Trauma-hemorrhagic shock-induced pulmonary epithelial and endothelial cell injury utilizes different programmed cell death signaling pathways

Abstract

Intestinal ischemia after trauma-hemorrhagic shock (T/HS) results in gut barrier dysfunction and the production/release of biologically active and tissue injurious factors in the mesenteric lymph, which, in turn, causes acute lung injury and a systemic inflammatory state. Since T/HS-induced lung injury is associated with pulmonary endothelial and epithelial cell programmed cell death (PCD) and was abrogated by mesenteric lymph duct ligation, we sought to investigate the cellular pathways involved. Compared with trauma-sham shock (T/SS) rats, a significant increase in caspase-3 and M30 expression was detected in the pulmonary epithelial cells undergoing PCD, whereas apoptosis-inducing factor (AIF), but not caspase-3, was detected in endothelial cells undergoing PCD. This AIF-mediated pulmonary endothelial PCD response was validated in an in situ femoral vein assay where endothelial cells were found to express AIF but not caspase-3. To complement these studies, human umbilical vein endothelial cell (HUVEC), human lung microvascular endothelial cell (HLMEC), and human alveolar type II epithelial cell (A549) lines were used as in vitro models. T/HS lymph induced the nuclear translocation of AIF in HUVEC and HLMEC, and caspase inhibition in these cells did not afford any cytoprotection. For proof of principle, AIF silencing in HUVEC reversed the cytotoxic effects of T/HS on cell viability and DNA fragmentation. In A549 cells, T/HS lymph activated caspase-3-mediated apoptosis, which was partially abrogated by N-benzyloxycarbonyl-Val-Ala-Asp (zVAD). Additionally, T/HS lymph did not cause the nuclear translocation of AIF in A549 cells. Collectively, T/HS-induced pulmonary endothelial PCD occurs via an AIF-dependent caspase-independent pathway, whereas epithelial cells undergo apoptosis by a caspase-dependent pathway.

Sodium hydrosulfide alleviates lung inflammation and cell apoptosis following resuscitated hemorrhagic shock in rats

“…Although different from the cell death patterns observed during LPS-induced lung injury, hyperoxia and ischemia-reperfusion injury are the main causes of complex cell death that include apoptosis, oncosis, and necrosis [20,21] . Dimtrios and colleagues have suggested that two programmed cell death pathways exist in the lungs in rat models of trauma-hemorrhagic shock [22] . These two pathways involve endothelial cell death via a caspase-independent way and epithelial cell apoptosis through a caspase-dependent pathway.…”

Factors associated with acute lung injury in combat casualties receiving massive blood transfusions: A retrospective analysis

“…Traumatic injury represents a leading cause of critical illness, and respiratory failure is a common complication of severe trauma [1]. Approximately 2% to 4% of persons with trauma develop acute lung injury (ALI).…”

“…Furthermore, focal chest trauma, whether blunt or penetrating, heightens the risk for ALI [4,5]. Similarly, the presence of hemorrhagic shock along with its treatment can potentiate ALI [1,6]. Thus, one aspect of trauma resuscitation, namely, blood transfusion, is independently linked to the development of ALI.…”

Mast-Cell-Releasing Tryptase Triggers Acute Lung Injury Induced by Small Intestinal Ischemia–Reperfusion by Activating PAR-2 in Rats

“…Small intestinal ischemia-reperfusion (IIR) injury can occur at great number of pathophysiologic conditions, including hemorrhagic shock [1,2] and acute mesenteric ischemia [3], which becomes one of most common clinical events. In addition to the local injury, IIR can also result in severe injury of remote tissues and concomitant distant organ dysfunction [4], especially affects the lungs, which accounts for the high mortality.…”