Critical Care Medicine

Adult Critical Care

Conditional Deletion of Nrf2 in Airway Epithelium Exacerbates Acute Lung Injury and Impairs the Resolution of Inflammation

Reddy NM, Potteti HR, Mariani TJ, et al (Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Univ of Rochester Med Ctr, NY) Am J Respir Cell Mol Biol 45:1161-1168, 2011^§

Abstract

Oxidant stress, resulting from an excess of reactive electrophiles produced in the lung by both resident (epithelial and endothelial) and infiltrated leukocytes, is thought to play an obligatory role in tissue injury and abnormal repair. Previously, using a conventional (whole-body) knockout model, we showed that antioxidative gene induction regulated by the transcription factor Nrf2 is critical for mitigating oxidant-induced (hyperoxic) stress, as well as for preventing and resolving tissue injury and inflammation in vivo. However, the contribution to pathogenic acute lung injury (ALI) of the cellular stress produced by resident versus infiltrated leukocytes remains largely undefined in vivo. To address this critical gap in our knowledge, we generated mice with a conditional deletion of Nrf2 specifically in Clara cells, subjected these mice to hyperoxic insult, and allowed them to recover. We report that a deficiency of Nrf2 in airway epithelia alone is sufficient to contribute to the development and progression of ALI. When exposed to hyperoxia, mice lacking Nrf2 in Clara cells showed exacerbated lung injury, accompanied by greater levels of cell death and epithelial sloughing than in their wildtype littermates. In addition, we found that an Nrf2 deficiency in Clara cells is associated with a persistent inflammatory response and epithelial sloughing in the lungs during recovery from sublethal hyperoxic insult. Our results demonstrate (for the first time, to the best of our knowledge) that Nrf2 signaling in Clara cells is critical for conferring protection from hyperoxic lung injury and for resolving inflammation during the repair process (Figs 2 and 3).

Figure 2 Hyperoxia-induced lung injury in Nrf2^f/f and Nrf2^Δcc mice. Nrf2^f/f and Nrf2^Δcc mice were exposed to room air (RA) or hyperoxia for 60 hours and killed, and their left lungs were inflated and fixed in 1.5% paraformaldehyde. Lung tissue sections were prepared and stained with hematoxylin and eosin (H&E). (A) Representative images of H&E-stained lungs sections of three mice are shown. Bottom: Enlarged images of lung tissue sections of Nrf2^f/f and Nrf2^Δcc mice exposed to 60 hours of hyperoxia. Arrows indicate epithelial sloughing in Nrf2^Δcc mice. (B) Evans blue dye (EBD) was injected intraperitoneally into the mice 2 hours before they were killed. Lungs were perfused, and lung EBD and serum EBD were extracted into formamide. Lungs were dried, and the ratios of lung EBD/serum EBD/dry ratios were calculated. The data shown represent means ± SEM (n = 5). (C) Bronchoalveolar lavage (BAL) fluid was collected from the right lung, and total protein was estimated in BAL fluids with a Bio-Rad protein assay. Data represent means ± SEM (n = 6). Significance was calculated using the Student t test. *P ≤ 0.05, room air versus hyperoxia or recovery. ^†P ≤ 0.05, Nrf2^f/f mice versus Nrf2^Δcc mice. Open bars, room-air controls; solid bars, hyperoxia. (Reprinted from Reddy NM, Potteti HR, Mariani TJ, et al. Conditional deletion of Nrf2 in airway epithelium exacerbates acute lung injury and impairs the resolution of inflammation. Am J Respir Cell Mol Biol. 2011;45:1161-1168, with permission from the Official Journal of the American Thoracic Society.)

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