Inhibition of Mammalian Target of Rapamycin Augments Lipopolysaccharide-Induced Lung Injury and Apoptosis

Abstract

Acute lung injury during bacterial infection is associated with neutrophilic inflammation, epithelial cell apoptosis, and disruption of the alveolar-capillary barrier. TLR4 is required for lung injury in animals exposed to bacterial LPS and initiates proinflammatory responses in part via the transcription factor NF-κB. Ligation of TLR4 also initiates a proapoptotic response by activating IFN-β and STAT1-dependent genes. We recently demonstrated that mammalian target of rapamycin (mTOR), a key controller of cell growth and survival, can physically interact with STAT1 and suppress the induction of STAT1-dependent apoptosis genes. We therefore hypothesized that the mTOR inhibitor rapamycin would increase LPS-induced apoptosis and lung injury in vivo. Rapamycin increased lung injury and cellular apoptosis in C57BL/6J mice exposed to intratracheal LPS for 24 h. Rapamycin also augmented STAT1 activation, and the induction of STAT1-dependent genes that mediate cellular apoptosis (i.e., Fas, caspase-3). LPS-induced lung injury was attenuated in STAT1 knockout mice. In addition, LPS and IFN-β–induced apoptosis was absent in cultured cells lacking STAT1, and, unlike in wild-type cells, a permissive effect of rapamycin was not observed. In contrast to its effect on STAT1, rapamycin inhibited NF-κB activation in vivo and reduced selected markers of inflammation (i.e., neutrophils in the bronchoalveolar lavage fluid, TNF-α). Therefore, although it inhibits NF-κB and neutrophilic inflammation, rapamycin augments LPS-induced lung injury and apoptosis in a mechanism that involves STAT1 and the induction of STAT1-dependent apoptosis genes.

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models

“…1B), suggesting that S6K1 is probably the key player downstream of mTORC1. Similar results have been reported in intestinal ischemia/ reperfusion injury and LPS-induced lung injury, further supporting our speculation (38,39). Recently, Faller et al (40), using multiple genetically engineered mouse alleles, found that S6K1/2, but not 4EBP1/2, was involved in intestinal regeneration and demonstrated that rapamycin functioned mainly through the mTORC1-S6K pathway rather than through the 4EBP1-eIF4E branch.…”

“…It is increasingly important to comprehensively understand the role of mTORC1 in acute injury, because adverse clinical effects have been reported associated with sirolimus therapy, especially in the case of lung transplants (25,45,46). In the studies based on animal models, rapamycin treatment has been demonstrated to result in acute renal failure, liver regeneration, and lung injury (39,47,48). In the current study, we demonstrated the positive contribution of mTORC1-mediated S6K1-Stat3 activation in colon tissues toward recovery from acute experimental colitis in mice.…”

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

“…Rapamycin can alter apoptosis and necrosis that influence inflammation, with differential effects by tissue and model (Fielhaber et al ., 2012). eRapa‐fed mice exhibited reduced apoptosis‐ (e.g., bak, casp3, fas, fasl ) and necroptosis‐related (e.g., ripk1, tradd ) genes in all immune cells tested (Table S5).…”

Effect of rapamycin on early stage apoptosis of neutrophils in Sprague-Dawley rats with acute lung injury

“…Acute pancreatitis-associated lung injury (APALI) is the most common and a severe complication in patients with multisystem organ failure. Previous studies indicated that neutrophils serve a critical role in inflammatory reactions in acute lung injury (2,3).…”

“…Rapamycin exerts an immunosuppressive effect by blocking signal transduction of various cytokine receptors, thereby preventing T lymphocytes and other cells from going from the G1 phase to the S phase of the cell cycle. A recent report has also indicated that rapamycin can inhibit the inflammatory reaction induced by nuclear factor (NF)-κB activation and neutrophils (2,3). Rapamycin also reportedly exacerbates the severity of acute lung injury induced by endotoxin and causes cell apoptosis (4).…”