Heme Impairs Alveolar Epithelial Sodium Channels Post Toxic Gas Inhalation
ABSTRACT We previously reported that cell-free heme (CFH) is increased in the plasma of patients with acute and chronic lung injury and causes pulmonary edema in animal model of acute respiratory distress syndrome (ARDS) post inhalation of halogen gas. However, the mechanisms by which CFH causes pulmonary edema are unclear. Herein we report for the first time the presence of CFH and chlorinated lipids (formed by the interaction of halogen gas, Cl2, with plasmalogens) in the plasma of patients and mice exposed to Cl2gas.Ex vivoincubation of red blood cells (RBC) with halogenated lipids caused oxidative damage to RBC cytoskeletal protein spectrin, resulting in hemolysis and release of CFH. A single intramuscular injection of the heme-scavenging protein hemopexin (4 µg/kg body weight) in mice, one hour post halogen exposure, reversed RBC fragility and decreased CFH levels to those of air controls. Patch clamp and short circuit current measurements revealed that CFH inhibited the activity of amiloride-sensitive (ENaC) and cation sodium (Na+) channels in mouse alveolar cells and trans-epithelial Na+transport across human airway cells with EC50of 125 nM and 500 nM, respectively. Molecular modeling identified 22 putative heme-docking sites on ENaC (energy of binding range: 86-1563 kJ/mol) with at least 2 sites within its narrow transmembrane pore, potentially capable of blocking Na+transport across the channel. In conclusion, results suggested that CFH mediated inhibition of ENaC activity may be responsible for pulmonary edema post inhalation injury..
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Preprint| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
bioRxiv.org - (2021) vom: 23. Feb. Zur Gesamtaufnahme - year:2021 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Aggarwal, Saurabh [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2020.01.22.909879 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
XBI000709549 |
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| 520 | |a ABSTRACT We previously reported that cell-free heme (CFH) is increased in the plasma of patients with acute and chronic lung injury and causes pulmonary edema in animal model of acute respiratory distress syndrome (ARDS) post inhalation of halogen gas. However, the mechanisms by which CFH causes pulmonary edema are unclear. Herein we report for the first time the presence of CFH and chlorinated lipids (formed by the interaction of halogen gas, Cl2, with plasmalogens) in the plasma of patients and mice exposed to Cl2gas.Ex vivoincubation of red blood cells (RBC) with halogenated lipids caused oxidative damage to RBC cytoskeletal protein spectrin, resulting in hemolysis and release of CFH. A single intramuscular injection of the heme-scavenging protein hemopexin (4 µg/kg body weight) in mice, one hour post halogen exposure, reversed RBC fragility and decreased CFH levels to those of air controls. Patch clamp and short circuit current measurements revealed that CFH inhibited the activity of amiloride-sensitive (ENaC) and cation sodium (Na+) channels in mouse alveolar cells and trans-epithelial Na+transport across human airway cells with EC50of 125 nM and 500 nM, respectively. Molecular modeling identified 22 putative heme-docking sites on ENaC (energy of binding range: 86-1563 kJ/mol) with at least 2 sites within its narrow transmembrane pore, potentially capable of blocking Na+transport across the channel. In conclusion, results suggested that CFH mediated inhibition of ENaC activity may be responsible for pulmonary edema post inhalation injury. | ||
| 700 | 1 | |a Lazrak, Ahmed |e verfasserin |4 aut | |
| 700 | 1 | |a Ahmad, Israr |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Zhihong |e verfasserin |4 aut | |
| 700 | 1 | |a Bryant, Ayesha |e verfasserin |4 aut | |
| 700 | 1 | |a Mobley, James A. |e verfasserin |4 aut | |
| 700 | 1 | |a Ford, David A. |e verfasserin |4 aut | |
| 700 | 1 | |a Matalon, Sadis |e verfasserin |4 aut | |
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