Dexamethasone reduces tachykinin but not ACh airway hyperreactivity after 03

We investigated whether dexamethasone pretreatment affected the acute increase in airway reactivity produced by high-level ozone exposure. Reactivity to intravenous IV substance P (SP), IV acetylcholine (ACh), or aerosolized capsaicin (CAP) before and 1 hr after ozone exposure (3 ppm for 2 hr) was determined by measuring specific airway resistance in anesthetized, spontaneously breathing guinea pigs, half of whom had been pretreated for 2 days pre-ozone with dexamethasone (2 mg/kg intramuscularly [IM] daily). The amount of IV SP, IV ACh, or inhaled capsaicin necessary to increase baseline specific airway resistance by 100% (ED₂₀₀ACh or ED_2OOSP) or 35% (ED₁₃₅CAP) was determined by interpolation from dose-response curves. Compared to their pre-ozone status on the day of exposure, we found that dexamethasone-pretreated animals manifested significantly less of an increase in airway reactivity postozone to IV SP or inhaled CAP than did untreated animals. Changes in logEDs of the pretreated group were 0.18 ±0.03 (mean ± SE) for SP and 2.20 ± 0.11 for CAP compared to 0.27 ± 0.04 and 3.38 ± 0.34, respectively, for the untreated groups post-ozone (p < 0.05 and n = 4 for each). In contrast, dexamethasone pretreatment had no effect on IV ACh reactivity postozone: changes in logED_2OOACh were 0.27 ± 0.08 and 0.28 ± 0.04 for the pretreated and untreated groups, respectively (n = 4). In animals pretreated with captopril to block possible dexamethasone stimulation of angiotensin-converting enzyme synthesis that could influence tachykinin reactivity, we found that the corticosteroid effect on post-ozone SP reactivity was as marked as that seen in animals without captopril (n = 4). Because these reactivity studies were consistent with the possibility that dexamethasone may ameliorate ozone-induced, tachykinin hyperreactivity by stimulating airway neutral endopeptidase (NEP), we measured NEP activity by high-performance liquid chromatography (HPLC) of each tracheal homogenate made from other groups of animals. Homogenates from ozone-exposed, dexamethasone-pretreated animals demonstrated significantly greater NEP activity (81 ± 24%) than that from ozone-exposed, untreated animals (p < 0.05, n = 5). We conclude that corticosteroid pretreatment reduces the acute increase in airway reactivity to exogenous and endogenous tachykinins caused by ozone. This reduction may be at least partly due to stimulation of airway NEP activity, perhaps most of which is nonmucosal in that ozone acutely inactivates mucosal NEP. Offprint requests to: C. G. Murlas     

Cytokine expression in meconium-induced lungs

Objective : In this article the authors present relationship between meconium exposure and inflammatory cytokine release in newborn lungs.Methods : The authors used forty 2-week-old rabbit pups for the study. One-half of the group were instilled with meconium and the other half with saline. Rabbits were sacrificed at 0, 2, 4, 8, and 24 hrs after installation and lung lavage was obtained and was examined for cytokine mRNA expression using RT-PCR and for cytokine proteins using ELISA technique. The data were collected in each of the study group.Results : Meconium instillation caused significant expression of inflammatory cytokines TNFα, IL-6, and IL-8 (p<0.05) with a peak at 8 hrs after meconium instillation. Levels of IL-10 were insignificant (p> 0.05). Also, we found significant increase in necrotic cells and neutrophils (p<0.05), compared to the control, saline instilled rabbit lungs.Conclusion: The present studies demonstrates that meconium induces inflammatory response and cytokines gene and protein expression in the lungs.     

Angiotensin II receptor blockade inhibits pneumocyte apoptosis in experimental meconium aspiration

Lung tissue inflammation and apoptosis are implicated in the pathogenesis of meconium aspiration-induced lung injury in the newborn, but the mechanisms of these reactions are still poorly known. We investigated the time-dependent leukocyte influx and appearance of apoptosis, as well as the contribution of angiotensin (ANG) II receptor action on these processes in the meconium-induced lung injury. Experimental meconium aspiration was induced by intratracheal instillation of human meconium in 18 rats, and eight rats were further pretreated with an unspecific ANG II receptor inhibitor saralasin. Rats were ventilated with 60% oxygen for 1, 3, or 5 h, and the lungs were then studied histologically for tissue injury and with DNA nick-end labeling and electron microscopy for apoptotic cell death. Lung tissue myeloperoxidase activity and expression of angiotensinogen mRNA and endothelial monocyte-activating polypeptide (EMAP) II protein were also analyzed. The meconium-instilled lungs showed increasing neutrophil migration and histologic injury after the first hour, whereas the number of epithelial apoptotic cells was elevated from the control level throughout the study. Myeloperoxidase activity was high, and the angiotensinogen mRNA and EMAP II protein was up-regulated at 5 h after the meconium insult. Pretreatment with saralasin significantly prevented the increase in lung tissue myeloperoxidase activity, EMAP II, and lung epithelial apoptosis. The results suggest that pulmonary meconium insult rapidly results in epithelial apoptosis, before significant neutrophil sequestration into the lungs. Apoptotic cell death is further connected with ANG II receptor action in the meconium-contaminated lung tissue.