Mechanisms of pulmonary inflammation in ageing and chronic lung disease

Abstract

The human respiratory tract is exposed to copious antigen over the course of the lifespan by virtue of its free communication with the external environment through the process of ventilation. The host immune system must therefore distinguish innocuous inhaled antigen in the respiratory tract from antigen potentially associated with infection, produce an inflammatory response with minimal collateral host damage if required, and allow a return to homeostasis once infection is cleared. Inadequacies of these processes can result in a predisposition to respiratory illnesses. Respiratory diseases are leading causes of morbidity and mortality worldwide. It is notable that the burden of respiratory disease disproportionately falls upon older adults, and disorders of inflammation arising with ageing may contribute to this disparity. The work in this thesis describes a viable platform for the assessment of pulmonary inflammation that could be adapted to facilitate experimental medicine studies characterising inflammation in advanced age or early phase trials of immunomodulatory drugs that might alter the course and resolution of inflammation. This thesis also describes a method to identify candidate immunomodulatory drugs using connectivity maps and puts forward Del-1 as a target for drugs that enhance the resolution of inflammation. In considering the role of inflammation in chronic lung disease, this thesis also presents an exploration of the mechanisms of inflammation in chronic hypersensitivity pneumonitis, using a systems biology approach to implicate tissue-resident memory T lymphocytes in the pathogenesis of the disease. This opens up the possibility of IL-15 signalling as a potential target for treatment of the disease where few treatments are currently proven to be effective.