Inhaled therapies for tuberculosis and the relevance of activation of lung macrophages by particulate drug-delivery systems

Pathogenic strains of Mycobacterium tuberculosis (Mtb) induce 'alternative activation' of lung macrophages that they colonize, in order to create conditions that promote the establishment and progression of infection. There is some evidence to indicate that such macrophages may be rescued from alternative activation by inhalable microparticles containing a variety of drugs. This review summarizes the experience of various groups of researchers, relating to observations of induction of a number of classical macrophage activation pathways. Restoration of a 'respiratory burst' and upregulation of reactive oxygen species and nitrogen intermediates through the phagocyte oxidase and nitric oxide synthetase enzyme systems; induction of proinflammatory macrophage cytokines; and finally induction of apoptosis rather than necrosis of the infected macrophage are discussed. It is suggested that there is scope to co-opt host responses in the management of tuberculosis, through the route of pulmonary drug delivery.