| Autor: |
Andres DK; Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, Maryland devon.k.andres.ctr@mail.mil., Keyser BM; Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, Maryland., Melber AA; Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, Maryland., Benton BJ; Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, Maryland., Hamilton TA; Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, Maryland., Kniffin DM; Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, Maryland., Martens ME; Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, Maryland., Ray R; Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, Maryland. |
| Abstrakt: |
To 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 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 < 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 < 0.01) and BALF ( P < 0.05). However, mFas-L increased only in BALF cells between 24 and 48 h ( P < 0.1 and P < 0.001, respectively). Fas-R increased only in BALF cells by 6 h ( P < 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. |
