ACUTE INFLAMMATORY LUNG INJURY AND VENTILATOR-INDUCED LUNG INJURY
Acute lung injury (ALI) is a devastating inflammatory lung syndrome with unabated lung inflammation resulting in profound leakiness of lung blood vessels and flooding of the lung with fluids from the blood, a process known as increased vascular permeability. Lung inflammation develops in response to a variety of local and systemic insults such as sepsis, trauma, pneumonia and aspiration and with its most severe form, acute respiratory distress syndrome (ARDS), afflicts approximately 250,000 patients per year in United States and carries a mortality rate of 30-40%. Virtually all ARDS patients receive mechanical ventilation (MV), a life-saving breathing device routinely used in hospitals for both simple and highly complex surgeries and in support of the majority of patients in Intensive Care Units (ICUs) with respiratory failure (unable to maintain adequate breathing). Although a necessary form of life support, over the past 2 decades, there is now unequivocal evidence that exposure to MV directly causes and/or worsens lung inflammation and injury contributing to the staggering high mortality rates in critically ill ICU patients. The ventilator produces high levels of mechanical stress which is a potent stimulus for the development of significant lung inflammation, increased vascular permeability and worsening respiratory failure, a process known as ventilator-induced lung injury. resulting in a vicious cycle often ending in death. MV contributes to extended ICU days and extraordinary healthcare costs. Currently, there are no FDA-approved drugs to reduce lung inflammation in ICU patients on MV or to limit or prevent VILI.
IDIOPATHIC PULMONARY FIBROSIS
Idiopathic pulmonary fibrosis (IPF) is a rapidly progressing and deadly lung disease characterized by excessive scar tissue formation and aberrant lung repair/remodeling that often results in fatal respiratory failure. Approximately 100,000 people are affected in the United States, and 30,000 to 40,000 new cases are diagnosed each year. Fifty percent of IPF patients die within 2 to 3 years after diagnosis. Current drugs only moderately slow the progression of the disease and no drug reverses fibrosis development. Lung transplantation is the only treatment of proven benefit but carries associated risks and is not a first-line option. Approximately 1,000 lung transplantations are performed annually in the U.S. to treat IPF, but many IPF patients are not eligible for this therapy or expire prior to receiving it. Survival after lung transplantation is only ~65% at 2 years and 39% at 5 years (7). As a result, IPF patients are burdened with high end-of-life medical costs due to healthcare resource utilization, including ICU stays. Thus, IPF remains an incurable disease with a dismal prognosis. There remains a desperate need to identify novel IPF therapies.
Pulmonary arterial hypertension (PAH) is a progressive disease) is often a fatal disease, due to the lack of effective curative therapies, caused by functional and structural changes in the lung’s blood vessels known as the pulmonary vasculature. These changes place undue strain on the heart and eventually can cause failure and death. Recent advances have solidified the role for lung inflammation in the pulmonary vascular remodeling that is essential to the development of PAH contributing directly to PAH’s unacceptably high mortality (three year survival rates of 40-60%). The mechanistic basis for severe PAH vascular remodeling and associated inflammation is poorly understood. There remains a need for improved understanding of PAH pathophysiology and a need for improved therapeutic options for these patients, as current therapies are severely limited.