TY - JOUR
T1 - Epidermal growth factor receptor regulates Beclin-1 in hyperoxic acute lung injury
AU - Harris, Zachary M.
AU - Korde, Asawari
AU - Khoury, Johad
AU - Manning, Edward P.
AU - Stanley, Gail
AU - Shin, Yosep
AU - Mitchell, Kennedy
AU - Von der Schulenburg, Alexa
AU - Sun, Ying
AU - Hu, Buqu
AU - Shin, Hyeon Jun
AU - Joerns, John
AU - Clark, Brian
AU - Placek, Lindsey
AU - Unutmaz, Derya
AU - Moldobaeva, Aigul
AU - Sharma, Lokesh
AU - Sauler, Maor
AU - Rajagopalan, Govindarajan
AU - Zhang, Xuchen
AU - Wang, He
AU - Ghaedi, Mahboobe
AU - Kang, Min Jong
AU - Koff, Jonathan L.
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.
PY - 2026/1/27
Y1 - 2026/1/27
N2 - Background While delivery of supplemental oxygen is a life-saving therapy, exposure to high oxygen, called hyperoxia, leads to increased intensive care unit mortality. Hyperoxia induces oxidant-mediated acute lung injury (ALI) and pulmonary cell death, called hyperoxic ALI (HALI). Elucidating molecular mechanisms in HALI could identify therapeutic targets in ALI. Methods In the current study, we examined in vivo effects of HALI on Beclin-1 (BCN1), which regulates autophagy, and modulation of BCN1 by epidermal growth factor receptor (EGFR). Effects of HALI on BCN1 and autophagy were examined in mice with genetically decreased EGFR (EGFRWa5/+). Wildtype (WT) and EGFRWa5/+ mice were exposed to 100% oxygen for 24–72hours along with normoxia controls (eight groups; n=4–6/group), and analysis of pulmonary BCN1 and autophagy was completed. Results In WT, HALI led to increased BCN1 (59% increased total BCN1/β-Actin; p<0.01) in lung and alveolar epithelium (484% increased H-score; p<0.001). HALI led to decreased microtubule-associated protein 1B-light chain (LC3B)-II/-I ratios (43% decrease; p<0.05) and increased p62 (93% increase; p<0.05), suggesting reduced autophagic flux. In human alveolar type-II cells derived from induced pluripotent stem cells (AT2siPSC), HALI caused increased LDH release (130% increase; p<0.0001) and decreased LC3B-II/-I ratios (32% decrease; p<0.05). We previously showed that EGFRWa5/+ mice are protected in HALI. In the current study, EGFRWa5/+ mice showed increased pulmonary BCN1 (122% increase; p<0.05), reduced phosphorylated-(p-)/total BCN1 (47% decrease; p<0.05) and decreased LC3B-II/-I ratios (70% decrease; p<0.01) in HALI compared with WT. In addition, wortmannin (1mg/kg), which decreases BCN1-mediated autophagy, increased mortality in HALI compared with vehicle control (n=10/group; 18% decreased hours survived; p<0.001). Conclusions These data delineate a novel cell death pathway in HALI involving BCN1 and EGFR with therapeutic potential.
AB - Background While delivery of supplemental oxygen is a life-saving therapy, exposure to high oxygen, called hyperoxia, leads to increased intensive care unit mortality. Hyperoxia induces oxidant-mediated acute lung injury (ALI) and pulmonary cell death, called hyperoxic ALI (HALI). Elucidating molecular mechanisms in HALI could identify therapeutic targets in ALI. Methods In the current study, we examined in vivo effects of HALI on Beclin-1 (BCN1), which regulates autophagy, and modulation of BCN1 by epidermal growth factor receptor (EGFR). Effects of HALI on BCN1 and autophagy were examined in mice with genetically decreased EGFR (EGFRWa5/+). Wildtype (WT) and EGFRWa5/+ mice were exposed to 100% oxygen for 24–72hours along with normoxia controls (eight groups; n=4–6/group), and analysis of pulmonary BCN1 and autophagy was completed. Results In WT, HALI led to increased BCN1 (59% increased total BCN1/β-Actin; p<0.01) in lung and alveolar epithelium (484% increased H-score; p<0.001). HALI led to decreased microtubule-associated protein 1B-light chain (LC3B)-II/-I ratios (43% decrease; p<0.05) and increased p62 (93% increase; p<0.05), suggesting reduced autophagic flux. In human alveolar type-II cells derived from induced pluripotent stem cells (AT2siPSC), HALI caused increased LDH release (130% increase; p<0.0001) and decreased LC3B-II/-I ratios (32% decrease; p<0.05). We previously showed that EGFRWa5/+ mice are protected in HALI. In the current study, EGFRWa5/+ mice showed increased pulmonary BCN1 (122% increase; p<0.05), reduced phosphorylated-(p-)/total BCN1 (47% decrease; p<0.05) and decreased LC3B-II/-I ratios (70% decrease; p<0.01) in HALI compared with WT. In addition, wortmannin (1mg/kg), which decreases BCN1-mediated autophagy, increased mortality in HALI compared with vehicle control (n=10/group; 18% decreased hours survived; p<0.001). Conclusions These data delineate a novel cell death pathway in HALI involving BCN1 and EGFR with therapeutic potential.
KW - ARDS
KW - Oxidative Stress
UR - https://www.scopus.com/pages/publications/105028836743
U2 - 10.1136/bmjresp-2025-003323
DO - 10.1136/bmjresp-2025-003323
M3 - Article
C2 - 41592865
AN - SCOPUS:105028836743
SN - 2052-4439
VL - 13
JO - BMJ Open Respiratory Research
JF - BMJ Open Respiratory Research
IS - 1
M1 - e003323
ER -