Our lab focuses on three major topics focused around mechanisms of microvascular endothelial cell (MVEC) dysfunction in the lung: ROS-induced Ca2+ signaling; mechanisms of checkpoint inhibitor toxicity; and MVEC mitochondrial structure/function/genomics
1. ROS-induced Ca2+ influx: Using endothelial cells (ECs) isolated from humans, mice and rats, as well as animal models of ALI and PAH, we investigate the role of elevated reactive oxygen species (ROS) and intracellular calcium in regulating disease-specific abnormalities in EC function. In ALI, we study signaling pathways governing formation of paracellular gaps between endothelial cells, which clinically leads to alveolar flooding and hypoxemia. For PAH, we study the effect of ROS and calcium signaling on EC migration and proliferation as it relates to formation of vaso-occlusive lesions in the distal arterioles of the lung, a known contributor to elevations in pulmonary artery pressures in this disease.
2. Mechanisms of checkpoint inhibitor toxicity: In collaboration with Dr. Jarushka Naidoo (Oncology) and Dr. Franco D'Alessio (Pulm/CC), we study clinical characteristics and biologic mechanisms of lung injury in patients who develop pneumonitis after receiving immune checkpoint inhibitors (ICIs) - termed checkpoint inhibitor pneumonitis (CIP). We are specifically interested in mechanisms of endothelial leak and alveolar inflammatory cell efflux in CIP.
3. Mitochondrial structure/function/genomics in PAH: We are interested in the impact of abnormal mitochondrial structure (e.g. increased fragmentation), function (changes in respiration and metabolism) and genomics (induction of somatic mutations) on cytosolic Ca2+ levels and promotion of abnormal MVEC behavior (EndMT, migration, proliferation) in PAH.
Clinical Trial Keywords
ROS signaling, calcium signaling, microvascular endothelial cell physiology, mitochondrial structure/function, mechanisms of immunotherapy toxicity
Optimization of steroid-refractory immune checkpoint inhibitors; Therapeutic options for autoimmune-associated interstitial lung disease
Suresh K, Servinsky L, Jiang H, Bigham Z, Huetsch J, Kliment C, Damarla M, Shimoda LA "ROS-induced Ca2+ via TRPV4 and microvascular endothelial dysfunction in the SU5416/Hypoxia model of pulmonary arterial hypertension", Am J Physiol Lung Cell Mol Physiol. 314(5): L893-L907, 2018 (APSselect – April 2018)
Suresh K, Servinsky L, Jiang H, Bigham Z, Zaldumbide J, Huetsch J, Kliment C, Acoba M, Claypool S, Damarla M, Shimoda LA. "Mitochondrial ROS and Intracellular Ca2+ regulate mitochondrial morphology in microvascular endothelial cells isolated from the SU5416/Hypoxia rat model of pulmonary arterial hypertension" Am J Physiol Lung Cell Mol Physiol [Epub ahead of print] 2019
Suresh K, Zhong Q, Voong R, Ettinger D, Marrone K, Kelly R, Hahn C, Levy B, Feliciano J, Brahmer J, Forde P, Feller-Kopman D, Lerner A, Lee H, Yarmus L, D’Alessio F, Danoff S, Naidoo J. Clinical Features and Bronchoalveolar Lavage Pneumonitis in non–small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors, J. Thoracic Onc. 13: 1930-1939, 2018 (Editorial by Tay, et al: "Checkpoint Inhibitor Pneumonitis – Real World Incidence and Risk").
Suresh K, Psoter K, Shankar B, Voong R, Ettinger D, Marrone K, Kelly R, Hahn C, Levy B, Feliciano J, Brahmer J, Forde P, Feller-Kopman D, Lerner A, Lee H, Yarmus L, D’Alessio F, Danoff S, Naidoo J. Impact of checkpoint inhibitor pneumonitis on survival in non-small cell lung cancer patients receiving immune checkpoint immunotherapy, J. Thoracic Onc. 14: 494-502, 2019 (Editor’s Choice – JTO, March 2018; Editorial by Le et al: "Checkpoint inhibitor pneumonitis: Too clinically serious for benefit?")
Suresh K*, Naidoo J*, Zhong, Q, Xiong Y, Mammen J, Villegas de Flores M, Cappelli L, Balaji A, Palmer T, Anagnastou V, Ettinger D, Marrone K, Kelly R, Hahn C, Levy B, Feliciano J, Forde P, Feller-Kopman D, Lerner A, Lee H, Yarmus L, Shafiq M, Lipson E, Soloski M, Brahmer J, Danoff S, D’Alessio F. The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis, J. Clin. Investig. [Epub ahead of print] 2019. * contributed equally.