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- Honorary Senior Research Associate
- Div of Medicine
- Faculty of Medical Sciences
Uncontrolled activation of the coagulation cascade contributes to the pathophysiology of several respiratory conditions, including pulmonary fibrosis. Current dogma assumes that coagulation zymogens are derived from the circulation and locally-activated in response to tissue injury. However, my recent data show for the first time that coagulation factor X (FX) gene expression is significantly upregulated in pulmonary fibrosis and that the bronchial/alveolar epithelium represents a prominent cellular source of FX - the activated form of which (FXa) exerts potent pro-inflammatory/pro-fibrotic effects. These findings herald a paradigm shift in our understanding of the tissue origin of excessive procoagulant signaling in lung disease, and are consistent with the existence of an inducible extravascular lung coagulation system. Our work has also highlighted the involvement of proteinase-activated receptor 1 (PAR1) as the major signaling receptor for coagulation proteinases in the injured lung.
My current research addresses the hypothesis that extravascular pro-coagulant activity, signaling via PAR1, influences innate immune mechanisms and chemokine production to drive the development of lung inflammation and fibrosis. As such, my aims are to determine what regulates the production of extravascular coagulation factors, and how these factors contribute to the establishment of the chemokine networks involved in recruitment of leukocytes and circulating mesenchymal progenitor cells to the injured lung. In addition, I am investigating the significance of pro-coagulant signalling on monocyte/macrophage activation and formation of secondary lymphoid tissue.
This research is being performed using a combination of in vitro and in vivo studies (using both pharmacological and genetic approaches), as well as human biopsy material. The work is being carried out by an active and dynamic group of scientists and clinician scientists at various stages of their academic careers, ranging from PhD student to advanced clinician scientist and is supported by grants obtained from The Medical Research Council, The Wellcome Trust, The British Lung Foundation and The Rosetrees Trust.
Besides expanding our knowledge of the fundamental crosstalk between the coagulation cascade, inflammation and immunity, this work will provide novel insights into the pathophysiological mechanisms underlying lung inflammation and fibrosis. Interfering with FX production or signaling may represent an extremely attractive target for therapeutic intervention in lung injury and fibrosis, and potentially other lung diseases associated with excessive pro-coagulant activity.