Caspase‐3 is activated by intrinsic apoptotic pathways during mechanical ventilation

Abstract

RationaleDiaphragmatic weakness is a well‐documented response to prolonged mechanical ventilation (MV). Several key proteases are activated during prolonged MV. Specifically, caspase‐3 has been shown to be required for diaphragmatic weakness. However, the mechanisms by which caspase‐3 is activated is unknown. We tested the hypothesis that during MV, caspase‐3 is activated by an intrinsic pathway.MethodsFemale Sprague‐Dawley rats (3 months old) were divided into two groups: 1) control and 2) animals that were mechanically ventilated for 12 hrs.ResultsCompared to control, MV resulted in an increase in the caspase‐3 specific cleavage product of alpha‐II spectrin and increased caspase‐3 activity in the diaphragm. Likewise, after MV, both caspase‐9 and caspase‐12 activities in the diaphragm were significantly higher than control. In contrast, there was no increase in diaphragmatic caspase‐8 activity after MV.ConclusionThese results confirm our hypothesis that during prolonged MV, diaphragmatic caspase‐3 is activated by both mitochondrial (caspase‐9) and sarcoplasmic reticulum (caspase‐12) mediated pathways rather than the external death ligand (caspase‐8) pathway. Supported by the NIH RO1 HL087839 awarded to SKP.