Activation of Nuclear Factor κB and Induction of Inducible Nitric Oxide Synthase byUreaplasma urealyticumin Macrophages

Abstract

Chronic lung disease (CLD) of prematurity is an inflammatory disease with a multifactorial etiology. The importance of Ureaplasma urealyticum in the development of CLD is debated, and steroids produce some improvement in neonates with this disease. In the present study, the capability of U. urealyticum to stimulate rat alveolar macrophages to produce nitric oxide (NO), express inducible nitric oxide synthase (iNOS), and activate nuclear factor B (NF-B) in vitro was characterized. The effect of NO on the growth of U. urealyticum was also investigated. In addition, the impact of dexamethasone and budesonide on these processes was examined. We found that U. urealyticum antigen (>4 ؋ 10 7 color-changing units/ml) stimulated alveolar macrophages to produce NO in a dose-and time-dependent manner (P < 0.05). This effect was further enhanced by gamma interferon (100 IU/ml; P < 0.05) but was attenuated by budesonide and dexamethasone (10 ؊4 to 10 ؊6 M) (P < 0.05). The mRNA and protein levels of iNOS were also induced in response to U. urealyticum and inhibited by steroids. U. urealyticum antigen triggered NF-B activation, a possible mechanism for the induced iNOS expression, which also was inhibited by steroids. NO induced by U. urealyticum caused a sixfold reduction of its own growth after infection for 10 h. Our findings imply that U. urealyticum may be an important factor in the development of CLD. The host defense response against U. urealyticum infection may also be influenced by NO. The down-regulatory effect of steroids on NF-B activation, iNOS expression, and NO production might partly explain the beneficial effect of steroids in neonates with CLD.

Mycoplasmas and Ureaplasmas as Neonatal Pathogens

“…Nitric oxide is a soluble, shortacting free-radical gas produced by a variety of cells that mediates a number of functions involved in the local inflammatory response. Two studies have demonstrated the ability of Ureaplasma to stimulate rodent macrophage cell lines to release nitric oxide (59,169). Nitric oxide production induced by Ureaplasma can be down-regulated by administration of corticosteroids (169).…”

“…Several recent investigations have examined the relationship between ureaplasmal colonization of the neonatal respiratory tract and release of inflammatory mediators that may be involved in pathogenesis of BPD, including clinical studies (154,214,309) evaluation of cell lines from humans or rodents cultivated in vitro and exposed to Ureaplasma antigen (59,(166)(167)(168)(169)187), and animal models (308,338). Ureaplasma spp.…”

Nuclear Factor κB Activation in Pulmonary Leukocytes from Infants with Hyaline Membrane Disease: Associations with Chorioamnionitis and Ureaplasma urealyticum Colonization

“…We focused on pulmonary inflammatory cells and related NF-B activation to TNF-␣ and IL-8 levels in tracheal aspirates from these infants. Perinatal factors that may contribute to lung inflammation include chorioamnionitis (21,22) and Ureaplasma urealyticum colonization/infection of the airway (23)(24)(25)(26)(27). We determined whether these conditions are also associated with evidence of NF-B activation in the infant lung.…”

Azithromycin Suppresses Activation of Nuclear Factor-kappa B and Synthesis of Pro-inflammatory Cytokines in Tracheal Aspirate Cells From Premature Infants

“…Because TNF-␣ plays a major role as a stimulator of chemokines in the lungs of premature neonates, we speculate that the early treatment with AZM may provide antiinflammatory protection by suppressing the activation of NF-B and reducing the synthesis of NF-B-dependant proinflammatory mediators. Infection and colonization of the respiratory tract with ureaplasma and Mycoplasma may also trigger a vigorous pro-inflammatory response in the lungs and increase the risk for the development of BPD in preterm infants (32). Ureaplasma urealyticum increases the activation of NF-B in alveolar macrophages (33).…”