The applicant seeks a research and training opportunity to successfully engage in understanding the role of a first of its kind novel therapeutic agent, Heat Shock Protein 70, in decreasing lung injury, decreasing mortality and increasing locomotor activity in a cecal ligation and double puncture (2CLP) rodent model of sepsis induced Acute Respiratory Distress Syndrome (ARDS). Sepsis, the leading cause of death in critically ill patients, is a syndrome of disordered inflammation with limited treatment options causing dysfunction in all organ systems. In survivors, recovery to resume activities of daily living is prolonged, profound and costly. Novel interventions that can eliminate the severity of organ dysfunction would be of immense value. The lung is the organ most affected by sepsis, with abnormalities taking the more severe form of ARDS. This is best treated with mechanical ventilation. However, use of exogenous respiratory support compounds immobility, muscular deconditioning, and critical illness polyneuropathy (CIP) that almost universally develop in patients with sepsis. Indeed, recent studies have shown that early mobilization of ARDS patients decreases intensive care unit and hospital length of stay. Thus, interventions that limit the extent of lung injury would provide both direct and indirect benefit. The commonly- used rodent model of sepsis 2CLP closely mimics many of the features of the human syndrome including sepsis, ARDS, sickness behavior, CIP, decreased locomotor activity, and difficulty in ventilator weaning. Sepsis causes dysfunction in a number of different types of cells, including pulmonary epithelial cells. One highly conserved endogenous mechanism that protects cells from injury is the Heat Shock Response (HSR) expressing HSPs. Our research focuses on the benefits of one specific family of HSPs, HSP70. 2CLP diminishes the expression of HSP70 in the lungs. This contributed significantly to increased lung injury consistent with ARDS and subsequently increased mortality. Augmentation of HSP70 expression using an adenovirus vector (AdHSP70) introduced into the lungs via tracheal injection significantly decreased lung injury and decreased mortality by 31%. Adenovirus therapy in humans may be problematic. Thus, strategies that enhance HSP70 abundance in pulmonary epithelial cells represent an under-explored therapeutic avenue. The applicant proposes an alternative delivery system, the use of a fusion protein (TAT-HSP70) that combines HSP70 with the HIV 1-TAT protein. We hypothesize three aims, that TAT-HSP70 will significantly attenuate lung injury and decrease mortality and further successful treatment with TAT-HSP70 will increase locomotor activity.
These aims are consistent with NINR's mission statement of creating nurse scientists dedicated to conducting rigorous research generating new developments to improve outcomes of serious illness.
This proposal is a first of its kind, novel study of the role of HSP70 in decreasing lung injury, mortality and increasing locomotor activity in a sepsis induced Acute Respiratory Distress Syndrome rodent model. It evaluates a novel therapeutic agent for disease prevention, treatment, and improving patient quality of life.
|Mondrinos, Mark J; Kennedy, Paul A; Lyons, Melanie et al. (2013) Protein kinase C and acute respiratory distress syndrome. Shock 39:467-79|