Reactive Oxygen and Oral Defense System 11 Fig. 3. The entero-salivary circulation of nitric oxide metabo- lites neutral medium. Dietary intake of nitrate-enriched vegeta- bles might play important roles in the protection of the oral and stomach against hazardous pathogens via the gastro- intestinal-salivary cycle of NO and related metabolites. Other environmental sources of nitrate and nitrite include cigarette smoke and car exhausts. These and other environ- mental pollutants contain volatile nitrogen oxides, some of which are converted to nitrate or nitrite in the body. After ingestion, nitrate is rapidly and effectively absorbed pro- ximally from the gastrointestinal tract into the bloodstream [46]. Most nitrate is ultimately excreted in the urine but some is excreted in the saliva, sweat and possibly also the intestines. Up to 25% of plasma nitrate is actively taken up by the salivary glands and secreted with saliva, and the resulting salivary nitrate concentrations are at least 10 times higher than the concentrations in plasma. Many of oral microorganisms express enzymes that can effectively reduce nitrate. Facultative anaerobic bacteria in the oral cavity reduce salivary nitrate to nitrite and this nitrite enhances the gastric generation of NO in acidic condition. Although nitrite is converted non-enzymatically to NO at low pH (3, 5), the rate of this conversion at the physiological pH (about 6.2–7.6) in the oral cavity is fairly low and, hence, the mechanism of oral production of NO remains obscure. In this context, we previously reported that neutrophils in the oral cavity of healthy humans generated NO by inducible NO synthase [9, 25]. Production of NO in the oral cavity has been known to increase in patients with dental caries [47]. One recent study reported that some species of streptococci Vol. 42, No. 1, 2008 in human saliva also generate NO [48]. References [1] Tabak, L.A., Levine, M.J., Mandel, I.D., and Ellison, S.A.: Role of salivary mucins in the protection of the oral cavity. J. Oral Pathol., 11, 1–17, 1982. [2] Slomiany, B.L., Murty, V.L., Piotrowski, J., and Slomiany, A.: Salivary mucins in oral mucosal defense. Gen. Pharmacol., 27, 761–771, 1996. [3] Grisham, M.B. and Ryan, E.M.: Cytotoxic properties of sali- vary oxidants. Am. J. Physiol., 258, C115–121, 1990. [4] Anderson, D.M., Ebersole, J.L., and Novak, M.J.: Functional properties of nonhuman primate antibody to Porphyromonas gingivalis. Infect. Immun., 63, 3245–3252, 1995. [5] McArthur, W.P. and Clark, W.B.: Specific antibodies and their potential role in periodontal diseases. J. Periodontol., 64, 807–818, 1993. [6] Scully, C.M. and Lehner, T.: Opsonization, phagocytosis and killing of Streptococcus mutans by polymorphonuclear leu- kocytes, in relation to dental caries in the rhesus monkey (Macaca mulatta). Arch. Oral Biol., 24, 307–312, 1979. [7] Utsumi, T., Klostergaard, J., Akimaru, K., Edashige, K., Sato, E.F., and Utsumi, K.: Modulation of TNF-alpha- priming and stimulation-dependent superoxide generation in human neutrophils by protein kinase inhibitors. Arch. Biochem. Biophys., 294, 271–278, 1992. [8] Akimaru, K., Utsumi, T., Sato, E.F., Klostergaard, J., Inoue, M., and Utsumi, K.: Role of tyrosyl phosphorylation in neu- trophil priming by tumor necrosis factor-alpha and granulo- cyte colony stimulating factor. Arch. Biochem. Biophys., 298, 703–709, 1992. [9] Sato, E.F., Utsumi, K., and Inoue, M.: Human oral neutro- phils: isolation and characterization. Methods Enzymol., 268, 503–509, 1996. [10] Forehand, J.R., Pabst, M.J., Phillips, W.A., and Johnston, R.B., Jr.: Lipopolysaccharide priming of human neutrophils for an enhanced respiratory burst. Role of intracellular free calcium. J. Clin. Invest., 83, 74–83, 1989. [11] Guthrie, L.A., McPhail, L.C., Henson, P.M., and Johnston, R.B., Jr.: Priming of neutrophils for enhanced release of oxy- gen metabolites by bacterial lipopolysaccharide. Evidence for increased activity of the superoxide-producing enzyme. J. Exp. Med., 160, 1656–1671, 1984. [12] Kaku, M., Yagawa, K., Nagao, S., and Tanaka, A.: Enhanced superoxide anion release from phagocytes by muramyl dipeptide or lipopolysaccharide. Infect. Immun., 39, 559–564, 1983. [13] Beutler, B.A., Milsark, I.W., and Cerami, A.: Cachectin/tu- mor necrosis factor: production, distribution, and metabolic fate in vivo. J. Immunol., 135, 3972–3977, 1985. [14] Steinbeck, M.J. and Roth, J.A.: Neutrophil activation by re- combinant cytokines. Rev. Infect. Dis., 11, 549–568, 1989. [15] Squier, M.K., Sehnert, A.J., and Cohen, J.J.: Apoptosis in leukocytes. J. Leukoc. Biol., 57, 2–10, 1995. [16] Savill, J. and Haslett, C.: Granulocyte clearance by apoptosis in the resolution of inflammation. Semin. Cell Biol., 6, 385–