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1.
Chinese Medical Journal ; (24): 2175-2185, 2021.
Article in English | WPRIM | ID: wpr-921109

ABSTRACT

BACKGROUND@#Macrophages are involved in the pathogenesis of idiopathic pulmonary fibrosis, partially by activating lung fibroblasts. However, how macrophages communicate with lung fibroblasts is largely unexplored. Exosomes can mediate intercellular communication, whereas its role in lung fibrogenesis is unclear. Here we aim to investigate whether exosomes can mediate the crosstalk between macrophages and lung fibroblasts and subsequently induce fibrosis.@*METHODS@#In vivo, bleomycin (BLM)-induced lung fibrosis model was established and macrophages infiltration was examined. The effects of GW4869, an exosomes inhibitor, on lung fibrosis were assessed. Moreover, macrophage exosomes were injected into mice to observe its pro-fibrotic effects. In vitro, exosomes derived from angiotensin II (Ang II)-stimulated macrophages were collected. Then, lung fibroblasts were treated with the exosomes. Twenty-four hours later, protein levels of α-collagen I, angiotensin II type 1 receptor (AT1R), transforming growth factor-β (TGF-β), and phospho-Smad2/3 (p-Smad2/3) in lung fibroblasts were examined. The Student's t test or analysis of variance were used for statistical analysis.@*RESULTS@#In vivo, BLM-treated mice showed enhanced infiltration of macrophages, increased fibrotic alterations, and higher levels of Ang II and AT1R. GW4869 attenuated BLM-induced pulmonary fibrosis. Mice with exosomes injection showed fibrotic features with higher levels of Ang II and AT1R, which was reversed by irbesartan. In vitro, we found that macrophages secreted a great number of exosomes. The exosomes were taken by fibroblasts and resulted in higher levels of AT1R (0.22 ± 0.02 vs. 0.07 ± 0.02, t = 8.66, P = 0.001), TGF-β (0.54 ± 0.05 vs. 0.09 ± 0.06, t = 10.00, P < 0.001), p-Smad2/3 (0.58 ± 0.06 vs. 0.07 ± 0.03, t = 12.86, P < 0.001) and α-collagen I (0.27 ± 0.02 vs. 0.16 ± 0.01, t = 7.01, P = 0.002), and increased Ang II secretion (62.27 ± 7.32 vs. 9.56 ± 1.68, t = 12.16, P < 0.001). Interestingly, Ang II increased the number of macrophage exosomes, and the protein levels of Alix (1.45 ± 0.15 vs. 1.00 ± 0.10, t = 4.32, P = 0.012), AT1R (4.05 ± 0.64 vs. 1.00 ± 0.09, t = 8.17, P = 0.001), and glyceraldehyde-3-phosphate dehydrogenase (2.13 ± 0.36 vs. 1.00 ± 0.10, t = 5.28, P = 0.006) were increased in exosomes secreted by the same number of macrophages, indicating a positive loop between Ang II and exosomes production.@*CONCLUSIONS@#Exosomes mediate intercellular communication between macrophages and fibroblasts plays an important role in BLM-induced pulmonary fibrosis.


Subject(s)
Angiotensin II , Animals , Bleomycin/toxicity , Exosomes , Fibroblasts , Lung , Macrophages , Mice , Mice, Inbred C57BL , Pulmonary Fibrosis/chemically induced , Receptor, Angiotensin, Type 1
2.
Article in Chinese | WPRIM | ID: wpr-286897

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the effect of angiotension II (AngII) on the activation of NLRP3 inflammasome and the expression of interleukin-1β (IL-1β) in human umbilical vein endothelial cells (HUVECs).</p><p><b>METHODS</b>HUVECs cultured in vitro were treated with different concentrations of AngII for varying lengths of time to determine the optimal concentration and time for AngII exposure. To test the impact of different agents on the effect of AngII exposure, HUVECs were pretreated with AngII receptor blocker losartan, NAD(P)H inhibitor DPI and H(2)O(2) scavenger CAT, caspase 1 inhibitor YVAD, or NLRP3 siRNA for silencing NLRP3, and the protein levels of NOX4, NLRP3, caspase-1 and IL-1β in HUVECs were analyzed by Western blotting.</p><p><b>RESULTS</b>AngII treatment at the optimal concentration (10(-9) mol/L) for 12 h significantly increased the protein levels of NOX4, NLRP3, caspase1 and IL-1β in HUVECs. Pretreatment with losartan, DPI, CAT, YVAD, or NLRP3 siRNA all attenuated the effects of AngII on the cells.</p><p><b>CONCLUSION</b>AngII can induce vascular inflammation by promoting the production of reactive oxygen species and activating NLRP3 inflammasome to increase the protein expression of IL-1β in HUVECs.</p>


Subject(s)
Adaptor Proteins, Signal Transducing , Pharmacology , Angiotensin II , Pharmacology , Blotting, Western , Carrier Proteins , Metabolism , Caspase 1 , Metabolism , Human Umbilical Vein Endothelial Cells , Metabolism , Humans , Hydrogen Peroxide , Inflammasomes , Metabolism , Interleukin-1beta , Metabolism , NADPH Oxidase 4 , NADPH Oxidases , Metabolism , NLR Family, Pyrin Domain-Containing 3 Protein , RNA, Small Interfering , Reactive Oxygen Species , Metabolism
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