Involvement of the renin–angiotensin system in the development of vascular damage in a rat model of arthritis: Effect of angiotensin receptor blockers

Objective

To explore the involvement of the renin–angiotensin system (RAS) in the development of vascular damage in adjuvant‐induced arthritis (AIA) in rats.

Methods

Angiotensin II (Ang II; 0.25 or 1.0 mg/kg/day) was infused in control rats and rats with AIA for 21 days, and the impact of systemic inflammation on Ang II–induced hypertension, endothelial dysfunction, and vascular hypertrophy was evaluated. Expression of angiotensin II type 1 receptor (AT₁R) and angiotensin‐converting enzyme (ACE) in the aortas of rats with AIA were examined by real‐time polymerase chain reaction (PCR) and Western blot analyses. Losartan (3 mg/kg/day) or irbesartan (5 mg/kg/day), both of which are AT₁R blockers, was administered orally to rats with AIA for 21 days. In situ superoxide production in aortas was assessed according to the fluorogenic oxidation of dihydroethidium to ethidium. The expression and activity of NAD(P)H oxidases in aortas were examined by real‐time PCR analysis and lucigenin chemiluminescence assay. Endothelial function in rats with AIA treated in vivo or ex vivo with AT₁R blockers was also determined.

Results

The Ang II–induced hypertensive response, endothelial dysfunction, and vascular hypertrophy were exacerbated in rats with AIA. Expression of AT₁R and ACE was increased in the aortas of rats with AIA. Both losartan and irbesartan decreased the levels of superoxide and the expression and activity NAD(P)H oxidases in the aortas of rats with AIA. The endothelial dysfunction in AIA was improved by the in vivo or ex vivo treatment with AT₁R blockers.

Conclusion

The locally activated RAS is involved in the increased vascular oxidative stress and endothelial dysfunction in AIA. Our findings have important implications for clinical approaches to the reduction of cardiovascular risk in patients with rheumatoid arthritis.

     

Age-dependent differential crosstalk between alpha()-adrenergic and angiotensin receptors

BACKGROUND

Previous reports of crosstalk between alpha(1)-adrenergic receptors (α₁-AR) and angiotensin receptors (ATR) have pointed to the existence of physiological regulation between the sympathetic nervous system and the renin-angiotensin system at the receptor level. This regulation may have an important role in the control of blood pressure and may be modified in different cardiovascular pathologies. Aging is considered to be an independent cardiovascular risk factor. Nevertheless, neither the variation in physiological action or interaction of signal transduction between these two receptors as a result of aging has been established. To clarify these aspects, the interaction between α₁-AR and ATR was evaluated.

METHODS

The inotropic response of α₁-AR to agonists was assessed in the presence and absence of angiotensin II using the left atria of 3.5-, 12-, 18- and 24-month-old (young adult, middle aged, elderly and aged, respectively) male Wistar rats. In the four age groups of rat hearts, the activities of tyrosine kinase were measured when just the AT₁R subtype was activated, or when both α₁-AR and AT₁R were activated. The activities of cytosolic phospholipase A₂ and the levels of cyclic GMP were investigated when just the AT₂R subtype was activated, or when both α₁-AR and AT₂R were activated.

RESULTS

No effect was found on the cumulative concentration-response curve for phenylephrine when AT₁R was activated in 3.5- or 12-month-old rats. However, in 18- and 24-month-old rats, the maximum positive inotropic response and the negative logarithm of the effective 50% concentration increased markedly. No effect was found on the cumulative concentration-response curve induced by phenylephrine when AT₂R was activated. The activities of tyrosine kinase increased significantly in 3.5- and 12-month-old rats, but there was no difference in 18- and 24-month-old rats when α₁-AR and AT₁R were both activated compared with when just AT₁R was activated. Cytosolic phospholipase A₂ activity and cyclic GMP levels decreased significantly when both α₁-AR and AT₂R were activated compared with when just AT₂R was activated.

CONCLUSIONS

In the isolated left atria of elderly and aged rats, the activation of AT₁R enhanced the positive inotropic response induced by the activation of α₁-AR. The activation of AT₂R had no effect on the positive inotropic response induced by the activation of α₁-AR. The action of α₁-AR increased the signal transduction of AT₁R in young-adult and middle-aged rat hearts but had no effect in elderly and aged hearts. The action of α₁-AR had no effect on AT₂R signal transduction.     

Relationships among protein tyrosine phosphatase 1B,angiotensin II,and insulin-mediated aortic responses in type 2 diabetic Goto–Kakizaki rats

Objective

We investigated the relationships among protein tyrosine phosphatase 1B (PTP1B), angiotensin II (Ang II), and insulin signaling in the presence of endothelial dysfunction in type 2 diabetic Goto–Kakizaki (GK) rat aortas.

Methods and results

Aortas isolated from GK or control Wistar rats were examined in the presence or absence of Ang II with or without a selective antagonist of the Ang II type 1 (AT₁) receptor or a PTP1B inhibitor to evaluate vascular functional and molecular mechanisms, such as insulin-induced relaxation, nitric oxide (NO) production, phosphorylation of insulin receptor substrate (IRS)-1, endothelial NO synthase (eNOS), and phosphorylation, and the subcellular localization of PTP1B. GK aortas exhibited reductions of: 1) insulin-induced relaxation, 2) NO production, 3) Ser¹¹⁷⁷-p-eNOS, and 4) Tyr⁶¹²-p-IRS-1. Pre-incubation with a PTP1B inhibitor normalized these reductions. In Wistar aortas, the four above-mentioned parameters were reduced by Ang II, but were completely inhibited by co-treatment with the PTP1B inhibitor. The membrane expression of PTP1B was greater in GK than in Wistar aortas, and it was increased by Ang II in Wistar rats. The membrane PTP1B expression in the presence of insulin + Ang II was reduced by the PTP1B inhibitor or AT₁-receptor antagonist.

Conclusions

These results suggest that the membrane PTP1B suppressed insulin-mediated aortic relaxation, and this was due to the Ang II-AT₁-receptor signaling pathway. The inhibition of PTP1B warrants further investigation as a potential therapeutic target for endothelial dysfunction in type 2 diabetes.     

Effect of dobutamine on lung aquaporin 5 in endotoxine shock-induced acute lung injury rabbit

Background

Dobutamine, a commonly used vasoactive drug, has been reported to reduce pulmonary edema and protect against acute lung injury (ALI) by up-regulating aquaporin 5 (AQP₅) expressions. However, the underlying mechanism is still elusive.

Methods

ALI was induced by intravenous injection of LPS. Seventy male New Zealand white rabbits were randomly divided into seven groups: sham group, ALI group, dobutamine low-dose group [group ALI + Dob (L)], dobutamine medium-dose group [group ALI + Dob (M)], dobutamine high-dose group [group ALI + Dob (H)], ALI + Dob (H) + ICI group and sham + ICI group. ICI 118,551, a potent and specific beta-2 antagonist, could block the effect of dobutamine. The animals were sacrificed at 3 h after endotoxic shock and lungs were removed. The arterial blood gas was analyzed. The lung wet to dry (W/D) ratio was determined. The level of cyclic AMP (cAMP) in lung tissue was assessed by ELISA. The expression of AQP₅ protein was determined by western blotting and immunohistochemistry. The pathological alteration in lung tissue was evaluated by optical microscopy and electron microscope, and lung injury score was assessed.

Results

Dobutamine increased AQP₅ protein expression and cAMP level in a dose-dependent manner. Meanwhile, the degree of lung pathological and ultrastructural lesion was ameliorated and arterial blood gas was improved obviously. Additionally, W/D ratio and histological scores decreased significantly. However, the AQP₅ protein expression and cAMP level were significantly decreased in group ALI + Dob (H) + ICI than that in group ALI + Dob (H), the degree of lung pathological and ultrastructural lesion was more serious in group ALI + Dob (H) + ICI than that in group ALI + Dob (H) and the arterial blood gas was not obviously improved.

Conclusions

These results suggested that protective effect of dobutamine against endotoxin shock-induced ALI may be due to its ability of up-regulating AQP₅ protein expression via increasing intracellular cAMP concentration.     

Incidence and risk factors for acute lung injury after open thoracotomy for thoracic diseases

Background

Acute lung injury (ALI) is a major cause of morbidity and mortality after open thoracotomy. The purpose of the study was to identify the incidence and risk factors for ALI so as to prevent its occurrence and improve surgical results.

Methods

A prospective controlled study was carried out in 364 patients undergone open thoracotomy. Fifty-eight high risk elderly patients and 56 young patients as matched controls were prospectively entered into the study. The two groups were compared to identify the possible risk factors for ALI.

Results

ALI occurred exclusively in elderly patients, accounted for 2.7% of the whole series (10/364) and 7.9% of elderly patients (10/127). The mortality for patients with ALI was 30%, significantly higher than those without (1.0%, P=0.001). Upon univariate analysis, increased age, obesity, chronic obstructive pulmonary disease (COPD), poor spirometry, and positive fluid balance on postoperative day 1 were associated with increased risk of developing ALI. Upon multivariate analysis, only poor spirometry and excessive positive fluid balance on postoperative day 1 were revealed as independent risk factors for ALI.

Conclusions

ALI after open thoracotomy has a high mortality. COPD and excessive positive fluid balance on the first postoperative day are significant predictors, suggesting stringent patient selection and timely conservative fluid management may be helpful in reducing this extremely devastating complication.     

Acute lung injury induced by the intravenous administration of cigarette smoke extract

OBJECTIVE:

To investigate the acute effects of intravenous administration of cigarette smoke extract (CSE) on histological, inflammatory, and respiratory function parameters in rats, as well as to compare this potential acute lung injury (ALI) model with that with the use of oleic acid (OA).

METHODS:

We studied 72 Wistar rats, divided into four groups: control (those injected intravenously with saline); CSE (those injected intravenously with CSE and saline); OA (those injected intravenously with saline and OA); and CSE/OA (those injected intravenously with CSE and OA).

RESULTS:

Mean lung compliance was significantly lower in the OA and CSE/OA groups (2.12 ± 1.13 mL/cmH₂O and 1.82 ± 0.77 mL/cmH₂O, respectively)than in the control group (3.67 ± 1.38 mL/cmH₂O). In bronchoalveolar lavage fluid, the proportion of neutrophils was significantly higher in the OA and CSE/OA groups than in the control group, as was the activity of metalloproteinases 2 and 9. Pulmonary involvement, as assessed by morphometry, was significantly more severe in the OA and CSE/OA groups (72.9 ± 13.8% and 77.6 ± 18.0%, respectively) than in the control and CSE groups (8.7 ± 4.1% and 32.7 ± 13.1%, respectively), and that involvement was significantly more severe in the CSE group than in the control group.

CONCLUSIONS:

The intravenous administration of CSE, at the doses and timing employed in this study, was associated with minimal ALI. The use of CSE did not potentiate OA-induced ALI. Additional studies are needed in order to clarify the potential role of this model as a method for studying the mechanisms of smoking-induced lung injury.     

Investigation of Interleukin-10 Promoter Polymorphisms and Interleukin-10 Levels in Children with Irritable Bowel Syndrome

Background/Aims

The aim of this study was to investigate whether genetic variations at positions -1082, -819, and -592 in the interleukin (IL)-10 promoter affect IL-10 production in children with irritable bowel syndrome (IBS).

Methods

Ninety-four children with IBS and 102 children as healthy controls (HCs) were enrolled. Genomic DNA was extracted, and IL-10 -1082, -819, and -592 polymorphisms were detected by direct sequencing from all participants. Peripheral blood mononuclear cells (PBMCs) from 46 IBS children and 38 HCs were isolated and cultured with and without 5 ng/mL Escherichia coli lipopolysaccharide (LPS). IL-10 levels in the culture supernatants were measured by enzyme-linked immunosorbent assay.

Results

There were no significant differences in the distribution of IL-10 -1082, -819, and -592 polymorphisms or in the allele and haplotype frequencies between IBS children and HCs. PBMCs from children with IBS had significantly lower IL-10 levels after LPS stimulation than PBMCs from HCs (p=0.011); however, LPS-induced IL-10 levels in PBMCs with different genotypes of -819 and -592 polymorphisms were not significantly different between IBS patients and HCs.

Conclusions

Although significantly lower LPS-induced IL-10 production by PBMCs was noted, it is unlikely that IL-10 production was fully genetically determined in our IBS children. ClinicalTrials.gov identifier: NCT01131442.     

Acute inflammatory and anabolic systemic responses to peak and constant-work-rate exercise bout in hospitalized patients with COPD

Study objectives:

To explore the acute systemic inflammatory and anabolic effects of cycling in hospital admitted patients with chronic obstructive pulmonary disease (COPD) and in patients with clinically stable disease.

Design:

Cross-sectional comparative study.

Setting:

University Hospital Gasthuisberg, a tertiary care setting.

Patients:

16 patients with clinically stable COPD (no acute exacerbation in the past 12 weeks; median age: 73 years (IQR: 60 to 75); median forced expiratory volume in the first second (FEV₁): 45% predicted (IQR: 33 to 58)) and 14 patients who were admitted to a hospital due an acute exacerbation of COPD (median age: 65 years (IQR: 59 to 74); median FEV₁ to on day 8 of hospital stay: 41% predicted (IQR: 33 to 54)).

Interventions:

None.

Measurements and results:

Circulating levels of C reactive protein, interleukin 6, interleukin 8 and insulin-like growth factor I were determined before, at the end and 2 and 30 minutes after a symptom-limited peak cycling test and before, at the end and 2 and 30 minutes after a symptom-limited constant-work-rate cycling test at 70% of the peak load. Non-significant changes in the circulating markers of inflammation and anabolism were found during or up to 30 minutes after ceasing the peak or constant-work-rate cycling exercise tests. The systemic responses of the hospitalized patients with COPD did not differ from those with clinically stable disease.

Conclusions:

High-intensity cycling exercises did not increase the circulating levels of inflammatory markers in patients with chronic obstructive pulmonary disease, irrespective of their clinical stability.     

Fluid Balance,Diuretic Use,and Mortality in Acute Kidney Injury

Summary

Background and objectives

Management of volume status in patients with acute kidney injury (AKI) is complex, and the role of diuretics is controversial. The primary objective was to elucidate the association between fluid balance, diuretic use, and short-term mortality after AKI in critically ill patients.

Design, setting, participants, & measurements

Using data from the Fluid and Catheter Treatment Trial (FACTT), a multicenter, randomized controlled trial evaluating a conservative versus liberal fluid-management strategy in 1000 patients with acute lung injury (ALI), we evaluated the association of post-renal injury fluid balance and diuretic use with 60-day mortality in patients who developed AKI, as defined by the AKI Network criteria.

Results

306 patients developed AKI in the first 2 study days and were included in our analysis. There were 137 in the fluid-liberal arm and 169 in the fluid-conservative arm (P = 0.04). Baseline characteristics were similar between groups. Post-AKI fluid balance was significantly associated with mortality in both crude and adjusted analysis. Higher post-AKI furosemide doses had a protective effect on mortality but no significant effect after adjustment for post-AKI fluid balance. There was no threshold dose of furosemide above which mortality increased.

Conclusions

A positive fluid balance after AKI was strongly associated with mortality. Post-AKI diuretic therapy was associated with 60-day patient survival in FACTT patients with ALI; this effect may be mediated by fluid balance.     

Factors affecting prognosis of small hepatocellular carcinoma in Taiwanese patients following hepatic resection

BACKGROUND:

Small hepatocellular carcinoma (HCC) affects millions of individuals worldwide. Surveillance of high-risk patients increases the early detection of small HCC.

OBJECTIVE:

To identify prognostic factors affecting the overall survival (OS) and recurrence-free survival (RFS) of patients with small HCC.

METHODS:

The present prospective study enrolled 140 Taiwanese patients with stage I or stage II small HCC. Clinical parameters of interest included operation type, tumour size, tumour histology, Child-Pugh class, presence of hepatitis B surface antigen and liver cirrhosis, hepatitis C status, alpha-fetoprotein, total bilirubin and serum albumin levels, and administration of antiviral and salvage therapies.

RESULTS:

Tumour size correlated significantly with poorer OS in patients with stage I small HCC (P=0.014); however, patients with stage II small HCC experienced a significantly poorer RFS (P=0.033). OS rates did not differ significantly between patients with stage I and stage II small HCC. Tumour margins, tumour histology and cirrhosis did not significantly affect OS or RFS (P>0.05).

DISCUSSION:

Increasing tumour size has generally been associated with poorer prognoses in cases of HCC. The present study verified the relationship between small HCC tumour size and OS; however, a reduction in OS with increasing tumour size was demonstrated for patients with stage I – but not for stage II – small HCC.

CONCLUSION:

Patients with stage II small HCC may benefit from aggressive surveillance for tumour recurrence and appropriate salvage treatment. Further studies are needed for additional stratification of stage I patients to identify those at increased risk of death.     

Anti-Phospholipase A2 Receptor Antibodies Correlate with Clinical Status in Idiopathic Membranous Nephropathy

Summary

Background and objectives

Circulating autoantibodies against the M-type phospholipase A₂ receptor (anti-PLA₂R) were recently identified in the majority of patients in the United States with idiopathic membranous nephropathy (iMN). The objectives of this study were to assess the prevalence of anti-PLA₂R in a separate, European cohort of iMN patients and to correlate the presence of anti-PLA₂R with clinical parameters reflective of disease activity.

Design, setting, participants, & measurements

Anti-PLA₂R levels were blindly assessed by a Western blot immunoassay in 54 serum samples from 18 patients with iMN collected in various stages of clinical disease. Anti-PLA₂R levels were correlated with other clinical parameters.

Results

77.8% of iMN patients in our cohort had antibodies reactive with human PLA₂R. The antibody levels in these patients correlated strongly with both clinical status and proteinuria (r = 0.73, P < 0.01).

Conclusions

The role of PLA₂R as a major antigen in iMN was confirmed in an independent, European patient cohort, and levels of circulating anti-PLA₂R revealed a strong correlation with clinical disease activity. We propose that detection and measurement of these autoantibodies may provide a tool for monitoring of disease activity and treatment efficacy.     

Effect of a noninvasive ventilatory support during exercise of a program in pulmonary rehabilitation in patients with COPD

Background:

Breathlessness is the most common symptom limiting exercise in patients with chronic obstructive pulmonary disease (COPD). Exercise training can improve both exercise tolerance and health status in these patients, intensity of exercise being of key importance. Nevertheless, in these patients extreme breathlessness and/or peripheral muscle fatigue may prevent patients from reaching higher levels of intensity.

Study objective:

This study was to determine whether inspiratory pressure support (IPS) applied during sub maximal exercise could enable individuals with severe but stable COPD to increase their exercise tolerance.

Participants:

Twelve subjects with severe stable COPD (mean (SD): age = 63(8.2) years; FEV₁ = 0.89(0.42) L (34)% predicted; FEV₁/FVC = 0.31(0.07) only nine subjects completed the study.

Intervention:

Each subject completed ten sessions of cycling at 25%–50% of their maximum power without NIVS and another ten sessions using NIVS.

Measurements and results:

Dyspnea was measured using Borg scale. Subjects reached high levels of dyspnea 4.7 (1.81) during the sessions without NIVS vs low levels of dyspnea during the sessions using NIVS 1.3 (0.6). Exercise time during the sessions without NIVS and with NIVS was 19.37 (3.4) and 33.75 (9.5) min, respectively. Maximal workload during the sessions without NIVS and with NIVS was 27 (3.7) and 50 (10.5) watt, respectively.

Conclusion:

We conclude that IPS delivered by nasal mask can improve exercise tolerance and dyspnea in stable severe COPD patients and hence this mode of ventilatory support may be useful in respiratory rehabilitation programs.     

Modulation of haemodynamics,endogeneous antioxidant enzymes,and pathophysiological changes by selective inhibition of angiotensin II type 1 receptors in pressure-overload rats

Background

Constriction of the thoracic or abdominal aorta provides an experimental model of pressure-overload cardiac hypertrophy. Blockade of AT₁ receptors is beneficial in preventing target-organ damage in hypertension.

Objective

To examine the effect of angiotensin II receptor antagonists on blood pressure, endogenous antioxidant enzyme and histopathological changes in pressure-overload rats.

Methods

Pressure overload was produced by abdominal aortic banding (AAB) using a blunt 22-guage needle in male rats as a model of cardiac hypertrophy. After surgery, the AAB-induced hypertension (AABIH) rats were treated with losartan 40 mg/kg/day, candesartan 10 mg/kg/day, irbesartan 10 mg/kg/day per os for 16 weeks. At 16 weeks of surgery, the rats were observed for general characteristics and mortality, and we determined non-invasive blood pressure (NIBP), endogenous antioxidant enzyme catalase and superoxide dismutase (SOD) activities, and histology of the target organs.

Results

In the AABIH group, significant increase in systolic blood pressure was observed from weeks 3 to 16 compared with the control group, along with reduced serum catalase and SOD activities. The treated groups showed significant reduction in systolic BP and increase in serum SOD and catalase activities. The histological changes induced in the target organs, namely heart, liver, kidneys and thoracic aorta in the AABIH rats were attenuated in the treated rats.

Conclusion

Blockade of the AT₁ receptor caused an improvement in the myocardial antioxidant reserve and decreased oxidative stress in the hypertensive rats, which was evidenced by the protection observed in the treatment groups.     

Incremental shuttle and six-minute walking tests in the assessment of functional capacity in chronic heart failure

BACKGROUND

The incremental shuttle test presents some theoretical advantages over the six-minute walk test in chronic heart failure (CHF), including better standardization and less dependency on collaboration.

OBJECTIVES

The present study evaluated test-retest repeatability, test accuracy in predicting a peak oxygen consumption (VO₂) of 14 mL/kg/min or less, as well as the prognostic value of both walking tests in stable CHF patients.

METHODS

Sixty-three patients (44 men; New York Heart Association functional class II to IV) underwent an incremental treadmill exercise test and, on another day, the walk test in duplicate.

RESULTS

Patients showed well-preserved functional capacity according to the distance walked in both tests (six-minute walk test 491±94 m versus incremental shuttle walk test 422±119 m; P<0.001). Interestingly, the six-minute and incremental shuttle walk test differences in distance walked were higher in more disabled patients. The mean bias ±95% CI of the within-test differences were similar (7±40 m and 8±45 m, respectively). Peak VO₂, but not distance walked in either test, was associated with survival (P<0.05).

CONCLUSIONS

The incremental shuttle walk test showed similar repeatability and accuracy in estimating peak VO₂ compared with the six-minute walk test in CHF patients. Direct measurement of peak VO₂, however, remains superior to either walking test in predicting survival – at least in patients with well-preserved functional capacity.     

Tramadol Alleviates Myocardial Injury Induced by Acute Hindlimb Ischemia Reperfusion in Rats

Background

Organ injury occurs not only during periods of ischemia but also during reperfusion. It is known that ischemia reperfusion (IR) causes both remote organ and local injuries.

Objective

This study evaluated the effects of tramadol on the heart as a remote organ after acute hindlimb IR.

Methods

Thirty healthy mature male Wistar rats were allocated randomly into three groups: Group I (sham), Group II (IR), and Group III (IR + tramadol). Ischemia was induced in anesthetized rats by left femoral artery clamping for 3 h, followed by 3 h of reperfusion. Tramadol (20 mg/kg, intravenous) was administered immediately prior to reperfusion. At the end of the reperfusion, animals were euthanized, and hearts were harvested for histological and biochemical examination.

Results

The levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were higher in Groups I and III than those in Group II (p < 0.05). In comparison with other groups, tissue malondialdehyde (MDA) levels in Group II were significantly increased (p < 0.05), and this increase was prevented by tramadol. Histopathological changes, including microscopic bleeding, edema, neutrophil infiltration, and necrosis, were scored. The total injuryscore in Group III was significantly decreased (p < 0.05) compared with Group II.

Conclusion

From the histological and biochemical perspectives, treatment with tramadol alleviated the myocardial injuries induced by skeletal muscle IR in this experimental model.     

Amelioration of Systemic Fibrosis in Mice by Angiotensin II Receptor Blockade

Objective

Systemic sclerosis (SSc) is characterized by microvascular damage, fibrosis of skin and visceral organs, and autoimmunity. Previous studies have shown that angiotensin II is involved in the synthesis of type I collagen. We investigated whether the blockade of angiotensin II receptor type I (AT₁) by irbesartan reduces skin and lung fibrosis in 2 murine models of SSc.

Methods

SSc was induced by daily intradermal injection of HOCl into the backs of BALB/c mice (HOCl‐induced SSc). Mice were treated daily with irbesartan by oral gavage.

Results

Irbesartan reduced dermal thickness, collagen concentration, Smad2/3, and α‐smooth muscle actin expression, as well as fibroblast proliferation and H‐Ras expression in the skin of mice with HOCl‐induced SSc. Mice treated with irbesartan also displayed less lung fibrosis, less inflammation, and a lower concentration of collagen in the lungs than untreated mice. Exhaled nitric oxide, inducible nitric oxide synthase, and 3‐nitrotyrosine expression in the lungs were decreased following irbesartan treatment. Moreover, irbesartan reduced the number and the proliferation of splenic B and T cells and the serum levels of anti–DNA topoisomerase I autoantibodies.

Conclusion

Irbesartan, an AT₁ antagonist, prevents fibrosis and inflammation and inhibits nitric oxide production in HOCl‐induced models of systemic fibrosis. Our findings extend the indication of an AT₁ antagonist to SSc patients with diffuse fibrosis, especially those with lung involvement.