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Date of Award

Fall 2011

Degree Type

Thesis

Degree Name

Master of Science (MSc)

Department

Medical Sciences (Division of Physiology/Pharmacology)

Supervisor

Parameswaran Nair

Co-Supervisor

Luke Janssen

Language

English

Committee Member

Roma Sehmi

Abstract

Introduction: Obesity is associated with asthma and airway hyperresponsiveness, though the mechanisms behind this relationship remain unclear. It is unlikely to be due to a direct effect of leptin on human airway smooth muscle cells (ASMC) (Nair, et al., 2009). Since adipocytes are known to produce a wide array of mediators, we hypothesized that adipocytes may directly modulate human ASMC biology.

Objectives: To determine and compare the effects of intra and extrathoracic adipocyte secretions on ASMC proliferation, chemotaxis, contractility and cytokine synthesis.

Methods: Human ASMC and human adipocytes were cultured from primary samples (intrathoracic or extrathoracic). Adipocyte-conditioned media was used as a treatment in proliferation cell count assays, Transwell migrations, muscle bath experiments and to induce interleukin (IL)-6, tumor necrosis factor (TNF)-α and eotaxin production (as measured with a Bioplex). The effects of adipocyte-myocyte co-culture were also investigated on the proliferation, migration and cytokine synthesis of the ASMC.

Results: Adipocyte supernatants and co-culture did not significantly affect the growth of ASMC in the presence of 10% fetal calf serum. The adipocyte supernatants were not chemotactic, and did not affect the migration of ASMC towards platelet derived growth factor (PDGF). Similarly, co-culture did not have any effect on ASMC chemotaxis. Cytokine synthesis was also unchanged by adipocytes. Adipocyte supernatants did not have any effect on the contractile or relaxant responses of bovine tracheal smooth muscle strips. There was no significant difference between adipocyte depot location, with intrathoracic and extrathoracic adipocytes having a similar effect.

Conclusion: Human adipocytes do not directly modulate airway smooth muscle proliferation, migration, contractility and cytokine synthesis. These data point to some other cause for the association between obesity and asthma, though the role of other cells present in the adipose tissue of obese individuals cannot be ruled out.

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