Exhaust fumes from automobiles, emissions from industries and refineries including power generating stations are major sources of outdoor pollution. In contrast, cooking, burning fuel, dry cleaning, and domestic heating activities contribute as indoor sources of pollution. The mixture of particulate matter (PM) and gases are inhaled and penetrated into lungs, leading to pulmonary and systemic health effects [24]. In healthy lung tissue, mTORC1 is basally activated and the autophagy-related protein LC3 II is suppressed, maintaining cell homeostasis, and protecting cell damage from stress. However, lung injury following exposures can result in the inhibition of mTORC1 causing the upregulation of LC3 II, leading to development of pulmonary disease. Intratracheal instillation of PM with a diameter of less than 2.5 microns (PM_2.5) in mice lungs induces pulmonary damage with vascular hyperpermeability and inflammatory responses. Mechanistically, PM_2.5 upregulates Toll-like receptor (TLR) expression, releasing inflammatory cytokines. Additionally, PM_2.5 inhibits mTOR signaling pathway, decreasing the levels of phosphorylated mTOR, Protein kinase B (Akt), and PI3K [25], worsening the lung injury. Consequently, the study reported a strong connection of complex signaling network between TLR, one of the sensors for autophagy and mTOR, also involved in lung inflammation [25, 26]. These findings suggest disruption of mTOR signaling contributes to PM-induced lung damage.

The fundamental insights of risk factors such as lack of physical activity, high calorie intake and high glycemic index have been well known for decades. However, a strong link between environmental factors in air and predisposition of diabetes mellitus has been growing recently. Moreover, extensive data from high fat diet induced murine model and humans suggests ambient air pollution with PM_2.5 exposure is critically associated with pathophysiological disturbances in metabolic disease conditions [27]. Autophagy serves as a protective mechanism in pancreatic B cell survival. Chronic activation of mTORC1 inhibits the autophagy and facilitates the progression of type 2 diabetes mellitus and insulin resistance [28–30]. Activated mTOR stimulates S6K1 to inhibit insulin receptor substrate-1 (IRS1), affecting the insulin pathway, causing insulin resistance [31–33]. mTOR also mediates lipogenesis and formation of adipose tissue. Role of S6K1 has been investigated in diet-induced obesity mice model, which suggested mice lacking S6K1 are protected against obesity [34]. In addition, the study suggests exposure to PM_2.5 exacerbates a key defect in insulin signaling via alterations in PI3K/AKT pathway increasing inflammation at adipose tissue macrophages [27]. Prospectively, abnormalities in PI3K/AKT pathway can be suggestive of cascade activation of mTOR implicating its potential in exaggerating inflammatory response in metabolic disease.

Metal nanoparticles have a wide range of applications from medicine to consumer products and incorporation into industrial processes. With potential manufacturing and widespread use of nanotechnology, exposure to engineered nanoparticles has also increased among consumers and manufacturers. Exposure to nanoparticles composed of metals and metal oxides have potential for adverse environmental and health effects [35]. Inhalation is the primary route of nanoparticle exposure in environmental and occupational settings, resulting in pulmonary damage leading to lung injury and development of respiratory diseases [36]. Several studies have reported autophagy is a consequence of metal nanoparticle exposure contributing to toxicity [37–41]. In particular, mesoporous silica nanoparticles induce autophagy in human bronchial epithelial cells (BEAS-2B) via mTOR inhibition, in a dose-dependent manner [42]. Specifically, mesoporous silica nanoparticle exposure resulted in decreased phosphorylation of mTOR and p62 levels, suggesting induction of autophagy, which was further confirmed in mouse lungs exposed to mesoporous silica nanoparticles via intratracheal instillation [42]. This silica-induced autophagy leads to macrophage activation, stimulating lung fibroblasts activity and progression of silicosis (pulmonary fibrosis) [43]. Overall, nanoparticle inhalation exposure may cause dysregulation of mTOR signaling inducing autophagy, potentially contributing to pulmonary damage and other respiratory health concerns.

Air pollution and nanoparticle exposures have the potential to induce neurotoxicity via direct interactions following transport from the lung to the brain or indirectly via secondary mechanisms. In particular, nanomaterials have applications in medicine as drug delivery systems due to their ability to increase drug bioavailability. However, some nanomaterials have the ability to produce reactive oxygen species (ROS), inducing oxidative stress leading to detrimental effects on the brain. ROS are produced in response to xenobiotics and environmental stressors and as a by-product of oxygen metabolism. An imbalance in production and removal of these ROS by biological system is termed as oxidative stress. This highly reactive oxygen containing species induces mitochondrial dysfunction and stimulates various signaling proteins kinases. These oxidative damage conditions can initiate autophagosome formation inducing autophagy [44, 45]. In biological system, NPs tends to form protein-NP corona depending on protein affinity and NPs characteristics. Additionally, NPs functions as molecular chaperon to carry out protein folding, stabilization and protein aggregates. However, alterations in formation of stable corona and high protein concentration can result in accumulation of protein aggregates [46]. Autophagy is crucial in clearing toxic intracellular proteins and aggregates [amyloid-β (Aβ), mutant huntingtin, α-synuclein, and, phosphor-tau] which contribute to neurodegenerative diseases [47, 48]. Glycogen synthase kinase-3 beta (GSK3β), the main kinase that phosphorylates tau protein, is a component of the PI3K/AKT/mTOR signaling pathway, Increased expression of GSK3β can lead to hyperphosphorylation of tau protein via activation of mTOR, resulting in its aggregation and the formation of neurofibrillary tangles, which are a major neuropathological feature of Alzheimer’s disease [49–52]. Furthermore, it has been evidently reported that air pollution with PM_0.1 triggers the development of central nervous system disorders such as Alzheimer’s, Parkinson’s and stroke. An investigation on exposure of PM_0.1 composed of aluminum emphasized the generation of ROS with association of autophagosome and oxidative DNA damage in neuronal cells. Interestingly, nanoparticles are proposed to cause autophagy by oxidative stress mechanism resulting in mitochondrial damage and accumulation of proteins. Hence, the likelihood of PM_0.1 exposure generating ROS that can induce autophagy contributing to neuronal damage and development of neurodegenerative diseases should not be disregarded [46].

Modern general anesthesia methods ensure the safety of numerous surgeries each year [53]. In clinical settings, the most utilized inhalational anesthetics are isoflurane, sevoflurane, and desflurane. Research on the safety of these anesthetics has indicated they can have both beneficial and harmful impacts on various organs, including the lungs, trachea, diaphragm muscle, liver, and kidneys [54]. Further, the use of anesthetic agents could potentially cause harm to the development of neurocognition, particularly during early childhood. Sevoflurane is a widely and popularly used inhalation anesthetic in children. It has been proposed that infant exposure to sevoflurane and isoflurane are associated with long-term loss of cognitive functions and neurobehavioral changes [55–57]. Autophagy is crucial for normal brain development since it is involved in nutritional supplementation during the prenatal period [58, 59]. Interfering with autophagy can disturb the proper coordination of cell growth, specialization, and programmed cell death that are required for developing the intricate structure of the nervous system [59]. This dysregulated autophagy was substantially studied in pregnant rats exposed to sevoflurane. It was determined inhalation of sevoflurane upregulated autophagy via the PTEN/Akt/mTOR pathway in fetus brains [58]. Further, phosphatase and tensin homolog on chromosome 10 (PTEN), is abundantly expressed in embryonic central nervous system and affects brain development. In mammalian cells, PTEN can modulate autophagy by counteracting PI3K via its lipid phosphatase function. Specifically, compared to the control group, the administration of sevoflurane resulted in a noteworthy increase of PTEN expression and a decrease in the levels of p-Akt/Akt and mTOR in fetal brains. This suggests the combined involvement of PTEN/Akt/mTOR signaling in activating autophagy in sevoflurane-induced neurotoxicity [58]. Broadly, these results suggest systemic effects following inhalation exposures could be mediated by variations in mTOR signaling.

It is widely acknowledged that cigarette smoking is the primary contributor to the development of lung cancer due to the strong correlation between the quantity of cigarettes consumed and the likelihood of developing the disease. The main cause of COPD is the inhalation of chemicals and oxidants present in cigarette smoke (CS), in addition to being exposed to dust, industrial, or household particles [64, 65]. COPD is marked by a cumulative and complete blockage of the airways (known as chronic bronchitis), damage to the alveolar walls (emphysema), and excess mucus production [66]. Cysteine cathepsins are important in lung homeostasis and their dysregulation plays a key role in lung injury and inflammation via degrading antimicrobial peptides and extracellular matrix components. Murine experimental emphysema reported to have increased levels of cathepsin S, which is a potent elastase involved in alveolar remodeling [67–69]. Specifically, nicotine-containing cigarette smoke extract (CSE) upregulates cathepsin expression in human macrophages via mTOR pathway, modulating epithelial integrity and enhancing its permeability in COPD. This was confirmed when macrophages exposed to nicotine-containing CSE and nicotine alone demonstrated similar fold increase in cathepsin upregulation suggesting nicotine to be driving factor of responses [64]. Furthermore, the signaling pathway was confirmed with treatment of rapamycin, a known mTOR inhibitor, which demonstrated increase in immunoreactive and mature cathepsin and decrease in phosphorylated transcription factor EB (TFEB), a central regulator of autophagy/lysosomal biogenesis [70]. Consequently, dysregulation of mTOR signaling contributes to CS-associated induction of pulmonary inflammation and disease.

Prevalently, 90% of lungs cancer diagnosis is associated with the use of tobacco. Tobacco smoke contains numerous components including aromatic amines and polychromatic hydrocarbons that promote carcinogenesis. Additionally, these components, especially nicotine and nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) produce active metabolites that promote DNA adduct formation. The carcinogenic effects of tobacco components involve activation of multiple signaling pathways that regulate cell cycle and proliferation. Of them, Akt/mTOR pathway is critically involved cell growth, metabolism, and survival. Abnormal and excessive mTOR activation promotes tumor growth, metastasis, and angiogenesis, a process that supplies carcinoma cells with oxygen and nutrients. Particularly, tobacco components damages DNA by activating Akt pathway and modulates PI3K, upstream regulator of Akt [71]. Experimentally, immunohistochemistry and immunoblotting on lung tissues of NNK-treated A/J mice reveals presence of phosphorylated Akt in airway epithelial cells and 5.5-fold increase in ratio of phosphorylated Akt to total Akt compared to phosphate buffered saline (PBS) control mice, respectively [72]. Similarly, in vitro studies on nicotine or NNK treated non-small cell lung cancer cells reports to increase phosphorylation of S6K1 and 4E-BP1, activate mTOR and induce cell proliferation [72, 73]. In short, tobacco smoke components foster cell proliferation and tumorigenesis via mTOR activation.