Mycoplasma pneumoniae (mycoplasmas) account for 20 to 30 percent of all pneumonias in humans, and exacerbate the pathophysiology of asthma, chronic obstructive disease and other pulmonary diseases. Man is the only host of M. pneumoniae, but Mycoplasma pulmonis infection in mice provides an excellent animal model that reproduces the essential features of human respiratory mycoplasmosis. When C3H/He mice are infected with mycoplasmas they develop a clinical condition similar to human respiratory mycoplasmosis. On the other hand, C57BL/6 mice are resistant to mycoplasmas. Presently, the basic mechanisms by which some hosts, but not others, kill mycoplasmas in vivo have not been elucidated. Based on our preliminary data, we hypothesize that in the early stages of infection (8-72 h), mycoplasmas are killed by reactive oxygen-nitrogen intermediates (ROS) produced by activated alveolar macrophages (AM). Surfactant protein A (SP-A) is essential and necessary or this killing to occur by (i) upregulating production of nitric oxide by activated AM, and (ii) stimulating phagocytosis of mycoplasmas by AM. Furthermore, injury to SP-A by reactive oxygen-nitrogen species abrogates its host-defense functions. We have designed a series of experiments to test this hypothesis in vitro, using AM isolated from the lungs of these mice, and in vivo using congenic germ-free knock-out mice which we are currently developing. Specifically, we plan to: (1) Identify the mechanisms by which normal but not nitrated SP-A mediates killing of mycoplasmas by resistant C57BL/6 AM; (2) Quantify the extent of killing of intanasally instilled mycoplasmas in the lungs of germ-free congenic C57BL/6 SP-A (-/-) and C57BL/6: NOS (-/-) mice in vivo and (3) Identify the mechanisms responsible for decreased mycoplasmal killing by AM from C3H/He mice. A better understanding of basic mechanisms of innate lung defenses may lead to the development of novel therapies, which may extend to other pathogens.
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