Exosomes as Potential Therapeutic Targets in Gulf War Illness
Abstract
Overarching Challenges: The multisymptom illness was more common among deployed Gulf War Veterans (GWV) than non-deployed Veterans. During their deployment, GWV were chronically exposed to a very harsh and specific environment. They developed Gulf War Illness (GWI), which is a collection of various symptoms including respiratory dysfunction caused by the inhalation of harmful chemicals and particles. GWI affects as many as 30% of the men and women who served during the Gulf War conflict. The diagnosis of this disease is often challenging. A recent study showed that over the course of the wars, the percentage of GWV who sought care for chronic respiratory conditions has increased over time. Decades of attempted therapies have been unsuccessful, suggesting that our understanding of this disease remains superficial. A better understanding of the disease mechanisms to develop novel effective therapies for GWI is urgently needed. Injured lung cells secrete exosomes, which are small membrane vesicles and contain inflammatory factors. Exosomes are circulating in the blood; therefore, they can spread damage to various neighboring cells. They can also deliver their harmful cargo to various organs leading to their failure. Moreover, exosomes can cross the blood-brain barrier and cause neuroinflammation. Objective and Rationale: We hypothesize that the environmental particles inhaled by GWV were deposited in the lungs and were not completely eliminated. The persistence of these particles induces the secretion of exosomes with the harmful content and leading to chronic lung diseases. Spreading of inflammation via exosomes circulating in the blood can explain the multiple symptoms in GWV and serve as key factors in GWI abnormalities. Our preliminary results indicate the presence of CD147 protein, which has an inflammatory function, in exosomes in plasma obtained from GWI patients. In the current project, we will use an antibody against CD147 to block harmful exosomes and inhibit spreading inflammation as a novel treatment. Antibodies have proven their effectiveness at fighting several diseases including pulmonary abnormalities and especially in cases where conventional therapy fails. Applicability: There is no commercial pharmaceutical drug to target harmful exosomes. There is an urgent need to develop novel treatments in GWI that interrupt this destructive cycle and restore the normal lung milieu to improve the outcomes and achieving the ultimate goal of curing patients with this illness. Our approach focused on targeting exosomes with a harmful function using an antibody against CD147 protein can inhibit their circulation and spreading inflammatory mediators to the lung and other organs. This strategy can lead to novel treatments to prevent or ameliorate at least some aspects of the GWI symptoms. We will also analyze the content of exosomes obtained from plasma of patients with GWI using various methods to identify other harmful factors that worsen GWI. Identified targets will be used to accurately diagnose GWI, monitor its progression, and develop novel therapeutic strategies to inhibit the spreading of exosomes with inflammatory loads and minimize this illness. Our study has clinical implications and can identify novel targets. Importantly, our obtained results can be relevant to other organ failures in GWI. Our short-term goal is to use antibodies against CD147 to inhibit the spreading of exosomes with harmful content to lung and other organs as a novel treatment. We will also identify other harmful factors in exosomes obtained from plasma of GWI patients to identify novel biomarkers of respiratory dysfunction and therapeutic targets. Our long-term goal is a clinical trial using antibodies to block the circulation of exosomes with harmful content in the blood. This approach can lead to lung regeneration. Obtained results and potential therapeutic approaches in the current project can be extended to al
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110400
Entities
People
- Karim Bahmed
Organizations
- Temple University
- United States Army