Manish Mittal

Acute lung injury (ALI), a significant cause of morbidity and mortality in the critically ill patient population, affecting 200,000 patients per year in the US and poses a mortality risk of 29–42%. ALI is an acute inflammatory disorder that compromises the integrity of the vascular barrier and disturbs tissue fluid homeostasis. Cellular characteristics of ALI include loss of alveolar–capillary membrane integrity, excessive transendothelial neutrophil migration, and massive release of pro-inflammatory cytotoxic mediators from activated neutrophils and macrophages. I am currently investigating the role of macrophage plasticity in modulating acute lung injury response and signaling mechanism of PMN transmigration across vascular barrier in septic conditions in two different projects as described below:

1. We recently identified an important role of TNF-alpha stimulated-gene-6 (TSG6) in suppression of endotoxin induced lung vascular injury in switching a phenotypic shift in macrophages from pro-inflammatory to anti-inflammatory phenotype (PNAS, 2016). We are currently investigating if the TSG6 treated polarized macrophages with M2 phenotype could be used as a cell based therapy to treat endotoxin induced acute lung injury in mouse model.

2. The role of Calcium and ROS signaling in PMN transmigration in inflammatory conditions has been reported in a number of studies. However, the identity of the calcium channel in endothelial cells that mediate PMN transmigration remains elusive. By genetic approach, we have created an inducible endothelial cell specific knockout mouse model, where a ROS activated Trp melastatin channel-2 (Trpm2) could be deleted in the vascular beds by tamoxifen injection. These mice when subjected to endotoxin challenge exhibit impaired PMN transmigration and shows a significant survival advantage compared to the WT mice. By understanding the pathophysiology of TRPM2 channel in inflammatory disease conditions, we will be able to design novel inhibitors in future to combat PMN transmigration and reduce mortality occurring from sepsis.

1. Soni D, Wang DM, Regmi SC, Mittal M, Vogel SM, Schlüter D, Tiruppathi C.Deubiquitinase function of A20 maintains and repairs endothelial barrier after lung vascular injury. Cell Death Discov. 2018 May 16;4:60.

2. Mittal M, Nepal S, Tsukasaki Y, Hecquet CM, Soni D, Rehman J, Tiruppathi C, Malik AB. Neutrophil Activation of Endothelial Cell-Expressed TRPM2 Mediates Transendothelial Neutrophil Migration and Vascular Injury. Circ Res. 2017 Oct 13;121(9):1081-1091.

3. Mittal M, Nepal S, Grzych D, Toya S, Gantner B, Tiruppathi C, Malik AB. TNF-α stimulated gene-6 (TSG6) protects mice against endotoxin induced acute lung injury by inducing macrophage transition from pro- to anti-inflammatory phenotype. Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):E8151-E8158.

4. Gong H, Shejuan A, Sassmann A, Liu M, Mittal M, Mastej V, Zhang W, Hong Z, Offermanns S, Rehman J, Malik AB. PAR1 Scaffolds TGFβRII to Downregulate TGF-β Signaling and Activate ESC Differentiation to Endothelial Cells. Stem Cell Reports. Nov 2016 (In Press).

5. Mittal M, Urao N, Hecquet CM, Zhang M, Sudhahar V, Gao XP, Komarova Y, Ushio-Fukai M, Malik AB. Novel Role of ROS-Activated trp Melastatin Channel-2 (TRPM2) in Mediating Angiogenesis and PostIschemic Neovascularisation. Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):877-87.

6. Toya SP, Wary KK, Mittal M, Li F, Toth PT, Park C, Rehman J, Malik AB. Interaction of ESC-Expressed Integrin α6β1 with Laminin Instructs Differentiation to Endothelial Cells. Stem Cells. 2015 Jun;33(6):1719-29. doi: 10.1002/stem.1974.

7. Gong H, Rehman J, Tang H, Wary K, Mittal M, Chaturvedi P, Zhao YY, Komarova YA, Vogel SM, Malik AB.HIF2α-Signaling Inhibits Adherens Junctional Disruption in Acute Lung Injury. The Journal of Clinical Investigation. 2015 Feb;125(2):652-64.

8. Hecquet CM, Zhang M, Mittal M, Vogel SM, Di A, Gao X, Bonini MG, Malik AB. Cooperative Interaction of trp Melastatin Channel TRPM2 with its Splice Variant TRPM2-S is Essential for Endothelial Cell Apoptosis. Circulation Research. 2014;114(3):469-79.

9. Mittal M, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Comprehensive Invited Review. Antioxidant Redox Signaling. 2014;20(7):1126-67.

10. Mittal M, Gu XQ, Pak O, Pamenter ME, Haag D, Fuchs DB, Schermuly RT, Ghofrani HA, Brandes RP, Seeger W, Grimminger F, Haddad GG, Weissmann N. Hypoxia induces Kv channel current inhibition by increased NADPH oxidase derived reactive oxygen species. Free Radical Biology and Medicine. 2012;52(6):1033-42.

11. Kleinschnitz C, Grund H, Wingler K, Armitage ME, Jones E, Mittal M, Barit D, Schwarz T, Geis C, Gailus-Durner V, Fuchs H, Klopstock T, de Angelis MH, Jandeleit-Dahm K, Shah AM, Weissmann N, Schmidt HH. Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLOS Biology. 2010;8(9). pii: e1000479.

12. Roth M, Rupp M, Hofmann S, Mittal M, Fuchs B, Sommer N, Parajuli N, Dony E, Schermuly RT, Ghofrani HA, Sausbier U, Rutschmann K, Wilhelm S, Seeger W, Ruth P, Grimminger F, Weissmann N. Vascular effects of heme oxygenase-2 and the BK-channel in acute, sustained, and chronic alveolar hypoxia. American Journal of Respiratory and Critical Care Medicine. 2009;180(4):353-64.

13. Weissmann N, Hackemack S, Dahal BK, Pullamsetti SS, Savai R, Mittal M, Fuchs B, Medebach T, Dumitrascu R, Eickels Mv, Ghofrani HA, Seeger W, Grimminger F, Schermuly RT. The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice. American Journal of Physiology Lung Cell Molecular Physiology. 2009;297(4):L658-65.