Grants Awarded

Cigarette Smoking and TSLP in the Pathogenesis of Pulmonary LCH

Principal Investigator      
Robert Vassallo MD
Pulmonary and Critical Care Medicine, Mayo Clinic – Rochester, Minnesota USA

Date of Award
December 2005

Amount of Award

Layperson Summary
Although numerous studies suggest that tobacco smoke causes, or induces pulmonary LCH, the mechanisms by which this happens are not known. Through this application, we will investigate a number of mechanisms by which smoking, together with a new factor called thymic stromal lymphopoietin (TSLP), lead to the formation of pulmonary LCH. The reason we have chosen to look at the role of TSLP in LCH is because of recent studies in patients with allergic dermatitis – an allergic inflammatory condition of the skin which is associated with many Langerhans cells infiltrating the skin – produces human TSLP. In these patients, biopsy of skin shows many Langerhans cells infiltrating at the site of production of TSLP protein. This was an important observation because TSLP is a very potent stimulant and regulator of Langerhans cell function.

Since the airways of the lung (air-conducting passages), are lined by cells similar to those found in the skin (airway epithelial cells), and because of the fact that normal Langerhans cells in the lung are located just beneath this layer of epithelial cells, we formulated the hypothesis that smoking induces airway epithelial cells to produce TSLP. This TSLP protein causes Langerhans cells in the vicinity to become activated, and induce other inflammatory cells to accumulate, leading to the early lesion of pulmonary LCH. Another factor produced by Langerhans cells from bony LCH lesions is prostaglandin E2 (PGE2). PGE2 may play an important role in this disease because it can alter the way in which Langerhans cells interact with T-cells (another major culprit cell found in the LCH lesion). We propose that smoking stimulates the production of PGE2 by Langerhans cells. In doing so, smoking favors the production of certain factors (cytokines) that lead to further recruitment of inflammatory cells in the lungs.

The theories proposed are supported by many lines of experimental and published evidence and will be tested by a number of experimental approaches that will proceed independently of each other. Understanding how pulmonary LCH occurs in smokers is essential in the quest for new treatments. In addition to smoking cessation, new targets for therapy may include inhibitors of TLSP and/or PGE2. These studies are also essential to help us sort out how pulmonary LCH differs from other forms of LCH that are not associated with cigarette smoking. The support provided by this grant will also be of critical importance to enable continued investigation in the natural history, long-term prognosis, and other ongoing pulmonary LCH research at the Mayo Clinic.