Asthma and Lung Inflammation

Asthma is a common disease that affects 300 million people worldwide. The pathogenesis of asthma involves airway inflammation, as well as airway remodeling and hyperreactivity, which leads to difficulty in breathing which can be deadly if not properly controlled. Steroid medications can successfully treat asthma in most cases. However, the side-effects of long-term steroid administration can be profound, and in the approximately 5% of patients with severe refractory asthma, these medications fail to adequately control the disease. Dr. Levine is focused on developing new treatment approaches for patients with severe asthma.

In a mouse model of experimental asthma, Dr. Levine's laboratory exposed mice to house dust mites (HDM). Using a genome-wide analysis of the lung transcriptome, Dr. Levine and colleagues have identified genes that are upregulated as a result of the disease and whose activity is not modulated by the administration of corticosteroids. Of the 68 steroid-unresponsive genes discovered through this approach, the Levine laboratory initially focused on one that had not been previously implicated in the pathogenesis of asthma, apolipoprotein E (ApoE).

Dr. Levine’s group has shown that ApoE, which is made by macrophages in the lung, binds to low density lipoprotein receptors (LDLR) that are expressed by ciliated airway epithelial cells. In doing so, ApoE attenuates airway remodeling (mucous cell metaplasia) and airway hyperreactivity. Moreover, he has demonstrated that the administration of a small ApoE mimetic peptide to HDM-challenged mice markedly attenuates the three key pathogenic features of asthma: airway inflammation, airway remodeling, and airway hyperreactivity.

In related studies, Dr. Levine is working with colleagues at the NHLBI to study the role of peptide mimetics of apolipoprotein A-I (apoA-I) in their murine model of asthma, as well as the role of apoA-I pathways in asthma pathogenesis. Dr. Levine’s group has extended these findings to asthmatics, where they have shown that increased serum levels of high-density lipoproteins and apoA-I are associated with less severe airflow obstruction. While furthering his research into the mechanisms that modulate disease severity in asthma, Dr. Levine is completing the next phase of preclinical work necessary to move the concept of an inhaled apoA-I mimetic peptide for the treatment of asthma from mouse models into the first human clinical trials.

A clinician-scientist, Dr. Levine supervises a clinical program to study severe asthma and advance promising experimental therapeutics toward patient use. He and his colleagues have an ongoing longitudinal study to better understand the progression of severe refractory asthma and its response to treatment. They also have a bronchoscopy study that allows them to collect fluid and cells from the lungs of asthmatics so that they can define the role of apolipoprotein pathways in the respiratory system. These studies will not only have direct clinical implications, but will also advance the basic side of Dr. Levine’s research program, leading to even further clinical progress and, eventually, the possibility of ensuring that everyone with asthma can manage it simply and effectively.