Apoptosis of airway epithelial cells in response to meconium
Introduction
MAS is a perinatal aspiration of meconium followed by acute lung inflammation and respiratory failure, in some cases leading to death. Previously we demonstrated meconium-induced damage of airways and alveoli (Zagariya et al., 2000). Increased pulmonary vascular resistance, severe inflammatory response, meconium toxicity and deactivation of pulmonary surfactant were observed by others (Tyler et al., 1978, Davey et al., 1993). Recent studies have suggested that apoptosis of airways and alveolar epithelial cells is an important factor in the pathogenesis of MAS. The apoptotic process in alveolar epithelium has been well studied. Hagimoto found apoptosis and expression of FAS in the alveolar epithelium of mice exposed to bleomycin (Hagimoto et al., 1995a, Hagimoto et al., 1995b). The angiotensinogen-converting enzyme (ACE) inhibitor captopril was able to inhibit experimentally induced lung fibrosis induced by the plant alkaloid monocrotaline (Molteni et al., 1985) or by gamma irradiation (Wang et al., 1999a). Recently, Uhal et al. found that captopril is also a potent inhibitor of FAS-induced apoptosis in human or rat lungs in vitro (Uhal et al., 1998).
Apoptosis and loss of alveolar epithelium cells were also seen in acute lung injury (Hagimoto et al., 1995a). In present study we investigated what type of cells in the lung tissue is damaged first after meconium instillation.
We hypothesized that meconium can induce lung cell apoptosis, which is preferentially localized in lung airway epithelial cells. We studied a meconium-induced injury in two-week-old rabbits.
Section snippets
Meconium preparation
Meconium was prepared according to a previously published procedure (Wiswell et al., 1994). Meconium samples were obtained from healthy full-term human neonates. The samples were pooled together and homogenized in 0.9% NaCl to a 10% (weight/volume) final concentration and cleared by centrifugation at 5,000 RPM for 20 min (4°C). The supernatant was filtered via a glass filter followed by sterilization via 0.2 μm filter (both filters were from Millipore Co., Bedford, MA). This debris-free
Results
Meconium instillation induced acute inflammatory reaction in the lungs accompanied with massive cell death (Zagariya et al., 2000). Using ISEL-labeling, we found fragmented DNA in numerous airways and alveolar epithelial nuclei (Fig. 1B). The airway and alveolar ISEL-positive staining demonstrate a presence of apoptotic cells in meconium group characterized by DNA fragmentation. ISEL-positive cell numbers were significantly (p < 0.05) increased in the lungs in response to meconium instillation.
Discussion
Previously we showed that meconium induces significant cell death by apoptosis but which cells are primarily affected by meconium was not known. The present studies demonstrate that lung airway epithelial cells are major site of meconium-induced injury. This observation has a great importance for understanding the implications of meconium-induced lung injury. We present several critical evidences in support of our hypothesis: ISEL-staining, caspase 3 expression, ANGEN expression and A549 cell
Acknowledgments
This work was supported by a Thrasher Research Foundation grant.
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