Retinoic Acid Inhibits Elastase-Induced Injury in Human Lung Epithelial Cell Lines

Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai, Japan.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 04/2003; 28(3):296-304. DOI: 10.1165/rcmb.4845
Source: PubMed

ABSTRACT The protective effects of retinoic acid on elastase-induced lung epithelial cell injury were studied using elastase extracted from purulent human sputum, the BEAS-2B human bronchial epithelial cell line, A549 human type II lung cell line, and primary cultures of human tracheal epithelial cells. Elastase decreased viability of BEAS-2B cells, A549 cells, and human tracheal epithelial cells in concentration- and time-dependent fashions. Elastase also induced apoptosis of BEAS-2B cells, A549 cells, and the tracheal epithelial cells detected with cell death detection enzyme-linked immunosorbent assay and terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) methods. Retinoic acid alone did not affect the viability of BEAS-2B cells, A549 cells, or the tracheal epithelial cells, and did not induce apoptosis of the cells. However, retinoic acid prevented the decreases in the viability and reduced apoptosis of BEAS-2B cells, A549 cells, and the tracheal epithelial cells induced by elastase. Likewise, retinoic acid inhibited caspase 3 activity in BEAS-2B cells and A549 cells induced by elastase, as well as proteolytic activity of elastase. Furthermore, caspase 3 inhibitor inhibited the elastase-induced apoptosis of the cells. These findings suggest that retinoic acid may inhibit elastase-induced lung epithelial cell injury partly through the inhibition of proteolytic activity of elastase and through the inhibition of caspase 3 activity by elastase. Retinoic acid may, therefore, have protective effects against the elastase-induced lung injury and subsequent development of pulmonary emphysema.

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    • "To investigate the molecular mechanisms of ATRA resistance in lung cancer cells, we investigated the effects of ATRA in regulating the PI3k/Akt pathway in the ATRA-resistant A549 cell line [26,27]. The results revealed a rapid activation of the PI3k/Akt pathway, measured by Akt phosphorylation at its serine 473, within 5 min of ATRA treatment and until 60 min after treatment (Figure 1A). "
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    ABSTRACT: Background All-trans retinoic acid (ATRA) is currently being used in clinical trials for cancer treatment. The use of ATRA is limited because some cancers, such as lung cancer, show resistance to treatment. However, little is known about the molecular mechanisms that regulate resistance to ATRA treatment. Akt is a kinase that plays a key role in cell survival and cell invasion. Akt is often activated in lung cancer, suggesting its participation in resistance to chemotherapy. In this study, we explored the hypothesis that activation of the Akt pathway promotes resistance to ATRA treatment at the inhibition of cell survival and invasion in lung cancer. We aimed to provide guidelines for the proper use of ATRA in clinical trials and to elucidate basic biological mechanisms of resistance. Results We performed experiments using the A549 human lung adenocarcinoma cell line. We found that ATRA treatment promotes PI3k-Akt pathway activation through transcription-independent mechanisms. Interestingly, ATRA treatment induces the translocation of RARα to the plasma membrane, where it colocalizes with Akt. Immunoprecipitation assays showed that ATRA promotes Akt activation mediated by RARα-Akt interaction. Activation of the PI3k-Akt pathway by ATRA promotes invasion through Rac-GTPase, whereas pretreatment with 15e (PI3k inhibitor) or over-expression of the inactive form of Akt blocks ATRA-induced invasion. We also found that treatment with ATRA induces cell survival, which is inhibited by 15e or over-expression of an inactive form of Akt, through a subsequent increase in the levels of the active form of caspase-3. Finally, we showed that over-expression of the active form of Akt significantly decreases expression levels of the tumor suppressors RARβ2 and p53. In contrast, over-expression of the inactive form of Akt restores RARβ2 expression in cells treated with ATRA, indicating that activation of the PI3k-Akt pathway inhibits the expression of ATRA target genes. Conclusion Our results demonstrate that rapid activation of Akt blocks transcription-dependent mechanism of ATRA, promotes invasion and cell survival and confers resistance to retinoic acid treatment in lung cancer cells. These findings provide an incentive for the design and clinical testing of treatment regimens that combine ATRA and PI3k inhibitors for lung cancer treatment.
    Molecular Cancer 05/2013; 12(1):44. DOI:10.1186/1476-4598-12-44 · 4.26 Impact Factor
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    • "Kennedy and collaborators treated premature infants with vitamin A and observed a reduction in the incidence of bronchopulmonary diseases and a reduction in the mortality [25]. Retinoids also restricted inflammation by reducing the cell death and extracellular matrix degradation [26, 27]. "
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    ABSTRACT: In this work, we evaluate the lung retinoids content to study the possible difference between male and female mice during prenatal development and to comprehend if the vitamin A metabolism is similar in both genders. The study occurred between developmental days E15 and E19, and the retinol and retinyl palmitate lung contents were determined by HPLC analysis. We established two main groups: the control, consisting of foetuses obtained from pregnant females without any manipulation, and vitamin A, composed of foetuses from pregnant females submitted to vitamin A administration on developmental day E14. Each of these groups was subdivided by gender, establishing the four final groups. In the lung of control group, retinol was undetected in both genders and retinyl palmitate levels exhibited a sexual dimorphism. In the vitamin A group, we detected retinol and retinyl palmitate in both genders, and we observed a more evident sexual dimorphism for both retinoids. Our study also indicates that, from developmental day E15 to E19, there is an increase in the retinoids content in foetal lung and a gender difference in the retinoids metabolism. In conclusion, there is a sexual dimorphism in the lung retinoids content and in its metabolism during mice development.
    Critical care research and practice 01/2013; 2013:760305. DOI:10.1155/2013/760305
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    • "Recent laboratory evidence suggests that vitamin A could have protective effects on the respiratory status of patients with cystic fibrosis (CF). Thus, while elastinolytic proteinases (elastases) constitute a likely cause of tissue injury in the lung in CF [1], vitamin A (retinoic acid, 100 nM), has been shown to protect against elastase-induced lung damage in bronchial epithelial cell lines in culture [2]. In addition, retinoic acid (1 AM) has an anti-oxidant effect in the lung, protecting against hyperoxia-mediated cell-cycle arrest of lung alveolar epithelial cells by preserving late G1 cyclin activities [3]. "
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    ABSTRACT: Laboratory evidence suggests that vitamin A could have a protective effect on respiratory status in patients with cystic fibrosis (CF). This study shows a significant correlation between serum vitamin A concentrations and every aspect of lung function tested in 38 patients with stable CF. Serum vitamin D and vitamin E concentrations were also measured but did not show any significant correlations with lung function.
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