Budesonide and Formoterol Reduce Early Innate Anti-Viral Immune Responses In Vitro

Asthma is a chronic inflammatory airways disease in which respiratory viral infections frequently trigger exacerbations. Current treatment of asthma with combinations of inhaled corticosteroids and long acting beta2 agonists improves asthma control and reduces exacerbations but what impact this might have on innate anti-viral immunity is unclear. We investigated the in vitro effects of asthma drugs on innate anti-viral immunity. Peripheral blood mononuclear cells (PBMC) from healthy and asthmatic donors were cultured for 24 hours with the Toll-like receptor 7 agonist, imiquimod, or rhinovirus 16 (RV16) in the presence of budesonide and/or formoterol. Production of proinflammatory cytokines and expression of anti-viral intracellular signalling molecules were measured by ELISA and RT-PCR respectively. In PBMC from healthy donors, budesonide alone inhibited IP-10 and IL-6 production induced by imiquimod in a concentration-dependent manner and the degree of inhibition was amplified when budesonide and formoterol were used in combination. Formoterol alone had little effect on these parameters, except at high concentrations (10−6 M) when IL-6 production increased. In RV16 stimulated PBMC, the combination of budesonide and formoterol inhibited IFNα and IP-10 production in asthmatic as well as healthy donors. Combination of budesonide and formoterol also inhibited RV16-stimulated expression of the type I IFN induced genes myxovirus protein A and 2′, 5′ oligoadenylate synthetise. Notably, RV16 stimulated lower levels of type Myxovirus A and oligoadenylate synthase in PBMC of asthmatics than control donors. These in vitro studies demonstrate that combinations of drugs commonly used in asthma therapy inhibit both early pro-inflammatory cytokines and key aspects of the type I IFN pathway. These findings suggest that budesonide and formoterol curtail excessive inflammation induced by rhinovirus infections in patients with asthma, but whether this inhibits viral clearance in vivo remains to be determined

Rhinovirus infection induces cytotoxicity and delays wound healing in bronchial epithelial cells

Background: Human rhinoviruses (RV), the most common triggers of acute asthma exacerbations, are considered not cytotoxic to the bronchial epithelium. Recent observations, however, have questioned this knowledge. The aim of this study was to evaluate the ability of RV to induce epithelial cytotoxicity and affect epithelial repair in-vitro. Methods: Monolayers of BEAS-2B bronchial epithelial cells, seeded at different densities were exposed to RV serotypes 1b, 5, 7, 9, 14, 16. Cytotoxicity was assessed chromatometrically. Epithelial monolayers were mechanically wounded, exposed or not to RV and the repopulation of the damaged area was assessed by image analysis. Finally epithelial cell proliferation was assessed by quantitation of proliferating cell nuclear antigen ( PCNA) by flow cytometry. Results: RV1b, RV5, RV7, RV14 and RV16 were able to induce considerable epithelial cytotoxicity, more pronounced in less dense cultures, in a cell-density and dose-dependent manner. RV9 was not cytotoxic. Furthermore, RV infection diminished the self-repair capacity of bronchial epithelial cells and reduced cell proliferation. Conclusion: RV-induced epithelial cytotoxicity may become considerable in already compromised epithelium, such as in the case of asthma. The RV-induced impairment on epithelial proliferation and self-repair capacity may contribute to the development of airway remodeling

Maternal genital colonization with Ureaplasma urealyticum promotes preterm delivery: Association of the respiratory colonization of premature infants with chronic lung disease and increased mortality

Background. Infection of the chorioamnion with Ureaplasma urealyticum has been associated with low birth weight. Respiratory tract colonization in preterm infants has been associated with the development of chronic lung disease (CLD). The purpose of the present study was to determine the frequency of colonization of the mother’s vagina and the preterm infant’s respiratory tract and to associate U. urealyticum with premature birth and with development of CLD in the newborn. Methods. The present prospective study involved 126 mothers with preterm delivery and 125 mothers with full-term delivery, as well as their offspring. Vaginal secretion specimens were obtained from each mother before delivery. Rhinopharyngeal secretion or tracheal lavage specimens were collected after the birth of each premature and full-term infant and then periodically during hospitalization. Results. Vaginal Ureaplasma colonization occurred among 36.5% of mothers with preterm delivery and among 38% of mothers with full-term delivery. The rate of vertical transmission was 33% and 17% for mothers with preterm delivery and mothers with full-term delivery, respectively. The transmission rate for infants, according to birth weight, was as follows: 60%, for infants with a birth weight of <1000 g; 50%, for infants with a birth weight of 1000-1500 g; and 15.3%, for infants with a birth weight of greater than or equal to1500 g (P = .001). The median gestational age of preterm infants born to colonized mothers was 28.5 weeks, and that of preterm infants born to noncolonized mothers was 32 weeks (P < .001). The median birth weight of colonized preterm infants was 1135 g, and that of noncolonized infants was 1670 g (P < .001). Twenty-four percent of preterm infants and 10% of full-term infants were colonized with U. urealyticum. Of colonized preterm infants, 27% developed CLD, compared with 9% of noncolonized infants (P = .03). Mortality was significantly higher among colonized preterm infants (P = .003). Conclusions. The rate of vertical transmission is highest among preterm infants with a birth weight of <1500 g. Vaginal colonization with Ureaplasma organisms is associated with premature delivery. Colonization of the respiratory tract of infants is associated with the development of CLD and with increased mortality