Desai, A., Choi, B., Dudley, S. C., Kittles, R., Machado, R. F., Garcia, J. G., Hillery, C., Indik, J. H., Goldman, S., Juneman, E. B., Groth, J., Nair, N., Rutledge, C., Kanady, J., Fleming, I., Batai, K., Weigand, K., Shi, G., Kim, T. Y., , Gupta, G., et al. (2018). IL-18 is a novel mediator of prolonged QTc and ventricular arrhythmias associated with Sickle Cell Disease. Proceedings of the National Academy of Sciences.
Joe GN Garcia, Steven Goldman
Desai, A., Choi, B., Dudley, S. C., Garcia, J. G., Kittles, R. A., Lussier, Y. A., Machado, R. F., Patel, A. R., Lang, R. M., Goonewardena, S., Zhou, T., Parikh, D. S., Kansal, M., Hilery, C., Christensen, J., Shi, G., Indik, J. H., Strom, J., Juneman, E., , Groth, J., et al. (2017). IL-18 mediates sickle cell cardiomyopathy and inducible ventricular arrhythmias. PNAS.
Joe GN Garcia, Yves A Lussier
Hecker, L., Garcia, J. G., Wang, T., Colson, B., Knox, A., Mohamed, M., Quijada, H., Desai, A., Ahmad, K., Shin, Y. J., & Palumbo, S. (2017). Dysregulated Nox4 ubiquitination contributes to redox imbalance and age-related severity of acute lung injury. American journal of physiology. Lung cellular and molecular physiology, 312(3), L297-L308.
Joe GN Garcia, Louise Hecker
Acute respiratory distress syndrome (ARDS) is a devastating critical illness disproportionately affecting the elderly population, with both higher incidence and mortality. The integrity of the lung endothelial cell (EC) monolayer is critical for preservation of lung function. However, mechanisms mediating EC barrier regulation in the context of aging remain unclear. We assessed the severity of acute lung injury (ALI) in young (2 mo) and aged (18 mo) mice using a two-hit preclinical model. Compared with young cohorts, aged mice exhibited increased ALI severity, with greater vascular permeability characterized by elevated albumin influx and levels of bronchoalveolar lavage (BAL) cells (neutrophils) and protein. Aged/injured mice also demonstrated elevated levels of reactive oxygen species (ROS) in the BAL, which was associated with upregulation of the ROS-generating enzyme, Nox4. We evaluated the role of aging in human lung EC barrier regulation utilizing a cellular model of replicative senescence. Senescent EC populations were defined by increases in β-galactosidase activity and p16 levels. In response to lipopolysaccharide (LPS) challenge, senescent ECs demonstrate exacerbated permeability responses compared with control "young" ECs. LPS challenge led to a rapid induction of Nox4 expression in both control and senescent ECs, which was posttranslationally mediated via the proteasome/ubiquitin system. However, senescent ECs demonstrated deficient Nox4 ubiquitination, resulting in sustained expression of Nox4 and alterations in cellular redox homeostasis. Pharmacological inhibition of Nox4 in senescent ECs reduced LPS-induced alterations in permeability. These studies provide insight into the roles of Nox4/senescence in EC barrier responses and offer a mechanistic link to the increased incidence and mortality of ARDS associated with aging.
Garcia, J. G., Garcia, J. G., Garcia, J. G., Garcia, J. G., Gonzalez-Garay, M. L., Gonzalez-Garay, M. L., Gonzalez-Garay, M. L., Gonzalez-Garay, M. L., Knox, K. S., Knox, K. S., Knox, K. S., Knox, K. S., Wang, T., Wang, T., Wang, T., Wang, T., Lussier, Y. A., Lussier, Y. A., Lussier, Y. A., , Lussier, Y. A., et al. (2018). MicroRNA and Protein-Coding Gene Expression Analysis in Idiopathic Pulmonary Fibrosis Yields Novel Biomarker Signatures Predicting Survival. American Journal of Respiratory Cell and Molecular Biology.
Rizzo, A. N., Sun, X., Letsiou, E., Garcia, J. G., & Dudek, S. M. (2016). Abl Family Kinases Mediate LPS-Induced Lung Vascular Permeability And Inflammation. Am J Respir Crit Care Med. doi:193: A5675