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Alda‐1 shields mitochondrial dynamic proteins from hyperoxia via Aldh2 activation
Author(s) -
Patil Sahebgowda,
Fukumoto Jutaro,
Saji Smita,
HernandezCuervo Helena,
Alleyn Matthew,
Lockey Richard F,
Kolliputi Narasaiah,
Galam Lakshmi
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.651.20
Subject(s) - hyperoxia , ards , oxidative stress , lung , aldh2 , bronchoalveolar lavage , reactive oxygen species , chemistry , inflammation , medicine , immunology , aldehyde dehydrogenase , biochemistry , gene
Rationale Acute respiratory distress syndrome (ARDS) is associated with fluid filled lungs and hypoxia. Thus, ARDS patients are placed on supplemental oxygen; however, hyperoxia can damage the lungs, cause mitochondrial dysfunction, and ultimately lead to acute lung injury in animal models of ARDS. Mitochondrial aldehyde dehydrogenase 2 (Aldh2) metabolizes dangerous, reactive products, such as 4‐hydroxynonenal, that otherwise causes oxidative stress. The focus of this research is to determine if Alda‐1, an Aldh2 activator enhances the activity of Aldh2, thus alleviating hyperoxia damage by preventing mitochondrial dysfunction and reducing immune cell infiltration. It also determined if administration of Alda‐1 recovers mitochondrial dynamics and reduces cytokine levels and immune cell infiltration. Methods C57BL/6 mice were exposed to hyperoxia for 48 hours with DMSO (Control) and Alda‐1 (20 mM) via alzet pumps on the dorsal side of mice. The mice were divided into four groups: normoxia + DMSO (room air), normoxia + Alda‐1, hyperoxia + DMSO, and hyperoxia + Alda‐1. The lungs were harvested and the bronchoalveolar lavage (BAL) fluid was collected and analyzed by immunoblot and cytokine levels. Results Immunoblot analysis of lung lysate demonstrates that mice treated with Alda‐1, compared to mice treated with DMSO, during hyperoxia have decreased levels of OPA1 and Drp1, indicating that Alda‐1 shields against oxidative stress for proteins associated with mitochondrial dynamics. Moreover, the BAL fluid analysis reveals less infiltration of macrophages in mice treated with Alda‐1 versus mice treated with DMSO alone. These results indicate that activation of Aldh2 via Alda‐1 is protective against hyperoxia‐induced acute lung injury and may be a viable therapeutic agent for ARDS. Conclusion These findings suggest that Alda‐1, an Aldh2 activator, maintains mitochondrial homeostasis and reduces immune cell infiltration in this mouse model of ARDS and may be a novel therapeutic agent in ARDS. Support or Funding Information This work is supported by NIH RO1 grant (HL105932) to N.K. and AHA grant (#17SDG32780002) to L.G. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .