Impaired energy metabolism and altered functional activity of alveolar type II epithelial cells following exposure of rats to nitrogen mustard

Toxicol Appl Pharmacol. 2022 Dec 1:456:116257. doi: 10.1016/j.taap.2022.116257. Epub 2022 Sep 27.


Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis. Alveolar Type II cells are primarily responsible for surfactant production; they also play a key role in lung repair following injury. Herein, we assessed the effects of NM on Type II cell activity. Male Wistar rats were administered NM (0.125 mg/kg) or PBS control intratracheally. Type II cells, lung tissue and BAL were collected 3 d later. NM exposure resulted in double strand DNA breaks in Type II cells, as assessed by expression of γH2AX; this was associated with decreased expression of the DNA repair protein, PARP1. Expression of HO-1 was upregulated and nitrotyrosine residues were noted in Type II cells after NM exposure indicating oxidative stress. NM also caused alterations in Type II cell energy metabolism; thus, both glycolysis and oxidative phosphorylation were reduced; there was also a shift from a reliance on oxidative phosphorylation to glycolysis for ATP production. This was associated with increased expression of pro-apoptotic proteins activated caspase-3 and -9, and decreases in survival proteins, β-catenin, Nur77, HMGB1 and SOCS2. Intracellular signaling molecules important in Type II cell activity including PI3K, Akt2, phospho-p38 MAPK and phospho-ERK were reduced after NM exposure. This was correlated with dysregulation of surfactant protein production and impaired pulmonary functioning. These data demonstrate that Type II cells are targets of NM-induced DNA damage and oxidative stress. Impaired functioning of these cells may contribute to pulmonary toxicity caused by mustards.

Keywords: Alveolar epithelial Type II cells; Apoptosis; Energy metabolism; Lung function; Nitrogen mustard.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Lung Injury* / chemically induced
  • Alveolar Epithelial Cells
  • Animals
  • Energy Metabolism
  • Male
  • Mechlorethamine* / toxicity
  • Oxidative Stress
  • Rats
  • Rats, Wistar
  • Surface-Active Agents / adverse effects


  • Mechlorethamine
  • Surface-Active Agents