Apoptotic cell death in rat lung following mustard gas inhalation

Devon K. Andres, Brian M. Keyser, Ashley A. Melber, Betty J. Benton, Tracey A. Hamilton, Denise M. Kniffin, Margaret E. Martens, Radharaman Ray
2017 American Journal of Physiology - Lung cellular and Molecular Physiology  
investigate apoptosis as a mechanism of sulfur mustard (SM) inhalation injury in animals, we studied different caspases (caspase-8, -9, -3, and -6) in the lungs from a ventilated rat SM aerosol inhalation model. SM activated all four caspases in cells obtained from bronchoalveolar lavage fluid (BALF) as early as 6 h after exposure. Caspase-8, which is known to initiate the extrinsic Fas-mediated pathway of apoptosis, was increased fivefold between 6 and 24 h, decreasing to the unexposed-control
more » ... level at 48 h. The initiator, caspase-9, in the intrinsic mitochondrial pathway of apoptosis as well as the executioner caspases, caspase-3 and -6, all peaked (P Ͻ 0.01) at 24 h; caspase-3 and -6 remained elevated, but caspase-9 decreased to unexposed-control level at 48 h. To study further the Fas pathway, we examined soluble as well as membrane-bound Fas ligand (sFas-L and mFas-L, respectively) and Fas receptor (Fas-R) in both BALF cells and BALF. At 24 h after SM exposure, sFas-L increased significantly in both BALF cells (P Ͻ 0.01) and BALF (P Ͻ 0.05). However, mFas-L increased only in BALF cells between 24 and 48 h (P Ͻ 0.1 and P Ͻ 0.001, respectively). Fas-R increased only in BALF cells by 6 h (P Ͻ 0.01) after SM exposure. Apoptosis in SM-inhaled rat lung specimens was also confirmed by both immunohistochemical staining using cleaved caspase-3 and -9 antibodies and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining as early as 6 h in the proximal trachea and bronchi, but not before 48 h in distal airways. These findings suggest pathogenic mechanisms at the cellular and molecular levels and logical therapeutic target(s) for SM inhalation injury in animals.
doi:10.1152/ajplung.00281.2015 pmid:28360112 fatcat:wambpcmwkffmxgqd4aonquaesa