Rtp801 Suppression of Epithelial mTORC1 Augments Endotoxin-Induced Lung Inflammation

Nadon, Aaron M.; Pérez, Mario J.; Hernández-Saavedra, Daniel; Smith, Lynelle P.; Yang, Yimu; Sanders, Linda; Gandjeva, Aneta; Chabon, Jacob J.; Koyanagi, Daniel E.; Graham, Brian B.; Tuder, Rubin M.; Schmidt, Eric P.

doi:10.1016/j.ajpath.2014.06.002

Cited by 24 publications

(41 citation statements)

References 22 publications

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Section: Introductionmentioning

confidence: 72%

“…This effect underscores the anti-inflammatory function of mTOR and supports its role in ameliorating lung inflammation [2]. The primary complex of mTOR mediates anti-inflammatory responses in the lung [2]. Sirolimus has also been shown to induce severe immunosuppression in mice, as a result of thymus involution due to cortical lymphocyte apoptosis [3].…”

Section: Introductionmentioning

confidence: 91%

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Sirolimus alters lung pathology and viral load following influenza A virus infection

et al. 2017

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BackgroundInhibitors of mTOR, such as sirolimus, have been shown to induce thymus involution and inflammatory lung disease in mice. The latter effect supports the role of this serine/threonine kinase in ameliorating lung inflammation. Other studies have shown sirolimus reduces/delays lung disease associated with various strains of influenza A virus (IAV). Thus, the effects of mTOR inhibitors on influenza infection deserve further studies.MethodsHere, we examined the changes in lung viral copies, pathology and pulmonary function associated with IAV (A/PR/8/34) infection in mice treated with sirolimus.ResultsBody weight loss peaked between days 6–11 post-infection and was more severe in IAV-infected mice that were administered sirolimus as compared to mice that received IAV alone (p = 0.030). Natural log viral gene copies, mean ± SD per mg lung tissue, in IAV-infected mice that were administered sirolimus were 17.31 ± 1.27 on day 4, 19.31 ± 7.46 on day 10, and 0 on day 25. The corresponding number of copies in mice that received IAV alone were 18.56 ± 0.95 on day 4 (p = 0.132), 1.52 ± 1.39 on day 10 (p = 0.008), and 0 on day 25. Lung pathology was evident on days 4, 10, and 25 post infection, with mean ± SD inflammatory score of 9.0 ± 4.5 in IAV-infected mice that were administered sirolimus, as compared to 11.5 ± 4.5 (p = 0.335) in mice received IAV alone (maximum score, 26.0). Impaired lung function was evident in IAV-infected mice on days 4 and 10, as demonstrated by increased airway resistance and decreased compliance.ConclusionsIn this model, the effects of sirolimus on influenza infection included severe weight loss and modified viral replication, respiratory function and lung inflammation. The adverse events associated with sirolimus treatment are consistent with its potent immunosuppressive activity and, thus, preclude its use in IAV infection.

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Section: Introductionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 91%

Sirolimus alters lung pathology and viral load following influenza A virus infection

et al. 2017

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“…Moreover, the individual expression levels of inflammation-associated genes may also influence the subsequent response to mTOR inhibitors. For example, in mice that are deficient for Rtp801, which is a negative regulator of mTORC1, rapamycin strongly enhances LPS-induced lung inflammation [39]. Interestingly, environmental cues such as cigarette smoke promote activation of Rtp801 [37].…”

Section: Discussionmentioning

confidence: 98%

“…Recently, it has been shown that activation of mTOR inhibits inflammatory responses and apoptosis in the lung of mice due to cigarette smoke or LPS [37][38][39]. Therefore, we speculated that inhibition of mTOR in the innate immune system might exaggerate an initial insult in the lung leading to augmented inflammatory responses and lung damage that may be at the base of DIP.…”

Section: Introductionmentioning

confidence: 92%

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

Üstün

Lassnig

Preitschopf

et al. 2015

Transplant Immunology

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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.

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“…We created Rtp801-overexpressing mice (Tg-TRE-RTP801) (20). TgRtp801 MLF were purified and cultured as described above.…”

Section: Rtp801 Overexpression In Mlfmentioning

confidence: 99%

RTP801 Amplifies Nicotinamide Adenine Dinucleotide Phosphate Oxidase-4–Dependent Oxidative Stress Induced by Cigarette Smoke

Hernández-Saavedra¹,

Sanders²,

Pérez³

et al. 2017

Am J Respir Cell Mol Biol

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Tobacco smoke (TS) causes chronic obstructive pulmonary disease, including chronic bronchitis, emphysema, and asthma. Rtp801, an inhibitor of mechanistic target of rapamycin, is induced by oxidative stress triggered by TS. Its up-regulation drives lung susceptibility to TS injury by enhancing inflammation and alveolar destruction. We postulated that Rtp801 is not only increased by reactive oxygen species (ROS) in TS but also instrumental in creating a feedforward process leading to amplification of endogenous ROS generation. We used cigarette smoke extract (CSE) to model the effect of TS in wildtype (Wt) and knockout (KO-Rtp801) mouse lung fibroblasts (MLF). The production of superoxide anion in KO-Rtp801 MLF was lower than that in Rtp801 Wt cells after CSE treatment, and it was inhibited in Wt MLF by silencing nicotinamide adenine dinucleotide phosphate oxidase-4 (Nox4) expression with small interfering Nox4 RNA. We observed a cytoplasmic location of ROS formation by realtime redox changes using reduction-oxidation-sensitive green fluorescent protein profluorescent probes. Both the superoxide production and the increase in the cytoplasmic redox were inhibited by apocynin. Reduction in the activity of Sod and decreases in the expression of Sod2 and Gpx1 genes were associated with Rtp801 CSE induction. The ROS produced by Nox4 in conjunction with the decrease in cellular antioxidant enzymatic defenses may account for the observed cytoplasmic redox changes and cellular damage caused by TS.

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Rtp801 Suppression of Epithelial mTORC1 Augments Endotoxin-Induced Lung Inflammation

Cited by 24 publications

References 22 publications

Sirolimus alters lung pathology and viral load following influenza A virus infection

Sirolimus alters lung pathology and viral load following influenza A virus infection

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

RTP801 Amplifies Nicotinamide Adenine Dinucleotide Phosphate Oxidase-4–Dependent Oxidative Stress Induced by Cigarette Smoke

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