Effect of preventive or therapeutic treatment with angiotensin 1–7 in a model of bleomycin-induced lung fibrosis in mice

Rago, Flávia; Melo, Eliza Mathias; Kraemer, Lucas; Galvão, Izabela; Cassali, Geovanni Dantas; Santos, Robson Augusto Souza; Russo, Remo C.; Teixeira, Mauro Martins

doi:10.1002/jlb.ma1218-490rr

Cited by 18 publications

(13 citation statements)

References 28 publications

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“…To prove this theory right, the immunohistochemical expression of TGF-β was assessed in histological sections of lungs with BLM-induced pulmonary fibrosis. As expected, untreated animals presented the greatest counts of TGF-β-expressing cells, which agrees with other studies previously reported [ 56 , 82 , 83 ]. The significant decrease in pulmonary cells expressing TGF-β in EOCW-treated groups at 100 and 200 mg/kg, as well as in the deflazacort-treated group, is fully supported by the analysis of α-SMA-positive cells, attesting to the close relation between this cytokine and myofibroblast differentiation.…”

Section: Discussionsupporting

confidence: 93%

“…In addition, as also observed in the current study, other investigations have demonstrated the attenuation of the severity of the pulmonary fibrosis through the use of drugs that suppress TGF-β expression, such as halofuginone, crocin [ 79 ], and amitriptyline [ 9 ]. Oral administration of angiotensin 1–7, a heptapeptide with anti-inflammatory activity, in a model of BLM-induced lung fibrosis in mice, decreased inflammation and collagen deposition, as well as ameliorated lung function [ 83 ], whereas the incubation of human lung fibroblasts with A779, an angiotensin 1–7 agonist, has shown to reduce levels of TGF-β and collagen type [ 84 ]. These data seem to support the relation between anti-inflammatory agents and downregulation of TGF-β, with consequent reduction of fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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Cymbopogon winterianus Essential Oil Attenuates Bleomycin-Induced Pulmonary Fibrosis in a Murine Model

et al. 2021

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The essential oil of Cymbopogon winterianus (EOCW) is a natural product with antioxidant, anti-inflammatory, and antifibrotic properties. We studied the effect of EOCW in the progression of histological changes of pulmonary fibrosis (PF) in a rodent model. The oil was obtained by hydrodistillation and characterized using gas chromatography–mass spectrometry. Intratracheal instillation of bleomycin was performed in 30 rats to induce PF, while Sham animals were subjected to instillation of saline solution. The treatment was performed using daily oral administration of distilled water, EOCW at 50, 100, and 200 mg/kg, and deflazacort (DFC). After 28 days, hemogram and bronchoalveolar lavage fluid (BALF), tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were assayed. Histological grading of PF, immunohistochemical expression of α-smooth muscle actin (α-SMA), and transforming growth factor-β (TGF-β) were also analyzed. The EOCW major compounds were found to be citronellal, geraniol, and citronellol. EOCW significantly reduced inflammation in BALF, reduced MDA levels, and increased SOD activity. EOCW attenuated histological grading of PF and reduced immunohistochemical expression of α-SMA and TGF-β in a dose-dependent way, likely due to the reduction of oxidative stress, inflammation, and TGF-β-induced myofibroblast differentiation.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Cymbopogon winterianus Essential Oil Attenuates Bleomycin-Induced Pulmonary Fibrosis in a Murine Model

et al. 2021

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“…1 Previous studies by our group found that macrophage activation, myofibroblast differentiation, and epithelial-mesenchymal transition (EMT) are important factors in the pathogenesis of silicosis, 2,3 while several other studies have confirmed that activation of the local renin-angiotensin system (RAS) in lung tissue is involved in the development of pulmonary fibrosis. [4][5][6] However, the pathomechanisms of silicosis remain to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

<p>ACE2 Attenuates Epithelial-Mesenchymal Transition in MLE-12 Cells Induced by Silica</p>

et al. 2020

DDDT

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The role of angiotensin-converting enzyme 2 (ACE2) in silicosis remains unknown, although previous studies have suggested that ACE2 may be beneficial. We, therefore, investigated the effect of ACE2 on silicosis, particularly with regard to its role in regulating the epithelial-mesenchymal transition (EMT) induced by silica, with the aim to uncover a new potential target for the treatment of pulmonary fibrosis. Materials and Methods: We employed wild-type mice treated with diminazene aceturate (DIZE, an ACE2 activator, 15 mg/kg/day for 4 weeks), hACE2-transgenic mice (overexpress the ACE2 gene), and the mouse lung type II epithelial cell line treated with DIZE (10 −7 M for 48 h) or angiotensin-(1-7) [Ang-(1-7)] (10 −4 M for 48 h), following induced fibrotic responses to determine the protective potential of ACE2. Silicosis models were established by orotracheal instillation of SiO 2 (2.5 mg/mouse). Immunostaining was used to determine αsmooth muscle actin (α-SMA) expression. The activities of angiotensin-converting enzyme (ACE) and ACE2 and the levels of angiotensin II (Ang II) and Ang-(1-7) were detected by enzyme-linked immunosorbent assay. The mRNA expression of ACE and ACE2, and protein expression of the renin-angiotensin system (RAS) components and EMT indicators were studied by qRT-PCR and Western blot, respectively. Results: DIZE treatment and overexpression of ACE2 markedly inhibited the formation of silica-induced lung fibrosis and increased the level of E-cadherin, with concomitant downregulation of pro-collagen, vimentin, and α-SMA via RAS signaling. Furthermore, DIZE and Ang-(1-7) attenuated the EMT and collagen deposition induced by silica in MLE-12 cells. Moreover, these effects were abrogated by MLN-4760 (a specific ACE2 inhibitor) and A779 (a specific Mas receptor blocker). Conclusion: The overexpression of ACE2 and treatment with DIZE can ameliorate EMT in silicotic mice via activation of the ACE2-Ang-(1-7)-Mas receptor axis, and these changes are accompanied by suppression of the ACE-Ang II-AT1 receptor axis.

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“…The cannula was fixed to the trachea by a silk thread and connected to the mechanical ventilator. Respiratory function was analyzed using a mechanical ventilator for small animals (FlexiVent, Scireq, Montréal, Canada) [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

Assessment of Alamandine in Pulmonary Fibrosis and Respiratory Mechanics in Rodents

Fernandes

Dias

Jaques

et al. 2021

J Renin Angiotensin Aldosterone Syst

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Introduction. Pulmonary fibrosis (PF) is characterized by an accelerated decline in pulmonary function and has limited treatment options. Alamandine (ALA) is a recently described protective peptide of the renin-angiotensin system (RAS) with essential tasks in several conditions. Our group previously demonstrated that ALA is reduced by 365% in the plasma of patients with idiopathic PF, and thus, it is plausible to believe that stimulation of this peptide could represent an important therapeutic target. In this sense, this study investigates the effects of ALA in an experimental model of PF. Materials and Methods. Bleomycin (BLM) was administrated in Wistar rats, and these fibrotic animals were treated with ALA for 14 days. Body weight, histology, respiratory, and hemodynamic parameters were analyzed to study the effects of ALA. Results. ALA treatment attenuated the development of fibrosis ( P < 0.0001 ), reduced respiratory system elastance ( P < 0.0001 ), and preserved weight gain ( P < 0.0001 ) in fibrotic animals without affecting the autonomic control of blood pressure and heart rate. Conclusion. The data from this study demonstrate the potential of ALA to alleviate pulmonary fibrosis and improve respiratory system mechanics in vivo. The promising results encourage more detailed investigations of the potential of ALA as a future and efficient antifibrotic.

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Effect of preventive or therapeutic treatment with angiotensin 1–7 in a model of bleomycin-induced lung fibrosis in mice

Cited by 18 publications

References 28 publications

Cymbopogon winterianus Essential Oil Attenuates Bleomycin-Induced Pulmonary Fibrosis in a Murine Model

Cymbopogon winterianus Essential Oil Attenuates Bleomycin-Induced Pulmonary Fibrosis in a Murine Model

<p>ACE2 Attenuates Epithelial-Mesenchymal Transition in MLE-12 Cells Induced by Silica</p>

Assessment of Alamandine in Pulmonary Fibrosis and Respiratory Mechanics in Rodents

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