Research Interests: Bronchial hyperreactivity in asthma. Effects of viral infection on airway function. Regulation of airway mucous secretion and vascular permeability.

Research Summary:
My research interests have long focused on the responses of the lungs and airways to inhaled materials. I first studied neural mechanisms of response in laboratory animals as a research fellow, but soon moved on to study responses in healthy adults and in patients with asthma, allergic rhinitis, cystic fibrosis, COPD, or other forms of lung disease. Finding that brief exposure to ozone causes both bronchial hyperreactivity and bronchial inflammation in healthy people led me to study the role of bronchial inflammation in asthma, and this in turn led to a lifetime interest in the causes, pathophysiology, and treatment of asthma. Drs. Fahy and I together demonstrated the validity of sputum induction as a non-invasive method for assessing airway mucosal inflammation and applied this and other methods to study new and existing therapies for asthma (egs., monoclonal anti-IgE antibody, inhaled corticosteroids, long-acting beta-agonists, and antagonists of leukotrienes, neuropeptides, and selectins). My interest in bronchial inflammation also led me to study the mechanisms by which viral respiratory infections, especially by human rhinoviruses (HRV) – the most common cause of the common cold - cause exacerbations of asthma, CF, and COPD. Our findings suggested that the severity of lower respiratory responses to HRV infection is a function of the state of differentiation of the bronchial epithelium (in turn a function of bronchial mucosal injury and repair) and of properties intrinsic to the infecting HRV strain. An outgrowth of this work was collaboration with Drs Derisi and Ganem in their development of a microarray-based approach to detecting viruses, and then, with the addition of a postdoctoral fellow, Amy Kistler, in expanding the array to include sequences for all known serotypes of rhinovirus. Applying this method to samples from asthmatic patients with upper respiratory infections, we showed a high diversity of RV serotypes circulating concurrently, higher than expected rates of infection with “rare” coronaviruses (HongKong University and NL063 ), and the existence a previously unknown phylogenetic branch of HRV’s, of which no member has so far been cultured. As a co-investigator with Dr. Fahy, I am also participating in a study of structural differences in the oligosaccharides in airway secretions as determinants of susceptibility to RV infection. As a co-investigator with Dr. Cabana, I am studying the effects of feeding lactobacillus to infants of allergic families in altering gut flora, in shifting CD4 cell responses to a Th1 pattern, in reducing the severity of responses to viral respiratory infection in the first year of life, and in preventing the development of allergic disease, especially of asthma. Finally, my interest in applying new methods for microbial detection has led me to collaborate with Drs. Kronish and Lynch at UCSF in applying a 16S-based “PhyloChip” method developed at Lawrence Berkeley National Labs, to determine whether distinct bacterial communities are present in the bronchi of people with asthma, and in environmental samples (house dust) from inner city, suburban, and rural homes.

If funded, research applications recently submitted will allow continuation of this work. I have applied to continue UCSF’s participation in the NHLBI’s clinical research network charged with conducting trials of asthma therapies (I have so far served as P.I. for the UCSF site for 15 years). Susan Lynch and I have also applied as co-PI’s to lead a “Basic Science Site for the NIAID’s “Inner City Asthma Consortium.” The theme of these proposed projects is investigation of relationships among the microbial environment, gastrointestinal and bronchial microbiota, immune function, viral respiratory infection, and the development of asthma.