO) mice genetically deficient in AQP5 or AQP1, and double knockouts (dKO) mice deficient in both. The Piantadosi Lab (funded separately) will subject the mice to their O2-toxicity protocol and then assess the mice for POT by wet/dry weights of the lungs, assays of cells and inflammatory factors collected by bronchoalveolar-lavage, and by routine pathological approaches.Significance. If the hypothesis is true, the proposed work would establish a genetic proof of principle that reduced AQP5 or AQP1 activity would be an effective countermeasure for POT. The next step would be a more detailed of AQP5/AQP1/O2-toxicity in mice, to pave the way for a transition to swine, and eventually to humans. This line of research could greatly improve performance and reduce pathology in divers and submariners
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 31, 2020
- Source ID
- N000142012737
Entities
People
- Walter Boron
Organizations
- Case Western Reserve University
- Office of Naval Research
- United States Navy