Effects of the mTOR inhibitor everolimus and the PI3K/mTOR inhibitor NVP-BEZ235 in murine acute lung injury models

Abstract

The mammalian target of rapamycin (mTOR) is a key signaling kinase associated with a variety of cellular functions including the regulation of immunological and inflammatory responses. Classic mTOR inhibitors such as rapamycin or everolimus are commonly used in transplant as well as cancer patients to prevent transplant rejection or cancer progression, respectively. Noninfectious drug-induced pneumonitis is a frequent side effect in mTOR-inhibitor-treated patients. Therefore, we tested the effects of the mTOR inhibitor everolimus and the novel dual PI3K/mTOR inhibitor NVP-BEZ235 in a murine lipopolysaccharide (LPS)-induced acute lung injury model. C57BL/6 mice were treated with either everolimus or NVP-BEZ235 on two consecutive days prior to intratracheal administration of LPS. LPS administration induced a significant increase in total cell, neutrophil and erythrocyte numbers in the bronchoalveolar lavage fluid. Histological examination revealed a serious lung injury as shown by interstitial edema, vascular congestion and mononuclear cell infiltration in these mice after 24h. Everolimus as well as NVP-BEZ235 did not noticeably affect overall histopathology of the lungs in the lung injury model. However, NVP-BEZ235 enhanced IL-6 and TNF-α expression after 24h. In contrast, everolimus did not affect IL-6 and TNF-α levels. Interestingly, both inhibitors reduced inflammatory cytokines in an LPS/oleic acid-induced lung injury model. In conclusion, the mTOR inhibitors did not worsen the overall histopathological severity, but they exerted distinct effects on proinflammatory cytokine expression in the lung depending on the lung injury model applied.

Acute Respiratory Distress Syndrome: Role of Oleic Acid‐Triggered Lung Injury and Inflammation

“…The serine/threonine kinase mammalian target of rapamycin (mTOR) is a key signaling kinase linked to several cellular functions including immunological and inflammatory responses. The mTOR inhibition reduced inflammatory cytokines in LPS/oleic acid-induced lung injury model [ 54 ].…”

Negative Effects of Chronic High Intake of Fructose on Lung Diseases

“…Specifically, in the lung, it has been observed that mTOR can regulate the biological activities of pulmonary vascular endothelium and alveolar epithelial cells in lung diseases [ 134 , 135 ]. mTOR forms the catalytic subunit of two complexes, mTORC1 and mTORC2 [ 132 ].…”

Hypoxia-Inducible Factor-1: A Potential Target to Treat Acute Lung Injury

“…Emodin can reduce the expression of NF-κB, thereby reducing the inflammatory response in ALI [122]. Mammalian target of rapamycin (mTOR) is involved in the regulation of the biological activities of pulmonary vascular endothelial cells and alveolar 5 Oxidative Medicine and Cellular Longevity epithelial cells in ALI and therefore plays an important role in the occurrence and development of ALI [123,124]. The activation of the mTOR signaling pathway may regulate the translocation of HIF-1α from the cytoplasm to the nucleus, thereby increasing the expression of VEGF, increasing the production of inflammatory factors, and exacerbating ALI [123,125].…”