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Human T lymphocytes do not circulate around the body in a random fashion. Expression of certain receptors ensure that they are guided around the body to maximise the efficiency of the immune system in combating infection, a process known as lymphocyte homing. In some disease processes there may be an over exuberant immune response effected in part by unnecessary lymphocyte homing. Mechanisms of lymphocyte homing to the lung are far from clear. Analysis of the chemokine and activation marker expression of T cells derived from human lung resection specimens, bronchoalveolar lavage fluid and peripheral blood in both health and disease by flow cytometry, may help to define patterns of expression which may be specific to the presence of a T cells within the lung or specific to a particular disease process. Using these techniques, I have demonstrated that there is polarization of the chemokine receptors CCR3 and CCR4 on bronchoalveolar Th2 cells in both health and disease, thus providing a potential mechanism for their differential recruitment to the lung in allergic disease such as asthma. I have provided evidence for the existence of a resident lung T cell population characterised by expression of multiple activation markers, and have shown that a high percentage of these cells express CXCR6 suggesting that this receptor may have a role in the recruitment and/or retention of these cells within the lung. Finally, I have demonstrated that in sarcoidosis, a disease where there is abnormal T cell accumulation within the lung, more BAL T cells express CXCR6 compared to cells derived from asthmatic patients or healthy controls, again suggesting a potential role for this receptor in T cell homing to the human lung in both health and disease.

Nitric oxide (NO) is a gaseous signalling molecule that is synthesised by nitric oxide synthases (NOSs) and has a variety of physiological and pathophysiological roles. Some of its physiological functions are primarily mediated via the activation of soluble guanylate cyclase. However, NO is also able to potently inhibit mitochondrial respiration at complex IV of the electron transport chain (ETC) in a manner that is reversible and in competition with oxygen (O2). Following prolonged exposure to NO, the ETC undergoes an NO-dependent modification at complex I, which results in a persistent inhibition of respiration. Activated macrophages were found to produce NO, via upregulation of the inducible isoform of NOS (iNOS), in sufficient quantities to inhibit respiration. This inhibition was initially reversible but became persistent with time. In addition, haem oxygenase-1 (HO-1) is upregulated in these cells, producing carbon monoxide (CO), which is also known to inhibit complex IV. The ability of exogenous and endogenous CO to inhibit respiration was investigated. Although less potent than NO, CO was shown to cause significant inhibition of respiration, particularly under hypoxic (1% O2) conditions. Furthermore, hypoxia was found to attenuate significantly the synthesis of NO from iNOS but not CO from HO-1. The consequences of inhibition of respiration were investigated under hypoxia, where the availability of O2 may be limiting for O2-dependent cellular processes. Specifically, the effects of respiratory inhibition were investigated with regards to the stability of hypoxia-induced hypoxia inducible factor la (HTFla). Hypoxia resulted in the stabilisation of HIF1α protein, a phenomenon that was prevented by inhibition of the ETC at various complexes. This destabilisation of HIFla was found to be due to a redistribution of intracellular O2 from mitochondrial consumption, resulting in an increased intracellular O2 concentration and the reactivation of the O2-dependent degradation of HIF1α protein.

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