Histological features associated to pulmonary function change and response to doxycycline treatment in lymphangioleiomyomatosis

• Grant number: 09/16919-8
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2010
• End date: January 31, 2013
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Marisa Dolhnikoff
• Grantee: Marisa Dolhnikoff
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Lymphangioleiomyomatosis (LAM) is a rare disease described in women of reproductive age. The disease often arises spontaneously in patients with no evidence of genetic disease and is present in approximately one third of women with tuberous sclerosis complex. LAM usually presents with symptoms of dyspnea or the sudden appearance of a pneumothorax. Pulmonary function tests frequently reveal an obstructive or mixed pattern and increased total lung capacity. LAM is a multisystem disorder characterized by the proliferation of immature-appearing smooth muscle cells (LAM cells) mainly in the lungs. The cell proliferation has been proposed to play a central role in the destruction of lung parenchyma due to high proliferative activity and metalloproteinases realease. Recently, some studies demonstrated that blocking and inhibiting MMP activity would be reasonable approaches to successfully treat LAM lung disease. The antibiotic doxycycline, a nonspecific MMP inhibitor, may be efficacious in the treatment of lymphangioleymiomatosis. Currently, there is no standard-of-care therapy for this disease, various strategies have been used; however, their effectiveness has not been demonstrated. Therefore an improved understanding of the molecular pathogenesis of the disease became essential to identify promising molecular targets. It has been discovered that in LAM, somatic or genetic mutations of tumor suppressor genes tuberous sclerosis complex 1 (TSC1) or TSC2 occur and the TSC1/TSC2 protein complex functions as a negative regulator of the mTOR signaling pathway. The constitutive activation of the mTOR kinase leads to increased protein translation and ultimately to inappropriate cellular proliferation, migration and invasion. Since so far there is no specific treatment to LAM with satisfactory results and the disease pathogenesis is not totally clear, the present project intend to evaluate different histological parameters of pulmonary lesion that could be correlated with decrease in pulmonary function and possible response to doxycycline treatment. (AU)