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Review
. 2018 Mar 8;19(3):778.
doi: 10.3390/ijms19030778.

The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis

Jessica Lawrence  1 , Richard Nho  2
Affiliations
Review

The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis

Jessica Lawrence et al. Int J Mol Sci. .

Abstract

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-dependent pathway is one of the most integral pathways linked to cell metabolism, proliferation, differentiation, and survival. This pathway is dysregulated in a variety of diseases, including neoplasia, immune-mediated diseases, and fibroproliferative diseases such as pulmonary fibrosis. The mTOR kinase is frequently referred to as the master regulator of this pathway. Alterations in mTOR signaling are closely associated with dysregulation of autophagy, inflammation, and cell growth and survival, leading to the development of lung fibrosis. Inhibitors of mTOR have been widely studied in cancer therapy, as they may sensitize cancer cells to radiation therapy. Studies also suggest that mTOR inhibitors are promising modulators of fibroproliferative diseases such as idiopathic pulmonary fibrosis (IPF) and radiation-induced pulmonary fibrosis (RIPF). Therefore, mTOR represents an attractive and unique therapeutic target in pulmonary fibrosis. In this review, we discuss the pathological role of mTOR kinase in pulmonary fibrosis and examine how mTOR inhibitors may mitigate fibrotic progression.

Keywords: fibrosis; idiopathic pulmonary fibrosis (IPF); mammalian target of rapamycin (mTOR); phosphoinositide 3-kinase (PI3K); protein kinase B (AKT); radiation-induced pulmonary fibrosis (RIPF).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Proposed model for IPF. Chronic lung injury promotes lung epithelial cell death while (myo)fibroblasts become activated as a result of fibrosis inducing growth factors and cytokines. The failure of re-epithelization and hyper-proliferation of (myo)fibroblasts relentlessly produce collagen rich extracellular matrix, which promotes the fibrotic process, leading to the progression of lung fibrosis.
Figure 2
Figure 2
Schematic figure describing the development of radiation-induced chronic lung fibrosis. Radiation causes damage to pneumocytes and induces secondary reactive oxygen species that contribute to a pro-inflammatory environment. Acutely injured lung triggers healing mechanisms that activate (myo)fibroblasts. Excessive accumulation of collagen, which normally inhibits further fibroblast growth, selects for pro-fibrotic, viable lung fibroblasts. Fibroblast activation and selection combined with the inflammatory cytokine cascade, epithelial to mesenchymal transition (EMT), and loss of parenchymal cells leads to ongoing lung fibrosis. The bidirectional arrow indicates that cell death creates inflammatory cytokine production which further increases cell death.
Figure 3
Figure 3
mTORC1 and mTORC2 complexes and environmental signals to regulate the PI3K/AKT/mTOR pathway to influence growth, proliferation and survival. T indicates the inhibition of the target molecule.
Figure 4
Figure 4
mTOR regulates cell growth, proliferation, and survival. The arrows indicates positive regulation while the symbol T indicates the inhibition of the target molecule(s).
Figure 5
Figure 5
Proposed mechanism by which mTOR may contribute to radiosensitivity and DNA damage repair and thereby potential means in which inhibition of mTORC1 or mTORC2 may alter cell cycle arrest, DNA repair and cell survival following radiation. Pathologic pro-fibrotic lung fibroblasts may depend on both mTORC1 and mTORC2 for efficient cell cycle arrest and repair of DNA damage following radiation damage. In non-radiation induced lung damage, DNA damage may result from various chemical or other microinjuries that create a similar population of fibroblasts that depend on mTOR complexes for survival and proliferation. The bidirectional arrow indicates that AKT activates mTORC2 while mTORC2 can also positively impact PI3K/AKT signaling. T indicates the inhibition of the target molecule. The purple “bolt” indicates ionizing radiation.
Figure 6
Figure 6
Schematic describing potential interactions of mTOR and TGF-β, a major driver of lung fibrosis. Both mTORC1 and mTORC2 likely plays a role in pulmonary fibrosis although the exact contribution from each complex is not clear. Both the canonical (Smad) and non-canonical (non-Smad) pathways may drive ongoing lung fibrosis, including altering metabolism, epithelial to mesenchymal transition (EMT), inflammation, and proliferation. It is possible that different mechanisms are predominate within different cell types to promote fibrosis; for example, Smad-dependent TGF-β signaling may trigger apoptosis in lung epithelial cells yet pro-fibrotic signals predominate in fibroblasts.
Figure 7
Figure 7
Potential roles of mTORC1 and mTORC2 in the development of EMT. TGF-β is important for the transdifferentiation of epithelial cells into fibroblast or myofibroblast-like cells. The exact roles of each mTOR complex are not clear in pulmonary fibrosis, but it is possible that the non-canonical TGF-β pathway contributes to mTORC1 activation, which induces EMT in lung epithelial cells near the site of injury. mTORC2 activity is induced in some cells undergoing EMT and may help ensure progression through the process. Rapamycin (mTORC1 inhibition) is capable of reversing EMT in some cells, suggesting transdifferentiation is disrupted.
Figure 8
Figure 8
PI3K/AKT dependent autophagy regulation in IPF fibroblasts. The arrows indicates positive regulation while the symbol T indicates the inhibition of autophagy.
Figure 9
Figure 9
The mTOR-dependent metabolic pathway.
Figure 10
Figure 10
Proposed interaction between mTOR and the induction of SASP signals. Senescent pneumocytes may contribute to pro-inflammatory and pro-fibrotic signals, which further contribute to the development of pulmonary fibrosis through the loss of parenchymal cells and selection for improved fibroblast survival.
Figure 11
Figure 11
The role of mTORC1 and mTORC2 in the development and progression of idiopathic pulmonary fibrosis (IPF) and radiation-induced pulmonary fibrosis (RIPF). mTORC1 and mTORC2 are intricately involved in promoting mechanisms that favor activated lung fibroblast survival and relentless collagen production. mTORC1 inhibitors have been shown to modulate RIPF and bleomycin-induced pulmonary fibrosis, suggesting they may be effective mitigators in fibroproliferative lung disease. The arrows indicate positive regulation while T indicates the inhibition of the target molecule.
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