Cadmium-potentiated metabolic reprogramming in pathogenesis of lung fibrosis

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Title: Cadmium-potentiated metabolic reprogramming in pathogenesis of lung fibrosis Project Summary Cd is a toxic environmental metal contaminant, number 7 on Agency for Toxic Substances and Disease Registry (ATSDR) Substance Priority List. Lung diseases are extremely common. Our previous study shows that lung Cd burden found in non-smoker's lung caused changes in the mouse lung metabolome, transcriptome and redox proteome with effects on airway reactivity, glycolysis and lipid metabolism, inflammation and fibrotic signaling. This has considerable implications for risk of pulmonary fibrosis and other interstitial lung diseases. Humans do not have an efficient mechanism for Cd removal; thus, Cd burden in humans increases with age. Respiratory syncytial virus (RSV) is a major cause of bronchiolitis in infants and causes considerable morbidity due to subsequent development of asthma in elderly. Our previous integrated omics analyses of low-dose Cd toxicity in lung showed association with zinc finger DHHC domain-containing palmitoyltransferase zDHHC11 and Cd-dependent response with activation of mTORC1 signaling, linked to lung fibrosis. Integrated network responses of metabolome to low dose Cd exposure with RSV infection showed mitochondrial dysfunction with disrupted energy metabolism and fatty acid biosynthesis as critical intermediate responses in Cd-dependent lung injury. Based on our findings and available data, we hypothesize that 1) infant RSV infection reprograms protein S-palmitoylation as an activator of mTORC1; 2) Cd reprograms mitochondrial metabolism and redox signaling to create a sustained driver of mTORC1 activity; 3) the combination of mTORC1 activators creates a vicious cycle because mTORC1 activates S-palmitoylation; 4) sustained mTORC1 activity causes lung fibrosis. We propose three Aims to test these mechanisms using molecular, cell biology, pathology and omics methods in mice and cultured lung cells with controlled Cd dosing. Aim 1 will determine whether Cd potentiates RSV-induced protein S-palmitoylation via regulating the activity of key proteins, zDHHC11, acyl protein thioesterase. Aim 2 is to examine the role of mTORC1 in Cd-potentiated fibrosis pathways using mouse and cell models. Aim 3 will test whether lung Cd burden serves as a driver for fibrosis following RSV infection by effects on mitochondria and activation of mTORC1 signaling. Targeted analyses will provide direct tests of the proposed mechanisms for low-dose Cd and RSV infection in lung fibrosis. The integrated omics approaches will additionally provide the first detailed look at the central network and sub-network structures, and identify molecular communities linked to lung responses to low-dose Cd in mice with prior RSV infection. The results will have sustained impact by providing an experimental animal model to study interactions of low intensity exposures in lung disease and by demonstrating whether low-dose environmental Cd interacts with RSV infection to increase lung fibrosis through disrupting the protein S- palmitoylation mechanism, altering mTORC1 activation and increasing mitochondrial oxidative stress.