ranadajaniaeshan@yahoo.com
Mentor: John Engelhardt, Ph.D.
Lab Phone: 335-9613

The role of submucosal glands in innate airway immunity

Cystic Fibrosis (CF) is the most common inherited lethal disease in Caucasians. Chronic lung infection and deterioration of lung function are the major causes of morbidity and death in CF. The genetic defect in CF is in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The function of CFTR is the regulation of chloride transport across the cell membrane. The mechanism by which CFTR mutations cause lung disease is unknown. A number of mechanisms have been proposed to explain lung disease in CF that focus on the properties of the airway surface liquid (ASL). It has been suggested that abnormalities in the ASL promote chronic bacterial colonization of the airways and provide an environment conducive to bacterial growth and P. biofilm formation. The composition, volume and physical properties of the ASL depend on secretions from airway submucosal glands (SMGs), the transporting properties of the surface epithelial cells, and convective movement of fluid up the airways.

We hypothesize that abnormal CFTR chloride transport in SMGs could impair antimicrobial secretion by serous cells, facilitating bacterial colonization and ultimately resulting in airway disease. However, appropriate animal models are required to conclusively determine whether SMGs are in fact involved in the CF disease process. Unlike mice, which do not possess SMGs distal to the trachea, the ferret lung is very similar to that of humans with respect to airway cell biology and the abundance of SMGs throughout the cartilaginous airways. It is therefore an ideal animal model for studying the CF disease process and the function of SMGs.

Using ferret tracheal xenograft models of airways with and without SMGs, we are investigating the following hypotheses:

1) Secretions from glandular airways have higher antibacterial activity than airways lacking submucosal glands.

2) Submucosal glands increase the ability of airway secretions to inhibit growth of P. aeruginosa .

3) Lysozyme contributes to SMGs’ fluid antibacterial/antibiofilm activity.



Abstracts:

Dajani R, Zhang Y, Taft P, Travis S, Welsh MJ, and Engelhardt JF. Direct Evidence for Antibacterial Function of Submucosal Gland-derived Lysozyme in Proximal Airways. 17th Annual North American Cystic Fibrosis Conference. Abstract #253 and oral presentation session W15 Innate Immunity, October, 2003.

Dajani R, Zhang Y, Taft P, Travis S, Welsh MJ, and Engelhardt JF. Direct Evidence for Antibacterial Function of Submucosal Gland-derived Lysozyme in Proximal Airways. College of Medicine/College of Public Health/VA Medical Center Research Week. Abstract #63, March 30, 2004.

Dajani R, Zhang Y, Taft P, Travis S, Welsh MJ, and Engelhardt JF. Direct Evidence for Antibacterial Function of Submucosal Gland-derived Lysozyme in Proximal Airways. 6th Annual Student Health Interdisciplinary Poster Session. Abstract #35, April 15, 2004.

Publications:

Dajani R, Sanlioglu S, Zhang Y, Li Q, Monick MM, Lazartigues E, Eggleston T, Davisson RL, Hunninghake GW, Engelhardt JF. Pleiotropic functions of TNF-alpha determine distinct IKKbeta-dependent hepatocellular fates in response to LPS. Am J Physiol Gastrointest Liver Physiol. 2007 Jan;292(1):G242-52. Epub 2006 Aug 24. PubMed PMID: 16935850.

Dajani R, Zhang Y, Taft PJ, Travis SM, Starner TD, Olsen A, Zabner J, Welsh MJ, Engelhardt JF. Lysozyme secretion by submucosal glands protects the airway from bacterial infection. Am J Respir Cell Mol Biol. 2005 Jun;32(6):548-52. Epub 2005 Mar 3. PubMed PMID: 15746432.