Background and Purpose: AVE 0991 (AVE) is a non‐peptide compound, mimic of the angiotensin (Ang)‐(1–7) actions in many tissues and pathophysiological states. Here, we have investigated the effect of AVE on pulmonary remodelling in a murine model of ovalbumin (OVA)‐induced chronic allergic lung inflammation.Experimental Approach: We used BALB/c mice (6–8 weeks old) and induced chronic allergic lung inflammation by OVA sensitization (20 μg·mouse⁻¹, i.p., four times, 14 days apart) and OVA challenge (1%, nebulised during 30 min, three times per·week, for 4 weeks). Control and AVE groups were given saline i.p and challenged with saline. AVE treatment (1 mg·kg⁻¹·per day, s.c.) or saline (100 μL·kg⁻¹·per day, s.c.) was given during the challenge period. Mice were anaesthetized 72 h after the last challenge and blood and lungs collected. In some animals, primary bronchi were isolated to test contractile responses. Cytokines were evaluated in bronchoalveolar lavage (BAL) and lung homogenates.Key Results: Treatment with AVE of OVA sensitised and challenged mice attenuated the altered contractile response to carbachol in bronchial rings and reversed the increased airway wall and pulmonary vasculature thickness and right ventricular hypertrophy. Furthermore, AVE reduced IL‐5 and increased IL‐10 levels in the BAL, accompanied by decreased Ang II levels in lungs.Conclusions and Implications: AVE treatment prevented pulmonary remodelling, inflammation and right ventricular hypertrophy in OVA mice, suggesting that Ang‐(1–7) receptor agonists are a new possibility for the treatment of pulmonary remodelling induced by chronic asthma.

There are few animal models of dengue infection, especially in immunocompetent mice. Here, we describe alterations found in adult immunocompetent mice inoculated with an adapted Dengue virus (DENV-3) strain. Infection of mice with the adapted DENV-3 caused inoculum-dependent lethality that was preceded by several hematological and biochemical changes and increased virus dissemination, features consistent with severe disease manifestation in humans. IFN-γ expression increased after DENV-3 infection of WT mice and this was preceded by increase in expression of IL-12 and IL-18. In DENV-3-inoculated IFN-γ^−/− mice, there was enhanced lethality, which was preceded by severe disease manifestation and virus replication. Lack of IFN-γ production was associated with diminished NO-synthase 2 (NOS2) expression and higher susceptibility of NOS2^−/− mice to DENV-3 infection. Therefore, mechanisms of protection to DENV-3 infection rely on IFN-γ-NOS2-NO-dependent control of viral replication and of disease severity, a pathway showed to be relevant for resistance to DENV infection in other experimental and clinical settings. Thus, the model of DENV-3 infection in immunocompetent mice described here represents a significant advance in animal models of severe dengue disease and may provide an important tool to the elucidation of immunopathogenesis of disease and of protective mechanisms associated with infection. Dengue is a mosquito-borne disease caused by one of four serotypes of Dengue virus (DENV-1-4). Dengue has escalated in geographic distribution and disease severity to become the most common arboviral infection of humans. There are no vaccines or specific therapies for dengue and the treatment is supportive. Immunopathogenesis of dengue disease is also poorly understood, in part, due to of the absence of proper animal models of infection. Here, we describe the phenotype of infection of immunocompetent mice with an adapted DENV-3 strain. Infection caused an inoculum-dependent lethality that was preceded by significant clinical, virological and biochemical changes resembling the severe manifestations of human infection. In addition, we demonstrate that IFN-γ production is essential for the host to deal with DENV-3 infection in a manner similar to that demonstrated previously for DENV-2. Hence, reduced IFN-γ production during DENV-3 infection was associated with diminished NOS2 expression and Nitric oxide production. Mice deficient for each of these molecules presented more severe disease manifestation and increased viral replication. Therefore, we describe a model of DENV-3 infection in immunocompetent mice that proves to be an interesting tool to study host–virus interactions and mechanisms mediating protection or those associated with severe disease manifestation.

Angiotensin-(1–7) [Ang-(1–7)], a counter-regulatory peptide of the renin–angiotensin system (RAS) exerts its effects through the G-protein-coupled receptor Mas, which is expressed in different tissues, including the brain. Ang-(1–7) has a broad range of effects beyond the well-described cardiovascular and renal actions, including the modulation of emotional and behavioural responses. In the present study we tested the hypothesis that Ang-(1–7) could attenuate the anxiety- and depression-like behaviours observed in transgenic hypertensive (mRen2)27 rats (TGRs). We also hypothesized that Ang-(1–7) could be involved in the anxiolytic-like effect induced by ACE (angiotensin-converting enzyme) treatment in these hypertensive rats. Therefore, TGRs and Sprague–Dawley rats were subjected to the Elevated Plus Maze (EPM) test, Forced Swimming Test (FST) and Novelty Suppressed Feeding (NSF). TGRs presented a decreased percentage of entries in the open arms of the EPM test, a phenotype reversed by systemic treatment with enalapril or intracerebroventricular infusion of Ang-(1–7). It is interesting that pre-treatment with A779, a selective Mas receptor antagonist, prevented the anxiolytic-like effect induced by the ACE inhibitor. In the NSF test, TGRs showed increased latency to eating, an indicative of a higher aversion in response to a new environment. These animals also showed increased immobility in the FST. Again, Ang-(1–7) reversed this phenotype. Thus, our data showed that Ang-(1–7) can modulate anxiety- and depression-like behaviours in TGRs and warrant further investigation as a new therapy for certain psychiatric disorders.

Background: A large body of studies characterized the renal and cardiovascular effects of the peptides of the renin-angiotensin system (RAS). We now recognize that, in addition to angiotensin (Ang) II and Ang III, other peptides, such as, Ang-(1-7), Ang-(1-9), Ang IV and Alamandine can mediate actions of the RAS in different tissues, including the brain. Effects elicited by angiotensins in the brain are complex, site specific and dependent on the interaction with selective receptors, angiotensin type 1 receptor (AT1), AT2, Mas or MrgD, which present widespread distribution in the central nervous system. Although the majority of studies indicate a neuroprotective action for the inhibition of angiotensin converting enzyme or blockade of AT1 receptor, recent studies point to the participation of other angiotensin peptides in the pathophysiology of the neurodegenerative diseases. Objectives and Methods: In this article, we revised the literature to describe recent findings related to the role of RAS in neurodegenerative diseases such as, Parkinson, Alzheimer, Huntington and Multiple Sclerosis. Results: The results obtained are promising and may stimulate the development of novel and more effective pharmacological tools to prevent and better control neurodegenerative diseases. In this brief review, we present results from studies showing the participation of the RAS with respect to neurodegenerative diseases, such as, Parkinson, Alzheimer, Huntington and Multiple Sclerosis. Conclusion: Increased RAS activity leading to increase in Ang II levels, may increase the risk of developing PD, AD, HD or MS. However, the alteration in the balance among angiotensin peptides resulting in increasing Ang-(1-7) or Alamandine may represent effective neuroprotective strategy in population groups at high risk or as coadjutant treatment to reduce the progression of these diseases. Although most studies suggest a neuroprotective action for ACE inhibition or AT1 receptor antagonism, many studies will still be needed to characterize the relative importance (and intracellular mechanisms) of each RAS peptide for the pathophysiology of neurodegenerative diseases. The results to date are promising and may lead to new and more effective pharmacological tools to prevent and better control neurodegenerative diseases.