Evaluation of NADPH Oxidase 1/4 Inhibition as a Novel Therapeutic Strategy Against Chronic Pancreatitis
Abstract
Pancreatitis is an inflammatory disease of the pancreas that results in significant morbidity, mortality, and hospitalizations. A single bout of pancreatic injury causes what is known as “acute pancreatitis.” Fortunately, pancreas has an inherent potential to recover from this injury and regain its normal form and function. However, if the injury to the pancreas persists, e.g., ongoing alcohol abuse or smoking, it results in continued inflammation of the pancreas and damage to the pancreatic tissue. This sets in a healing response from the body and results in excessive fibrosis similar to that of a chronic wound. This entity from which pancreas is not able to recover and get back to its normal form and function is called “chronic pancreatitis” (CP). CP leads to deficient pancreatic function, i.e., insufficient digestive enzymes, poor insulin production leading to diabetes, etc. Patients with CP also have unbearable pain, which can lead to a spiral of drug abuse and alcoholism with the accompanying social and economic consequences. Unfortunately, due to the high prevalence of the etiological factors including alcoholism, smoking, and drug abuse, our military personnel and veterans bear a significant brunt of this disease. Despite the evident need, to date there is no specific therapy for CP, owing to our incomplete understanding of the pathophysiology of this disease. While oxidant stress has been hypothesized to play a major role in development of CP, systematic studies evaluating relieving oxidant stress as a therapeutic strategy for CP are lacking. Oxidant stress is a result of imbalance between production of reactive oxygen species (ROS) and their clearance. NADPH oxidase (NOX) is an enzyme involved in the production of ROS. While there are many subtypes of NOX, NOX-1 and -4 have been shown to be critical in the development of various diseases including liver fibrosis. In fact, one pharmacological inhibitor of NOX-1 and -4 (Setanaxib or GKT137831) has been shown to be safe and effective in humans against liver fibrosis. Excitingly, in our preliminary studies, we have observed that this NOX-1 and -4 inhibitor is effective against CP in an animal model. Therefore, in our current grant proposal, using well-described and established models of CP, we will study the role of NOX-1 and -4 in CP. Briefly, we will assess if drugs that can block NOX-1 and -4 function can decrease severity of CP. Since the NOX-1 and -4 inhibitor (Setanaxib or GKT137831) we are using in our animal studies is already known to be safe for use in humans, based on the results of these proposed studies, a clinical trial evaluating the NOX-1 and -4 inhibition for the treatment of CP can be expeditiously started. In the proposed studies, we will also study the mechanism by which NOX-1 and -4 inhibition reduces the severity of CP. These studies will lead to discovery of other novel targets, which can be addressed to develop novel and effective therapies against this formidable disease. Thus, the proposed studies are very translational and have the potential to revolutionize the treatment of CP. Development of novel and effective treatments for CP will greatly improve the outcome of a large US patient population, including our veterans and military personnel, suffering from this formidable disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110516
Entities
People
- Vikas Dudeja
Organizations
- United States Army
- University of Alabama at Birmingham