Effects of Exogenous Nitric Oxide Gas on Mycobacterium tuberculosis in vitro and in mice

In 1992, inhaled NO (iNO) at low doses entered the practice of medicine for cardiopulmonary indications. Recently, iNO at higher doses has been tested in diverse pulmonary infections. However, nothing is known about the ability of exogenous NO gas to kill Mycobacterium tuberculosis (Mtb), the leading cause of death from infection between major viral pandemics. Here we mimicked exposure conditions used in recent human studies of high-dose iNO to explore the effects of NO gas against Mtb in vitro and in mice. We saw a profound bactericidal effect of NO gas in vitro against Mtb incubated in shallow, mildly acidic fluid. Mtb-infected mice tolerated inhaled NO well, except for developing more methemoglobinemia than humans at the same level of exposure. In Mtb-infected mice with poorly aerated pulmonary infiltrates, inhaled NO had an anti-inflammatory effect but did not reduce the bacterial burden. These results may help inform the decision whether to test inhaled NO as an adjunctive treatment for tuberculosis, and if so, in what settings and with what goals.