Susceptibility to ozone-induced airway inflammation is associated with decreased levels of surfactant protein D

BACKGROUND: Ozone (O(3)), a common air pollutant, induces exacerbation of asthma and chronic obstructive pulmonary disease. Pulmonary surfactant protein (SP)-D modulates immune and inflammatory responses in the lung. We have shown previously that SP-D plays a protective role in a mouse model of allergic airway inflammation. Here we studied the role and regulation of SP-D in O(3)-induced inflammatory changes in the lung. METHODS: To evaluate the effects of O(3 )exposure in mouse strains with genetically different expression levels of SP-D we exposed Balb/c, C57BL/6 and SP-D knockout mice to O(3 )or air. BAL cellular and cytokine content and SP-D levels were evaluated and compared between the different strains. The kinetics of SP-D production and inflammatory parameters were studied at 0, 2, 6, 12, 24, 48, and 72 hrs after O(3 )exposure. The effect of IL-6, an O(3)-inducible cytokine, on the expression of SP-D was investigated in vitro using a primary alveolar type II cell culture. RESULTS: Ozone-exposed Balb/c mice demonstrated significantly enhanced acute inflammatory changes including recruitment of inflammatory cells and release of KC and IL-12p70 when compared with age- and sex-matched C57BL/6 mice. On the other hand, C57BL/6 mice had significantly higher levels of SP-D and released more IL-10 and IL-6. Increase in SP-D production coincided with the resolution of inflammatory changes. Mice deficient in SP-D had significantly higher numbers of inflammatory cells when compared to controls supporting the notion that SP-D has an anti-inflammatory function in our model of O(3 )exposure. IL-6, which was highly up-regulated in O(3 )exposed mice, was capable of inducing the expression of SP-D in vitro in a dose dependent manner. CONCLUSION: Our data suggest that IL-6 contributes to the up-regulation of SP-D after acute O(3 )exposure and elevation of SP-D in the lung is associated with the resolution of inflammation. Absence or low levels of SP-D predispose to enhanced inflammatory changes following acute oxidative stress

Antenatal and postnatal corticosteroid and resuscitation induced lung injury in preterm sheep

<p>Abstract</p> <p>Background</p> <p>Initiation of ventilation using high tidal volumes in preterm lambs causes lung injury and inflammation. Antenatal corticosteroids mature the lungs of preterm infants and postnatal corticosteroids are used to treat bronchopulmonary dysplasia.</p> <p>Objective</p> <p>To test if antenatal or postnatal corticosteroids would decrease resuscitation induced lung injury.</p> <p>Methods</p> <p>129 d gestational age lambs (n = 5-8/gp; term = 150 d) were operatively delivered and ventilated after exposure to either 1) no medication, 2) antenatal maternal IM Betamethasone 0.5 mg/kg 24 h prior to delivery, 3) 0.5 mg/kg Dexamethasone IV at delivery or 4) Cortisol 2 mg/kg IV at delivery. Lambs then were ventilated with no PEEP and escalating tidal volumes (<it>V</it>_T) to 15 mL/kg for 15 min and then given surfactant. The lambs were ventilated with <it>V</it>_T8 mL/kg and PEEP 5 cmH₂0 for 2 h 45 min.</p> <p>Results</p> <p>High V_Tventilation caused a deterioration of lung physiology, lung inflammation and injury. Antenatal betamethasone improved ventilation, decreased inflammatory cytokine mRNA expression and alveolar protein leak, but did not prevent neutrophil influx. Postnatal dexamethasone decreased pro-inflammatory cytokine expression, but had no beneficial effect on ventilation, and postnatal cortisol had no effect. Ventilation increased liver serum amyloid mRNA expression, which was unaffected by corticosteroids.</p> <p>Conclusions</p> <p>Antenatal betamethasone decreased lung injury without decreasing lung inflammatory cells or systemic acute phase responses. Postnatal dexamethasone or cortisol, at the doses tested, did not have important effects on lung function or injury, suggesting that corticosteroids given at birth will not decrease resuscitation mediated injury.</p

IL-6 is constitutively expressed during lung morphogenesis and enhances fetal lung explant branching

Previous studies have shown that chorioamnionitis, with increased IL-6, promotes fetal lung maturation and decreases the incidence of respiratory distress syndrome in premature neonates. However, the expression pattern and the effects of IL-6 on fetal lung growth mechanisms remain unknown. IL-6 expression was assessed by in situ hybridization and by real-time PCR between 14.5 and 21.5 d postconception. Normal and nitrofen-induced hypoplastic lung explants were cultured with increasing IL-6 doses or IL-6 neutralizing antibodies. Branching, cellular proliferation (Ki-67) and MAPK phosphorylation in fetal lung explants were analyzed. Pulmonary primitive epithelium expressed IL-6 constitutively throughout all gestational ages, displaying highest levels during earliest stages. In normal and hypoplastic lung explants, IL-6 neutralizing antibodies significantly reduced, whereas IL-6 supplementation induced a biphasic effect (lower doses increased, while the highest dose did not accomplish additional effect) on branching and cellular proliferation. IL-6 enhanced p38-MAPK phosphorylation without changing MEK1/2 and JNK pathways. The present study suggests a physiological role for IL-6 on pulmonary branching mechanisms most likely involving p38-MAPK intracellular signalling pathway

Dose and time response after intraamniotic endotoxin in preterm lambs

Intraamniotic endotoxin causes chorioamnionitis, which is followed by improved fetal lung function after 4 d in fetal sheep. We evaluated 0.1 mg, 1 mg, 4 mg, and 10 mg endotoxin for inflammation and lung maturation effects after 7 d. Four and 10 mg endotoxin caused similar lung maturation and inflammation in the lung and chorioamnion. The number of neutrophils in cord blood and the inflammatory cells in alveolar lavage and fetal lung tissue increased in a dose-dependent manner. Lower endotoxin doses induced indicators of chorioamnionitis, lung and systemic inflammation without inducing lung maturation. Therefore, some degree of inflammation can occur without subsequent lung maturation. The inflammatory changes caused by 4 mg endotoxin were assessed after 5 h, 24 h, 72 h, and 7 d to discern local versus systemic inflammation after intraamniotic endotoxin. At 5 h active inflammatory cells were in the airways producing hydrogen peroxide, and interleukin-6 and -8 were increased in the cord blood indicating both lung and systemic responses. Cells recruited into the amniotic fluid produced proinflammatory cytokine mRNA for 7 d with no cytokine mRNA in chorioamnion, lung, or spleen after 72 h. The cells in the amniotic fluid may be a source of prolonged fetal exposure to proinflammatory cytokines