-Supplemental oxygen therapy (hyperoxia) in preterm babies with respiratory stress is associated with lung injury and the development of bronchopulmonary dysplasia. Endoplasmic reticulum (ER) homeostasis plays critical roles in maintaining cellular functions such as protein synthesis, folding, and secretion. Interruption of ER homeostasis causes ER stress and triggers the unfolded protein response, which can lead to apoptosis in persistently stressed cells. ERp57 is an ER protein and is associated with calreticulin and calnexin in protein glycosylation. In this study, we found hyperoxia downregulated ERp57 in neonatal rat lungs and cultured human endothelial cells. Transient transfection of ERp57 small interfering RNA significantly knocked down ERp57 expression and reduced hyperoxia-or tunicamycin-induced apoptosis in human endothelial cells. Apoptosis was decreased from 26.8 to 9.9% in hyperoxia-exposed cells and from 37.8 to 5.0% in tunicamycin-treated cells. The activation of caspase-3 induced by hyperoxia or tunicamycin was diminished and immunoglobulin heavy chain-binding protein/ glucose-regulated protein 78-kDa (BiP/GRP78) induction was increased in ERp57 knockdown cells. Overexpression of ERp57 exacerbated hyperoxia-or tunicamycin-induced apoptosis in human endothelial cells. Apoptosis was increased from 10.1 to 14.3% in hyperoxia-exposed cells and from 14.0 to 21.2% in tunicamycintreated cells. Overexpression of ERp57 also augmented tunicamycininduced caspase-3 activation and reduced BiP/GRP78 induction. Our results demonstrate that ERp57 can regulate apoptosis in human endothelial cells. It appears that knockdown of ERp57 confers cellular protection against hyperoxia-or tunicamycin-induced apoptosis by inhibition of caspase-3 activation and stimulation of BiP/GRP78 induction. endoplasmic reticulum stress; unfolded protein response; lung injury; bronchopulmonary dysplasia; immunoglobulin heavy chain-binding protein INFANTS BORN VERY PREMATURELY are at substantial risk for the development of bronchopulmonary dysplasia (BPD), a form of neonatal chronic lung disease (3). Supplemental oxygen therapy (hyperoxia) is commonly administered to premature infants to maintain acceptable systemic oxygen level. Reactive oxygen species (ROS) generated by hyperoxia can induce cell death, cause lung tissue injury, and result in abnormal lung repair (1,5,36), which may disrupt postnatal alveolarization and pulmonary vascularization and lead to development of BPD. Even very premature infants who do not develop the complete diagnostic criteria for BPD may demonstrate pulmonary dysfunction during the first year of life (37, 41).The pathogenesis of BPD is not fully understood and may vary from baby to baby in the relative importance of the multiple contributing injurious factors thought to be involved. Oxygen toxicity caused by oxygen therapy/hyperoxia is believed to be one of the major contributing factors (17). Supplemental oxygen therapy produces ROS, which can damage cell components by inducing DNA damage and protein and...
Navarro A, Perez RE, Rezaiekhaligh MH, Mabry SM, Ekekezie II. Polarized migration of lymphatic endothelial cells is critically dependent on podoplanin regulation of Cdc42.
Perez RE, Navarro A, Rezaiekhaligh MH, Mabry SM, Ekekezie II. TRIP-1 regulates TGF-1-induced epithelial-mesenchymal transition of human lung epithelial cell line A549. Am J Physiol Lung Cell Mol Physiol 300: L799 -L807, 2011. First published March 4, 2011 doi:10.1152/ajplung.00350.2010.-Epithelialmesenchymal transition (EMT) is a process by which epithelial cells undergo conversion to a mesenchymal phenotype contributing to wound repair by fibrosis and to cancer cell acquisition of invasive ability. Recently, we showed that type II TGF- receptor interacting protein-1 (TRIP-1), a protein identified as a phosphorylation target of the TGF- type II receptor kinase and as a functional component of eukaryotic translation initiator factor 3 (eiF3) multiprotein complex, is a novel modulator of fibroblast collagen contraction, an important step in wound repair stimulated by TGF-1 action. TGF-1 drives EMT, but it is not known whether TRIP-1 expression influences EMT induction. To investigate whether TRIP-1 plays a role in EMT induction we studied the effect of downregulating TRIP-1 expression in the well-characterized A549 model of TGF-1 induction of EMT. Here we report that short hairpin RNA (shRNA)-mediated depletion of TRIP-1 gene transcripts in A549 cells promotes EMT as assessed by changes in phenotypic markers, morphology, and migrative ability. Knockdown of TRIP-1 dramatically increased A549 responsiveness to TGF-1 induction of EMT. Mechanistically, a pathway involving increased TGF- type II receptor level, enhanced Smad3 phosphorylation, and the transcription factor SLUG is implicated. Altogether, the findings point to regulation of endogenous TRIP-1 protein expression as a potential strategy to target EMT, and related invasive behavior, in cancer cells.transforming growth factor-; type II transforming growth factor- receptor interacting protein-1
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