Louise Hecker
Associate Professor, BIO5 Institute
Associate Professor, Clinical Translational Sciences
Associate Professor, Medicine
Primary Department
Department Affiliations
(520) 626-2855
Work Summary
Louise Hecker’s research is focused on understanding why the process of regenerative biology and mechanisms of tissue injury-repair "goes awry" in aging. She is working to identifying novel pathways that can be targeted to reverse age-associated diseases, such as Idiopathic pulmonary fibrosis (IPF).
Research Interest
Dr. Hecker's research background and training are rooted in regenerative biology and investigating mechanisms of tissue injury-repair. Regenerative biology studies the molecular and cellular processes by which tissues and organs renew or repair themselves. However, the normal healing and repair process becomes less efficient as we age. Dr. Hecker’s research is focused on understanding why this process "goes awry" in aging and identifying novel pathways that can be targeted to reverse age-associated diseases, such as Idiopathic pulmonary fibrosis (IPF). Research by Dr. Hecker and her colleagues at UAB identified a novel role for NADPH oxidase-4, or Nox4, an oxidant-generating enzyme that plays a critical role in the formation of scar tissue (fibrosis) in the lung (results were published in Nature Medicine in 2009). Dr. Hecker’s ongoing research involves discovering new drug candidates to target Nox4 and preclinical testing of novel therapies aimed to treat IPF. She is founder and chief scientific officer of Regenerative Solutions, LLC, a contract research organization that provides highly specialized preclinical testing services for biotechnology and pharmaceutical companies with drug development platforms in pulmonary fibrosis. She is principal investigator on a study, “Aging, Fibroblast Senescence, and Apoptosis in Lung Fibrosis,” funded through June 2017 by a nearly $1 million grant from the Department of Veterans Affairs (1 IK2 BX001477-01A1).

Publications

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.
BIO5 Collaborators
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.

Hecker, L., Vittal, R., Jones, T., Jagirdar, R., Luckhardt, T. R., Horowitz, J. C., Pennathur, S., Martinez, F. J., & Thannickal, V. J. (2009). NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nature medicine, 15(9), 1077-81.

Members of the NADPH oxidase (NOX) family of enzymes, which catalyze the reduction of O(2) to reactive oxygen species, have increased in number during eukaryotic evolution. Seven isoforms of the NOX gene family have been identified in mammals; however, specific roles of NOX enzymes in mammalian physiology and pathophysiology have not been fully elucidated. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants. The prototypical member of this family, NOX-2 (gp91(phox)), is expressed in phagocytic cells and mediates microbicidal activities. Here we report a role for the NOX4 isoform in tissue repair functions of myofibroblasts and fibrogenesis. Transforming growth factor-beta1 (TGF-beta1) induces NOX-4 expression in lung mesenchymal cells via SMAD-3, a receptor-regulated protein that modulates gene transcription. NOX-4-dependent generation of hydrogen peroxide (H(2)O(2)) is required for TGF-beta1-induced myofibroblast differentiation, extracellular matrix (ECM) production and contractility. NOX-4 is upregulated in lungs of mice subjected to noninfectious injury and in cases of human idiopathic pulmonary fibrosis (IPF). Genetic or pharmacologic targeting of NOX-4 abrogates fibrogenesis in two murine models of lung injury. These studies support a function for NOX4 in tissue fibrogenesis and provide proof of concept for therapeutic targeting of NOX-4 in recalcitrant fibrotic disorders.

Hecker, L., Khait, L., Sessions, S. K., & Birla, R. K. (2008). Functional evaluation of isolated zebrafish hearts. Zebrafish, 5(4), 319-22.

Traditional working heart preparations, based on the original Langendorff setup, are widely used experimental models that have tremendously advanced the cardiovascular field. However, these systems can be deceivingly complex, requiring the maintenance of pH with CO(2), the delivery of oxygenated perfusate, and the need for extensive laboratory equipment. We have examined the feasibility of using isolated zebrafish (Danio rerio) hearts as an experimental model system, in which experimental procedures can be performed in the absence of the traditional requirements and sophisticated setup equipment. Isolated zebrafish hearts exhibited spontaneous contractile activity, could be electrically paced, and were responsive to pharmacologic stimulation with isoproterenol for 1.5 h after in vivo removal. Isolated zebrafish hearts offer a time- and cost-effective alternative to traditional Langendorff/working heart preparation models, and could be used to investigate cardiac function and repair.

Hecker, L., Cheng, J., & Thannickal, V. J. (2012). Targeting NOX enzymes in pulmonary fibrosis. Cellular and molecular life sciences : CMLS, 69(14), 2365-71.

Oxidative stress has been associated with a number of human fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Oxidative stress is most often defined as an imbalance between the generation of reactive oxygen species (ROS) in excess of the capacity of cells/tissues to detoxify or scavenge them. Additionally, the regulated production of ROS participates in cellular signaling. Therapeutic strategies to treat IPF have, thus far, focused on augmenting anti-oxidant capacity. Recent studies have demonstrated a critical role for ROS-generating enzymatic systems, specifically, NADPH oxidase (NOX) family oxidoreductases in fibrotic processes. In this review, we examine the evidence for NOX isoforms in the generation and perpetuation of fibrosis, and the potential to target this gene family for the treatment of IPF and related fibrotic disorders.

Bime, C., Zhou, T., Wang, T., Slepian, M. J., Garcia, J. G., & Hecker, L. (2016). Reactive oxygen species-associated molecular signature predicts survival in patients with sepsis. Pulmonary circulation, 6(2), 196-201.

Sepsis-related multiple organ dysfunction syndrome is a leading cause of death in intensive care units. There is overwhelming evidence that oxidative stress plays a significant role in the pathogenesis of sepsis-associated multiple organ failure; however, reactive oxygen species (ROS)-associated biomarkers and/or diagnostics that define mortality or predict survival in sepsis are lacking. Lung or peripheral blood gene expression analysis has gained increasing recognition as a potential prognostic and/or diagnostic tool. The objective of this study was to identify ROS-associated biomarkers predictive of survival in patients with sepsis. In-silico analyses of expression profiles allowed the identification of a 21-gene ROS-associated molecular signature that predicts survival in sepsis patients. Importantly, this signature performed well in a validation cohort consisting of sepsis patients aggregated from distinct patient populations recruited from different sites. Our signature outperforms randomly generated signatures of the same signature gene size. Our findings further validate the critical role of ROSs in the pathogenesis of sepsis and provide a novel gene signature that predicts survival in sepsis patients. These results also highlight the utility of peripheral blood molecular signatures as biomarkers for predicting mortality risk in patients with sepsis, which could facilitate the development of personalized therapies.