Rapid induction of mRNA for nitric oxide synthase II in rat alveolar macrophages by intratracheal administration of Mycobacterium tuberculosis and Mycobacterium avium

Proc Soc Exp Biol Med. 1995 May;209(1):46-53. doi: 10.3181/00379727-209-43876.


Mycobacterium avium complex (MAC) organisms are among the most common bacterial cause of disseminated infection in patients with acquired immune deficiency syndrome (AIDS). An increase in the incidence of virulent Mycobacterium tuberculosis (MTB) is also occurring throughout the world. In vitro data suggest that nitric oxide (NO) may be important in restricting the growth of MAC. However, the ability of MTB to stimulate NO production and the susceptibility of MTB to the bactericidal activity of NO produced by murine alveolar macrophages (AM) is controversial. This study tested the hypothesis that in vivo administration of heat-killed MAC (strain 100 and 101) and human virulent MTB (strain F1) to rats stimulated NO production by rat AM, ex vivo. We show that heat-killed MTB instilled into rat lungs rapidly induced mRNA for NO synthase (iNOS) II in AM obtained by bronchoalveolar lavage (BAL). In contrast, expression of AM iNOS mRNA was only found in 40% of the rats given MAC. Moreover, the change in iNOS mRNA in the AM obtained from rats given MTB and MAC correlated with the production of the reactive nitrogen intermediates (RNI) NO2- and NO3- in BAL fluid, lung homogenate, and the spontaneous generation of RNI by isolated AM ex vivo and occurred without measurable increases in BAL fluid tumor necrosis factor-alpha (TNF-alpha). L-NG-monomethylarginine (50 mg/kg, ip) given 30 min before MAC or MTB attenuated the increase in RNI in lung homogenates and BAL fluid. This is the first demonstration that in vivo exposure to MTB results in rapid upregulation of gene expression for iNOS which is associated with functional RNI production by rat AM. These results show that MTB human virulent strain 1 has the ability to rapidly upregulate iNOS mRNA in AM. If human AM generate NO from L-arginine by either iNOS or other NADPH oxidases then NO may play a role in the overall host-defense response of the lung to MAC and MTB.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Oxidoreductases / biosynthesis*
  • Animals
  • Arginine / analogs & derivatives
  • Arginine / pharmacology
  • Base Sequence
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • Humans
  • Lung / chemistry
  • Lung / microbiology
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / enzymology
  • Macrophages, Alveolar / metabolism*
  • Male
  • Molecular Sequence Data
  • Mycobacterium avium Complex / immunology*
  • Mycobacterium tuberculosis / immunology*
  • Nitrates / analysis
  • Nitrates / blood
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide Synthase
  • Nitrites / analysis
  • Nitrites / blood
  • RNA, Messenger / biosynthesis*
  • Rats
  • Rats, Sprague-Dawley
  • Tumor Necrosis Factor-alpha / analysis
  • omega-N-Methylarginine


  • Nitrates
  • Nitrites
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • omega-N-Methylarginine
  • Nitric Oxide
  • Arginine
  • Nitric Oxide Synthase
  • Amino Acid Oxidoreductases