Article

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: 4.15). 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.

0 Bookmarks
 · 
74 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE:: To explore the relationship between lung function and serum retinol (SR) in cystic fibrosis (CF) patients. METHODS:: This is a cross-sectional study conducted in a group of 98 young CF patients (6.8-22.3 years of age), after the exclusion of those with pulmonary exacerbation, vitamin A deficiency or other risks, from an initial group of 124 cases. RESULTS:: Data of forced expiratory volume in one second (FEV1) were widely scattered (87.7 ± 16.9%). They were similar in the 78 pancreatic insufficient patients (PI) and those 11 pancreatic sufficient (PS). Serum retinol (SR) (56.6 ± 18.4 μg/dL) was above the 2.5 percentile of healthy people in the whole group, though 31 patients were situated above the 97.5 percentile (higher value: 110 μg/dL). The FEV1 in these latter was noticeably higher than in those within the normal range (93.6 ± 14.0 vs. 85.0 ± 17.6 μg/dL; p < 0.05). The Z score of SR correlated positively with FEV1 (r = 0.364; p = 0.000), after adjusting data for gender, age, BMI and pancreatic function. The odds ratio for a FEV1 greater than 80% is 3.78 in patients with SR above the 97.5 P, versus only 0.26 in those within the normal range. There were no cases with retinol toxicity. CONCLUSION:: FEV1 of young CF patients correlates positively with SR, regardless of age, pancreatic function or nutritional condition.Those with a moderately high retinol (up to 110 μg/dl) maintain the best respiratory function (FEV1 ≥ 80% in more than 90% of them) without any signs of toxicity.
    Journal of pediatric gastroenterology and nutrition 02/2013; · 2.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 RARalpha to the plasma membrane, where it colocalizes with Akt. Immunoprecipitation assays showed that ATRA promotes Akt activation mediated by RARalpha-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 RARbeta2 and p53. In contrast, over-expression of the inactive form of Akt restores RARbeta2 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. · 5.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic pulmonary obstructive disease (COPD) is the fourth leading cause of death worldwide, however, the pathogenic factors and mechanisms are not fully understood. Pulmonary emphysema is one of the major components of COPD and is thought to result from oxidative stress, chronic inflammation, protease-antiprotease imbalance and lung epithelial (LE) cell apoptosis. In our previous studies, COPD patients were noted to have higher levels of placenta growth factor (PlGF) in serum and bronchoalveolar lavage fluid than controls. In addition, transgenic mice overexpressing PlGF developed pulmonary emphysema and exposure to PlGF in LE cells induced apoptosis. Furthermore, intratracheal instillation of porcine pancreatic elastase (PPE) on to PlGF wild type mice induced emphysema, but not in PlGF knockout mice. Therefore, we hypothesized that PPE generates pulmonary emphysema through the upregulation of PlGF expression in LE cells. The elevation of PlGF then leads to LE cell apoptosis. In the present study, we investigated whether PPE induces PlGF expression, whether PlGF induces apoptosis and whether the downstream mechanisms of PlGF are related to LE cell apoptosis. We found that PPE increased PlGF secretion and expression both in vivo and in vitro. Moreover, PlGF-induced LE cell apoptosis and PPE-induced emphysema in the mice were mediated by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways. Given these findings, we suggest that the increase in PlGF and PlGF-induced JNK and p38 MAPK pathways contribute to PPE-induced LE cell apoptosis and emphysema. Regulatory control of PlGF and agents against its downstream signals may be potential therapeutic targets for COPD.
    Cell Death & Disease 01/2013; 4:e793. · 6.04 Impact Factor