A Novel Pleiotropic Anti-Inflammatory Drug to Reduce ARDS Incidence
Abstract
Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area: Acute Lung Injury - Preventive techniques and therapeutics to reduce the incidence of acute respiratory distress syndrome (ARDS) after acute lung injury in trauma patients. Following severe trauma that often occurs on the battlefield, patients can develop excessive systemic inflammation that over-stimulates the body s immune system. Activation of white blood cells by the immune system causes the release of toxic molecules, which are designed to kill bacteria but in excess can lead to damage of all organ systems. If unchecked, this systemic inflammatory response syndrome (SIRS) can cause ARDS. This severe form of lung injury causes the lung to collapse and flood with edema fluid, making it impossible to oxygenate the blood without the assistance of mechanical ventilation. There are over 190,000 cases of ARDS that lead to 74,000 deaths per year in the United States alone, and the mortality is still unacceptably high at greater than 40%. Indeed, more people die each year from ARDS than do from breast cancer. Recent evidence suggests that ARDS is a progressive disease, similar to cancer; however, few attempts have been made to block the disease progression early in an attempt to reduce ARDS incidence. The current standard of care is to wait until the patient s lung disease progresses into established ARDS and then simply support the patient with mechanical ventilation. There are two problems with this strategy: (1) it has been shown that once established, ARDS is refractory to almost all treatments, and (2) similar to late-stage cancer treatment, application of protective ventilation in late-stage ARDS will result in very poor outcomes. Our novel concept is to use a novel inhibitor of multiple inflammatory mediators that are responsible for driving the progression from trauma to ARDS. Following severe trauma, inflammatory cells release excessive-levels of molecules termed matrix metalloproteinases (MMPs) that damage connective tissue in the lung causing the lung to flood with edema fluid. MMPs come in two categories, those that are constitutive (cMMP) and perform a continuing physiologic function and those that are inducible (iMMP), being released in response to trauma. However the inducible form can be released in excess causing serious lung damage and is a key mechanism causing ARDS. However, it has been shown that inhibiting all MMPs is actually detrimental. Thus, there is a critical need to develop new non-toxic selective inhibitors of iMMP that can be given to all trauma patients at high risk of developing ARDS. To this end, our group has developed a non-toxic inhibitor of multiple inflammatory mediators including a selective inhibition of iMMPs. We postulate that blocking excessive levels of iMMP, while maintaining the beneficial effects of cMMP, will reduce the incidence, morbidity, and mortality associated with ARDS. Our central hypothesis is that TRB-N0224, a non-toxic pleiotropic inhibitor of inflammatory mediators including a selective inhibition of iMMPs, can be delivered prophylactically and will significantly reduce lung pathology and incidence of ARDS. The rationale is that the combined anti-inflammatory properties of TRBN0024 will make it an effective drug for reducing ARDS incidence following trauma. Proving this concept is significant because it will change our current clinical practice paradigm from treating ARDS after it manifests to preventing it from ever developing.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610288
Entities
People
- Gary F Nieman
Organizations
- State University of New York Upstate Medical University
- United States Army