angiotensin-i and Pulmonary-Fibrosis

A large body of evidence demonstrates that angiotensin II and angiotensin receptors are required for the pathogenesis of experimental lung fibrosis. Angiotensin has a number of profibrotic effects on lung parenchymal cells that include the induction of growth factors for mesenchymal cells, extracellular matrix molecules, cytokines and increased motility of lung fibroblasts. Angiotensin is also proapoptotic for lung epithelial cells, and is synthesized by a local system (i.e., entirely within the lung tissue) after lung injury by a variety of agents of both xenobiotic and endogenous origins. Recent evidence shows that the counterregulatory molecule angiotensin 1-7, the product of the enzyme ACE-2, inhibits epithelial cell apoptosis and thus acts as an antifibrotic epithelial survival factor. This manuscript reviews the evidence supporting a role for angiotensin in lung fibrogenesis and discusses the signalling mechanisms underlying its action on lung parenchymal cells important in the pathogenesis of pulmonary fibrosis.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Angiotensins; Animals; Apoptosis; Cytoprotection; Humans; Lung Injury; MAP Kinase Kinase 4; Peptide Fragments; Peptidyl-Dipeptidase A; Pulmonary Fibrosis; Respiratory Mucosa; Signal Transduction

Topics: Alveolar Epithelial Cells; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Betacoronavirus; Coronavirus Infections; COVID-19; Host Microbial Interactions; Humans; Lung; Pandemics; Peptide Fragments; Peptidyl-Dipeptidase A; Pneumonia, Viral; Pulmonary Fibrosis; Receptors, Coronavirus; Receptors, Virus; Renin-Angiotensin System; SARS-CoV-2; Transforming Growth Factor beta

The hedgehog (HH) signaling pathway plays an important role in lung development, but its significance in silicosis is unclear. We showed that in human coal pneumoconiosis autopsy specimens, Sonic Hedgehog (SHH) and the Glioma-associated oncogene homolog transcription factors family (GLI) 1 proteins were up-regulated, whereas Patch-1 (PTC) was down-regulated. The protein levels of SHH, smoothened (SMO), GLI1, GLI2, α-smooth muscle actin (α-SMA) and collagen type Ⅰ (Col Ⅰ) were also elevated gradually in the bronchoalveolar lavage fluid (BALF) of different stages of coal pneumoconiosis patients, dynamic silica-inhalation rat lung tissue and MRC-5 cells induced by Ang II at different time points, whereas the PTC and GLI3 levels were diminished gradually. Ac-SDKP, an active peptide of renin-angiotensin system (RAS), is an anti-fibrotic tetrapeptide. Targeting RAS axis also has anti-silicotic fibrosis effects. However, their roles on the HH pathway are still unknown. Here, we reported that Ac-SDKP + Captopril, Ac-SDKP, Captopril, or Ang (1-7) could alleviate silicotic fibrosis and collagen deposition, as well as improve the lung functions of silicotic rat. These treatments decreased the expression of SHH, SMO, GLI1, GLI2, α-SMA, and Col Ⅰ and increased the expression of PTC and GLI3 on both the silicotic rat lung tissue and MRC-5 cells induced by Ang II. We also reported that Ang II may promote myofibroblast differentiation via the GLI1 transcription factor and independently of the SMO receptor.

Topics: Adult; Aged; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Anthracosis; Captopril; Cell Differentiation; Cell Line; Collagen; Disease Models, Animal; Female; Hedgehog Proteins; Humans; Lung; Male; Middle Aged; Myofibroblasts; Oligopeptides; Peptide Fragments; Pulmonary Fibrosis; Rats, Wistar; Renin-Angiotensin System; Signal Transduction; Silicosis

Idiopathic pulmonary fibrosis is characterized by aberrant fibroblast activation and excessive collagen deposition that may eventually lead to organ dysfunction. Lung fibrosis is frequently observed in cancer patients undergoing bleomycin (BLM) treatment. Therefore, BLM instillation in mice is the most frequent model used to investigate pulmonary fibrosis. Angiotensin 1-7 [Ang-(1-7)] is a heptapeptide with anti-inflammatory and proresolving activity. Here, we studied the effects of preventive and therapeutic oral administration of Ang-(1-7) in a model of BLM-induced lung fibrosis in mice. Male C57Bl/6j mice were instilled with BLM and followed for weight loss and survival or euthanized to examine pulmonary inflammation, fibrosis, and lung function. For preventive treatment, mice were treated with Ang-(1-7) 1 h before instillation and then twice daily. We observed that preventive treatment with Ang-(1-7) decreased weight loss, inflammation and collagen deposition, increased survival, and ameliorated lung function. Therapeutic treatment with Ang-(1-7), starting 3 days after BLM instillation resulted in decreased inflammation, decreased collagen deposition, and ameliorated lung function, although the effects were of lower magnitude than the preventive treatment. Therapeutic treatment with Ang-(1-7) starting 7 or 14 days after BLM instillation failed to alter any of the changes observed. Therefore, although oral preventive treatment with Ang-(1-7) is effective to decrease pulmonary inflammation, fibrosis, and functional changes induced by BLM, therapeutic effects are much less significant, arguing against its use in patients with chronic fibrosis. It remains to be determined whether other proresolving molecules will have better therapeutic effects in the context of chronic pulmonary fibrosis.

Topics: Angiotensin I; Animals; Bleomycin; Disease Models, Animal; Leukocytes, Mononuclear; Lung; Male; Mice, Inbred C57BL; Peptide Fragments; Pulmonary Fibrosis; Survival Analysis

Early pulmonary fibrosis is the leading cause of poor prognosis in patients with acute respiratory distress syndrome (ARDS). However, whether the renin-angiotensin system (RAS) can serve as a therapeutic target is unknown. In this study, an animal model of early pulmonary fibrosis was established via the LPS three-hit regimen. Afterwards, the animals were treated with intraperitoneal injections of Ang-(1-7), AVE0991, or A779 once per day for 20 days. The plasma and BALF AngII levels of the animals were increased, while there were no significant changes in Ang-(1-7) levels in lung tissue after LPS treatment. Furthermore, the AT1R protein levels were significantly increased and the Mas levels were significantly decreased on days 14 and 21. Administration of Ang-(1-7) downregulated LPS-induced AT1R mRNA expression, which was upregulated by A779. The expression of Mas mRNA responded in the opposite direction relative to AT1R. Moreover, LPS caused decreased levels of Mas and E-cadherin and increased AT1R, Vimentin, and Src phosphorylation levels. Ang-(1-7) or AVE0991 blocked these effects but was counteracted by A779 treatment. Our findings suggested that AngII and AT1R levels exhibit opposite dynamic trends during LPS-induced early pulmonary fibrosis, as do Ang-(1-7) and Mas. Ang-(1-7) exerts protective effects against early pulmonary fibrosis, mainly by regulating the balance between AngII and AT1R and between Ang-(1-7) and Mas and by inhibiting Src kinase activation.

Topics: Angiotensin I; Angiotensin II; Animals; Bronchoalveolar Lavage Fluid; Cadherins; Drug Evaluation, Preclinical; Imidazoles; Lipopolysaccharides; Lung; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pulmonary Fibrosis; Random Allocation; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Transforming Growth Factor beta; Vasodilator Agents; Vimentin

What is the central question of this study? What are the effects of the antifibrotic peptide acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) on the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas axis during the occurrence and progression of silicosis? What is the main finding and its importance? Ac-SDKP inhibited lung fibrosis in rats exposed to silica by activation of the ACE2-angiotensin-(1-7)-Mas axis. Angiotensin-(1-7) potentially promotes Ac-SDKP by increasing the level of meprin α, the major synthetase of Ac-SDKP. Thus, the interaction Ac-SDKP and angiotesin-(1-7) in silicosis could provide a new therapeutic strategy.. The central role of angiotensin-converting enzyme (ACE) in the occurrence and progression of silicosis has been established. The antifibrotic peptide acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) can be degraded by ACE. The ACE2-angiotensin-(1-7)-Mas axis is protective and acts to counterbalance the detrimental effects of ACE-angiotensin II (Ang II)-Ang II type 1 receptor and exerts antifibrotic effects. Here, we demonstrate an interaction between Ac-SDKP and Ang-(1-7) in the inhibition of collagen deposition and myofibroblast differentiation in rats exposed to silica. Treatment with Ac-SDKP increased the level of ACE2-Ang-(1-7)-Mas in rats or in cultured fibroblasts and decreased the levels of collagen type I and α-smooth muscle actin. Furthermore, exogenous Ang-(1-7) had similar antifibrotic effects and increased the level of meprin α, a major Ac-SDKP synthetase, both in vivo and in vitro. Compared with non-silicotic patients exposed to silica, the level of serum ACE was increased in patients with silicosis phase III; the levels of Ang II and Ang-(1-7) were high in patients with silicosis phase II; and the level of Ac-SDKP was high in the silicosis phase III group. These data imply that Ac-SDKP and Ang-(1-7) have an interactive effect as regulatory peptides of the renin-angiotensin system and exert antifibrotic effects.

Topics: Actins; Angiotensin I; Angiotensin II; Animals; Cell Differentiation; Cells, Cultured; Collagen; Collagen Type I; Fibroblasts; Humans; Male; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pulmonary Fibrosis; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Silicosis

Angiotensin-(1-7) [Ang-(1-7)] has been shown to play a significant role in the pathogenesis of lung inflammation via Mas receptor; however, its effect in chronic obstructive pulmonary disease (COPD) remains unknown. To explore the effect of Ang-(1-7) on a cigarette smoke (CS) exposure-induced COPD model, 40 C57BL/6J mice were divided into four groups (n = 10) and exposed to air or CS for 8 weeks. After that, they were treated with saline or Ang-(1-7) at 0.3 mg/kg for 2 weeks by subcutaneous infusion using osmotic pump. The day following drug/vehicle challenge, lung function was examined and bronchoalveolar lavage (BAL) was performed. Chemokine (C-X-C motif) ligand 1, interleukin-6, and tumor necrosis factor-α protein levels in BAL fluid were determined using ELISA; the corresponding mRNA levels in lung tissues were measured using RT-PCR. Mas1 receptor, pIκBα, IκBα, nuclear NF-κB-p65 protein, pERK1/2, ERK2, pp38, and p38 proteins expression in lung tissues were examined by immunohistochemical staining and western blotting. Ang-(1-7) challenge had no effect on the decreased lung function and emphysema induced by CS exposure. However, Ang-(1-7) treatment blocked CS exposure-induced lung inflammatory responses and lung fibrosis, as determined by Masson's Trichrome staining. Exposure to CS for 8 weeks caused irreversible loss of lung function and emphysema, which could not be reversed by Ang-(1-7) treatment. Thus, the beneficial effect of Ang-(1-7) may be confined to pulmonary inflammation and fibrosis.

Topics: Angiotensin I; Animals; Bronchoalveolar Lavage Fluid; Chemokine CXCL1; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Injections, Subcutaneous; Interleukin-6; Lung; Male; Mice; Mice, Inbred C57BL; NF-KappaB Inhibitor alpha; Nicotiana; Peptide Fragments; Phosphorylation; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Receptors, G-Protein-Coupled; Signal Transduction; Smoke; Transcription Factor RelA; Tumor Necrosis Factor-alpha

MicroRNA-21 (mir-21) induced by angiotensin II (AngII) plays a vital role in the development of pulmonary fibrosis, and the NLRP3 inflammasome is known to be involved in fibrogenesis. However, whether there is a link between mir-21 and the NLRP3 inflammasome in pulmonary fibrosis is unknown. Angiotensin-converting enzyme 2/angiotensin(1-7) [ACE2/Ang(1-7)] has been shown to attenuate AngII-induced pulmonary fibrosis, but it is not clear whether ACE2/Ang(1-7) protects against pulmonary fibrosis by inhibiting AngII-induced mir-21 expression. This study's aim was to investigate whether mir-21 activates the NLRP3 inflammasome and mediates the different effects of AngII and ACE2/Ang(1-7) on lung fibroblast apoptosis and collagen synthesis. In vivo, AngII exacerbated bleomycin (BLM)-induced lung fibrosis in rats, and elevated mir-21 and the NLRP3 inflammasome. In contrast, ACE2/Ang(1-7) attenuated BLM-induced lung fibrosis, and decreased mir-21 and the NLRP3 inflammasome. In vitro, AngII activated the NLRP3 inflammasome by up-regulating mir-21, and ACE2/Ang(1-7) inhibited NLRP3 inflammasome activation by down-regulating AngII-induced mir-21. Over-expression of mir-21 activated the NLRP3 inflammasome via the ERK/NF-κB pathway by targeting Spry1, resulting in apoptosis resistance and collagen synthesis in lung fibroblasts. These results indicate that mir-21 mediates the inhibitory effect of ACE2/Ang(1-7) on AngII-induced activation of the NLRP3 inflammasome by targeting Spry1 in lung fibroblasts.

Topics: Angiotensin I; Angiotensin II; Animals; Apoptosis; Bleomycin; Cells, Cultured; Collagen Type I; Fibroblasts; Inflammasomes; Lung; Male; MAP Kinase Signaling System; MicroRNAs; Nerve Tissue Proteins; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Peptide Fragments; Peptide Hormones; Pulmonary Fibrosis; Rats; Rats, Wistar; Signal Transduction

Studies have shown that angiotensin-converting enzyme 2 (ACE2) plays modulating roles in lung pathophysiology, including pulmonary fibrosis (PF) and acute lung injury. Pulmonary fibrosis is a common complication in these interstitial lung diseases, and PF always has a poor prognosis and short survival. To date, there are few promising methods for treating PF, and they are invariably accompanied by severe side effects. Recent studies have showed that the traditional Chinese herbal extract, osthole, had beneficial effects on lipopolysaccharide (LPS) induced acute lung injury (ALI) via an ACE2 pathway. Here we further investigated the protective effects of osthole on bleomycin induced pulmonary fibrosis and attempted to determine the underlying mechanism. PF mode rats were induced by bleomycin (BLM) and then subsequently administered osthole. Histopathological analyses were employed to identify PF changes. The results showed that BLM resulted in severe PF and diffuse lung inflammation, together with significant elevation of inflammatory factors and a marked increase in expression of angiotensin II (ANG II) and transforming growth factor-beta 1 (TGF-β1). ACE2 and angiotensin-(1-7) [ANG-(1-7)] were both greatly reduced after BLM administration. Meanwhile, osthole treatment attenuated BLM induced PF and inflammation, decreased the expression of these inflammatory mediators, ANG II, and TGF-β1, and reversed ACE2 and ANG-(1-7) production in rat lungs. We conclude that osthole may exert beneficial effects on BLM induced PF in rats, perhaps via modulating the ACE2/ANG-(1-7) axis and inhibiting lung inflammation pathways.

Topics: Acute Lung Injury; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Anti-Inflammatory Agents; Bleomycin; Collagen; Coumarins; Cytokines; Edema; Lung; Male; Peptide Fragments; Peptidyl-Dipeptidase A; Pulmonary Fibrosis; Rats, Sprague-Dawley; Transforming Growth Factor beta1

Reactive oxygen species (ROS) generated by NADPH oxidase-4 (NOX4) have been shown to initiate lung fibrosis. The migration of lung fibroblasts to the injured area is a crucial early step in lung fibrosis. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7) [Ang(1-7)]/Mas axis, which counteracts the ACE/angiotensin II (AngII)/angiotensin II type 1 receptor (AT1R) axis, has been shown to attenuate pulmonary fibrosis. Nevertheless, the exact molecular mechanism remains unclear.. To investigate the different effects of the two axes of the renin-angiotensin system (RAS) on lung fibroblast migration and extracellular matrix accumulation by regulating the NOX4-derived ROS-mediated RhoA/Rho kinase (Rock) pathway.. In vitro, AngII significantly increased the NOX4 level and ROS production in lung fibroblasts, which stimulated cell migration and α-collagen I synthesis through the RhoA/Rock pathway. These effects were attenuated by N-acetylcysteine (NAC), diphenylene iodonium, and NOX4 RNA interference. Moreover, Ang(1-7) and lentivirus-mediated ACE2 (lentiACE2) suppressed AngII-induced migration and α-collagen I synthesis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway. However, Ang(1-7) alone exerted analogous effects on AngII. In vivo, constant infusion with Ang(1-7) or intratracheal instillation with lenti-ACE2 shifted the RAS balance toward the ACE2/Ang(1-7)/Mas axis, alleviated bleomycin-induced lung fibrosis, and inhibited the RhoA/Rock pathway by reducing NOX4-derived ROS.. This study suggests that the ACE2/Ang(1-7)/Mas axis may be targeted by novel pharmacological antioxidant strategies to treat lung fibrosis induced by AngII-mediated ROS.. The ACE2/Ang(1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Cell Movement; Cells, Cultured; Collagen Type I; Collagen Type I, alpha 1 Chain; Fibroblasts; Male; NADPH Oxidase 4; NADPH Oxidases; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pulmonary Fibrosis; Rats, Wistar; Reactive Oxygen Species; Receptors, G-Protein-Coupled; rho-Associated Kinases; rhoA GTP-Binding Protein

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Humans; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A; Pulmonary Fibrosis; rho-Associated Kinases

Accumulating evidence has demonstrated that up-regulation of the angiotensin (Ang)-converting enzyme (ACE)/AngII/AngII type 1 receptor (AT1R) axis aggravates pulmonary fibrosis. The recently discovered ACE2/Ang-(1-7)/Mas axis, which counteracts the activity of the ACE/AngII/AT1R axis, has been shown to protect against pulmonary fibrosis. However, the mechanisms by which ACE2 and Ang-(1-7) attenuate pulmonary fibrosis remain unclear. We hypothesized that up-regulation of the ACE2/Ang-(1-7)/Mas axis protects against bleomycin (BLM)-induced pulmonary fibrosis by inhibiting the mitogen-activated protein kinase (MAPK)/NF-κB pathway. In vivo, Ang-(1-7) was continuously infused into Wistar rats that had received BLM or AngII. In vitro, human fetal lung-1 cells were pretreated with compounds that block the activities of AT1R, Mas (A-779), and MAPKs before exposure to AngII or Ang-(1-7). The human fetal lung-1 cells were infected with lentivirus-mediated ACE2 before exposure to AngII. In vivo, Ang-(1-7) prevented BLM-induced lung fibrosis and AngII-induced lung inflammation by inhibiting the MAPK phosphorylation and NF-κB signaling cascades. However, exogenous Ang-(1-7) alone clearly promoted lung inflammation. In vitro, Ang-(1-7) and lentivirus-mediated ACE2 inhibited the AngII-induced MAPK/NF-κB pathway, thereby attenuating inflammation and α-collagen I production, which could be reversed by the Mas inhibitor, A-779. Ang-(1-7) inhibited AngII-induced lung fibroblast apoptotic resistance via inhibition of the MAPK/NF-κB pathway and activation of the BCL-2-associated X protein/caspase-dependent mitochondrial apoptotic pathway. Ang-(1-7) alone markedly stimulated extracellular signal-regulated protein kinase 1/2 phosphorylation and the NF-κB cascade. Up-regulation of the ACE2/Ang-(1-7)/Mas axis protected against pulmonary fibrosis by inhibiting the MAPK/NF-κB pathway. However, close attention should be paid to the proinflammatory effects of Ang-(1-7).

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Apoptosis; bcl-X Protein; Bleomycin; Cells, Cultured; Collagen Type I; Disease Models, Animal; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Humans; Infusions, Subcutaneous; Lung; Male; MAP Kinase Signaling System; NF-kappa B; Peptide Fragments; Peptidyl-Dipeptidase A; Phosphorylation; Pneumonia; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pulmonary Fibrosis; Rats; Rats, Wistar; Receptors, G-Protein-Coupled

Pulmonary fibrosis (PF) is a common complication in those interstitial lung diseases patients, which will result in poor prognosis and short survival. Traditional therapeutic methods such as glucocorticoid and cytotoxic drugs are insufficient for treating PF and may cause severe side effects. Recent studies showed that traditional Chinese herbal abstraction such as Tanshinone IIA (TIIA) was displayed significant anti-PF effects in animal models. However, the exact mechanisms underlying the protective effects of TIIA were not fully understood. Here we further investigated the protective effects of TIIA and its mechanisms underlying. PF models of rat were induced by bleomycin (BLM); TIIA was administered subsequently. The PF changes were identified by histopathological analyses. The results showed that BLM resulted in severe PF and alveolar inflammation; together with significant elevation of transforming growth factor-β 1 (TGF-β1). Angiotensin-converting enzyme 2 (ACE-2) together with angiotensin-(1-7) [ANG-(1-7)] were both greatly reduced after BLM administration. TIIA treatment notably attenuated BLM induced PF and inflammation, decreased expression of TGF-β1 and reversed ACE-2 and ANG-(1-7) production in rat lungs. Thus we may draw the conclusion that TIIA may exert protective effects on BLM induced PF in rats, and the ACE-2/ANG-(1-7) axis may ascribe to those protective effects.

Topics: Abietanes; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Bleomycin; Humans; Inflammation; Peptide Fragments; Peptidyl-Dipeptidase A; Pulmonary Fibrosis; Rats; Transforming Growth Factor beta

Pulmonary fibrosis occurs in approximately 60% of patients with acute respiratory distress syndrome and has been significantly correlated with a poor outcome. The overexpression of angiotensin (Ang) II can induce lung inflammation and fibrosis. This observation, coupled with the knowledge that Ang-(1-7) is considered to be an endogenous antagonist of Ang II, led us to hypothesize that Ang-(1-7) would prevent lung remodeling in patients with acute respiratory distress syndrome.. The protocol involved five groups: (1) control, (2) lipopolysaccharide (LPS), (3) losartan as a positive control group, (4) Ang-(1-7), and (5) [D-Ala7]-Ang-(1-7) (A779), an antagonist of the Ang-(1-7) receptor. Acute lung injury was induced by an intratracheal injection of LPS 5 mg/kg in C57BL/6 mice. Losartan (10 mg/kg) was administered by gavage daily, starting from 1 d before LPS stimulation. Ang-(1-7) or A779 in saline (100 ng/kg/min) was infused subcutaneously 1 h before acute lung injury induction for 3 or 7 d. The lung tissues were harvested for analysis at day 3 or 7 after injection of LPS.. LPS stimulation resulted in significantly increased inflammation, edema, and lung collagen production. With Ang-(1-7) treatment, the lung fibrosis score and hydroxyproline level were significantly reduced, and the expression of transforming growth factor-β and Smad2/3 were decreased on days 3 and 7. Losartan attenuated lung fibrosis similarly to Ang-(1-7) after LPS exposure. In the A779 group, a tendency was seen to aggravate collagen deposition and lung remodeling.. These findings indicate an antiremodeling role for Ang-(1-7) in acute lung injury, similar to the blocker of Ang II receptor, that might be at least partially mediated through an Ang-(1-7) receptor.

Topics: Acute Lung Injury; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Disease Models, Animal; Lipopolysaccharides; Losartan; Male; Mice; Mice, Inbred C57BL; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pulmonary Fibrosis; Receptors, G-Protein-Coupled; Respiratory Distress Syndrome; Vasodilator Agents

To explore the anti-fibrotic effects of angiotensin (Ang) 1-7 on bleomycin (BLM) -induced pulmonary fibrosis in rats.. Eighteen Wistar male rats were randomly divided into 3 groups, including control group (intratracheal instillation with physiological saline and subcutaneous micro-pump with bi-distilled water at the rate of 0.29 µl/h), BLM group (intratracheal instillation with bleomycin and subcutaneous micro-pump with bi-distilled water at the same rate) and BLM+Ang1-7 group (intratracheal instillation with bleomycin and subcutaneous micro-pump with Ang1-7 at a dose of 25 µg·kg(-1) · h(-1) at the same rate). At Day 28, lung tissues were collected. Histological changes of lungs were evaluated by hematoxylin and eosin and Masson's trichrome stains. Collagen content of lung tissues was assessed by hydroxyprolin concentration. Then the products of protein and RNA were collected. And Western blot and realtime polymerase chain reaction (RT-PCR) were used to detect the protein or mRNA of TGF-β1 and α-collagenI. Human embryonic lung fibroblast (HFL-1) was divided into 5 groups: (1) control group: no stimulation; (2) AngII group: stimulation of AngII (10(-7)mol/L) ; (3) Ang1-7 group: stimulation of Ang1-7 (10(-7)mol/L); (4) Ang1-7 plus AngII group: stimulation by AngII (10(-7)mol/L) with Ang1-7 (10(-7)mol/L) pre-treatment; (5) Ang1-7+AngII+A-779 group: stimulation by AngII and Ang1-7 (10(-7) mol/L) with Mas receptor inhibitor A-779 (10(-6)mol/L) pre-treatment. Then the products of protein and RNA were collected. And QuantiGene and RT-PCR were used to detect the activation of TGF-β1, and α-collagenI mRNA.. Compared with control group, fibrosis score and hydroxyproline concentrations increased significantly in BLM group, but declined in BLM+Ang1-7 group. The difference was statistically significant (P < 0.05). TGF-β1 mRNA, α-collagenI mRNA and α-collagenI protein level were up-regulated by BLM (4.45 ± 0.45 vs 1.00 ± 0.20, 5.14 ± 0.55 vs 1.00 ± 0.08, 1.48 ± 0.34 vs 0.23 ± 0.11) (all P < 0.05); while compared with BLM group, those of BLM+Ang1-7 group were down-regulated (2.80 ± 0.35, 3.10 ± 0.52, 0.49 ± 0.11) (all P < 0.05). In vitro: TGF-β1 mRNA and α-collagen I mRNA level were up-regulated by AngII (1.67 ± 0.26 vs 1.00 ± 0.10, 4.86 ± 1.36 vs 1.46 ± 0.54) (all P < 0.05); while those of AngII+Ang1-7 group were down-regulated (0.91 ± 0.30, 1.57 ± 0.27) compared with AngII group (all P < 0.05); no significant difference existed between the AngII+Ang1-7+A-779 group (1.25 ± 0.14, 1.29 ± 0.49) and AngII+Ang1-7 group (P > 0.05).. Ang1-7 has anti-fibrous effect upon bleomycin-induced pulmonary fibrosis in rats and such an effect of Ang1-7 may be associated with AngII-induced expression of TGF-β1.

Topics: Angiotensin I; Animals; Bleomycin; Collagen Type I; Male; Peptide Fragments; Pulmonary Fibrosis; Rats; Rats, Wistar; Transforming Growth Factor beta1

An activated vasoconstrictive, proliferative, and fibrotic axis of the renin angiotensin system (angiotensin-converting enzyme [ACE]/angiotensin [Ang]II/AngII type 1 receptor) has been implicated in the pathophysiology of pulmonary fibrosis (PF) and pulmonary hypertension (PH). The recent discovery of a counterregulatory axis of the renin angiotensin system composed of ACE2/Ang-(1-7)/Mas has led us to examine the role of this vasoprotective axis on such disorders.. We hypothesized that Ang-(1-7) treatment would exert protective effects against PF and PH.. Lentiviral packaged Ang-(1-7) fusion gene or ACE2 cDNA was intratracheally administered into the lungs of male Sprague Dawley rats. Two weeks after gene transfer, animals received bleomycin (2.5 mg/kg). In a subsequent study, animals were administered monocrotaline (MCT, 50 mg/kg).. In the PF study, bleomycin administration resulted in a significant increase in right ventricular systolic pressure, which was associated with the development of right ventricular hypertrophy. The lungs of these animals also exhibited excessive collagen deposition, decreased expression of ACE and ACE2, increased mRNA levels for transforming growth factor β and other proinflammatory cytokines, and increased protein levels of the AT₁R. Overexpression of Ang-(1-7) significantly prevented all the above-mentioned pathophysiological conditions. Similar protective effects were also obtained with ACE2 overexpression. In the PH study, rats injected with MCT developed elevated right ventricular systolic pressure, right ventricular hypertrophy, right ventricular fibrosis, and pulmonary vascular remodeling, all of which were attenuated by Ang-(1-7) overexpression. Blockade of the Mas receptor abolished the beneficial effects of Ang-(1-7) against MCT-induced PH.. Our observations demonstrate a cardiopulmonary protective role for the ACE2/Ang-(1-7)/Mas axis in the treatment of lung disorders.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Bleomycin; Genetic Therapy; Hypertension, Pulmonary; Male; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Transduction, Genetic