Pulmonary Fibrosis is a metabolic disorder of the lung
Treatment of mice with LXR agonist to enhance lipid synthesis, decreases ER stress and attenuates lung fibrosis in response to silica.
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that causes progressive scarring of the lung and usually leads to death within a few years of diagnosis. One major risk factor for the development of IPF is advanced age and this believed to contribute to disease by comprising the ability of lung epithelial cells to regenerate after injury. In my lab, we study how aging affects the ability of the lung epithelium to metabolically adapt to pulmonary insults. We and others have shown that the aging epithelium does not properly divert nutrients/energy to areas of the cell in greatest need after injury, leading to persistent cellular damage that ultimately drives cells toward either an apoptotic or cellular senescence phenotype. Studies in my lab aim to understand how young cells metabolically adapt to injury so as to better understand how aging compromises these responses. Our hope is that by better understanding responses in young cells we can develop novel treatment approaches for age-related diseases like IPF.
Antifibrotic therapies for the treatment of pulmonary fibrosis
Pulmonary fibrosis is not a single disease but rather a group of conditions that cause scarring of the lung. Because collagen I-rich fibrils comprise the majority of all pulmonary scars, we are testing whether blocking a key step in type collagen I production is effective in limiting the progression of scar tissue in pulmonary fibrosis. The novel biological that is being tested was developed by Dr. Fertala at Thomas Jefferson University and works by blocking one of the earliest steps in the formation of collagen fibrils. Our pilot and published data indicate that this antibody not only binds to its intended target in the lung but also exhibits limited side effects. In ongoing studies, we are applying this antibody to the treatment pulmonary fibrosis using several animal models of disease and we are testing whether this therapy works synergistically with other clinically-relevant benchmark drugs. Because the target we have identified is identical in mice and humans, this therapy has real potential to help patients.
Obesity primes the lung for injury
Acute respiratory distress syndrome (ARDS) is a severe form of respiratory failure that develops abruptly in patients hospitalized with other serious conditions like pneumonia, sepsis, pancreatitis or major trauma. Currently, there are no FDA-approved drugs for ARDS and approximately 1/3 of all patients will die even after receiving the most advanced ICU care. It is now appreciated that a major risk factor for ARDS is obesity, but the underlying mechanisms linking these conditions are unknown. In my laboratory, we are studying how obesity alters lung health in the hopes of understanding how it might predispose to the development of ARDS. To this end, my laboratory employs a variety of genetic and diet-induced obesity models to study the effects of obesity on lung health and in particular on the lung endothelium. Our primary objective is to identify unique biological pathways that can be exploited for developing novel treatments to prevent and/or limit the severity of this deadly condition.
The "Alcoholic fatty lung"
Alcohol-induced “fatty lung”. Oil Red O staining of the lung demonstrates massive neutral accumulation in alveolar macrophages from EtOH fed rats and a more modest accumulation of lipid droplets was also observed in AEII cells.
Chronic alcohol abuse is a major public health problem and predisposes to a wide range of diseases including those that affect the lung like bacterial pneumonia, tuberculosis and the Acute Respiratory Distress Syndrome (ARDS). In my laboratory, we found that chronic alcohol ingestion alters metabolic responses in type II pneumocytes in ways similar to its effects in the liver. We have shown that in response to alcohol exposure type II pneumocytes increase their production of triglycerides by over 100 percent and free fatty acids by nearly 300 percent, compared to animals fed a control diet. Furthermore, we have found that many of these lipids spill into the distal alveolar spaces of the lung leading to macrophage foam cell formation and the development of immunological impairments. Based on these findings we coined the phrase “the alcoholic fatty lung” to describe this unique pathological phenotype. In ongoing investigations, we examining whether pharmacological or genetic approaches to inhibiting lipid accumulation (targeting production or clearance) in the lung are effective in reducing susceptibility of the alcoholic lung to pneumonia/ARDS.