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VOL. 71 (2), 283-319, 2005 PURINERGIC SIGNALLING: THERAPEUTIC POTENTIAL

receptor may help to devise new strategies to combat the most potent
and enduring of human pathogens (14). Infection with M.
tuberculosis causes macrophages to release ATP, which leads to
oxygen-radical production, providing antibacterial effects at sites of
infection. In later studies, it was shown that the ATP-induced
bactericidal activity towards virulent M. tuberculosis requires an
increase in cytosolic Ca2+ in infected macrophages and it was
hypothesised that the Ca2+-dependence was linked to promotion of
phagosome-lysosome fusion. The P2X7 receptor plays a fundamental
role in lipopolysaccharide signal transduction and activation of
macrophages and may therefore represent a therapeutic target for
Gram-negative bacterial septicaemia. Vibrio cholerae, the causative
organism of the intestinal disease cholera, secretes enzymes that
lead to ATP degradation; this may allow the pathogen to evade the
immune system by reducing the apoptotic actions of the P2X7
receptor. Evidence has been presented to support the view that, while
the cytotoxic actions of ATP on macrophages was via P2X7 receptors,
the bacteriocidal effects of ATP (and UTP) were probably via P2Y2
receptors.

ATP moderates anti-IgE-induced release of histamine from lung
mast cells and may therefore be mechanistically involved in human
allergic/asthmatic reactions. Alveolar macrophages express P2X7
receptors, which upon stimulation trigger pro-inflammatory
responses, including activation of IL1-6 cytokines and granulomatous
reactions (15).

Extracellular ATP inhibits the activation of CD4+T lymphocytes
via P2Y receptors, which suggests a novel therapeutic target for
topical immunosuppression in eye, skin or airway inflammatory
disease. In addition to the apoptosis mediated by P2X7 receptors, a
lower level of activation sometimes results in cell proliferation; it has
been suggested that the expression and function of P2X7 receptors
on B lymphocytes may correlate with the severity of B-cell chronic
lympocytic leukaemia.

During the acute phase of Trypanosoma cruzi infection, the
eteologic agent of Chagas’ disease, thymic atrophy occurs; ATP also
induces cell death in CD4+/CD8+ double-positive thymocytes and may
play a central role in thymus atrophy during T. cruzi infection.

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