Formulation and Characterization of Solid Lipid Nanoparticles Loading RF22-c, a Potent and Selective 5-LO Inhibitor, in a Monocrotaline-Induced Model of Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a rare but fatal disease characterized by persistent elevated blood pressure in the pulmonary circulation, due to increased resistance to blood flow, through the lungs. Advances in the understanding of the pathobiology of PAH clarify the role of leukotrienes (LTs) that appear to be an exciting new target for disease intervention. Over the years, our group has long investigated this field, detecting the 1,2-benzoquinone RF-22c as the most powerful and selective competitive inhibitor of the enzyme 5-lipoxygenase (5-LO). With the aim to improve the bioavailability of RF-22c and to confirm the role of 5-LO as therapeutic strategy for PAH treatment, we developed a solid lipid nanoparticle (SLN) loaded with drug. Therefore, in monocrotaline (MCT) rat model of PAH, the role of 5-LO has been investigated through the formulation of RF-22c-SLN. The rats were randomly grouped into control group, MCT group, and MCT + RF22-c group. After 21 days, all the animals were sacrificed to perform functional and histological evaluations. RF22-c-SLN treatment was able to significantly reduce the mean pulmonary arterial pressure (mPAP) and precapillary resistance (R-pre) compared to the MCT group. The MCT induced rise in medial wall thickness of pulmonary arterioles, and the cardiomyocytes width were significantly attenuated by RF22-c-SLN formulation upon treatment. The results showed that the selective inhibition of 5-LO improved hemodynamic parameters as well as vascular and cardiac remodeling by preventing induced pulmonary hypertension. The improved sustained release properties and targeting abilities achieved with the innovative nanotechnological approach may be therapeutically beneficial for PAH patients as a consequence of the increase of pharmacological effects and of the possible reduction and/or optimization of the drug frequency of administration.

Montelukast Improves Symptoms and Lung Function in Asthmatic Women Compared With Men.

Purpose: Gender differences exist in the prevalence of asthma and allergic diseases, partially due to the effects of sex hormones on the development of allergic manifestations. Women, compared with men, are more prone to suffer allergic asthma, experience difficulties in controlling asthma symptoms, and show adverse responses to drugs. However, there are knowledge gaps on the effectiveness of anti-leukotrienes drugs on lung function, symptoms, and pulmonary and systemic inflammation in adult asthmatic women compared with men. We conducted a prospective cohort study to characterize the effectiveness of an anti-leukotrienes drug, montelukast (MS), in asthmatic adult women and men. Methods: Twenty-one asthmatic subjects (11 women and 10 men), who were on low-dose inhaled corticosteroids (ICS), were treated with MS. The optimal control of the symptoms was achieved in both groups according to the Global Initiative for Asthma guidelines. At enrollment, and after 13 weeks from the beginning of MS, pulmonary function tests and asthma control tests were performed, and the fraction of exhaled nitric oxide and blood eosinophils levels were measured. Results: From baseline until the end of the study, women treated with MS + ICS had better control of the asthmatic symptoms, defined as higher asthma control test (ACT) score (17.00 ± 1.07 to 23.36 ± 0.45; p < 0.0015), improved pulmonary function [with higher forced expiratory volume in 1 s (from 77.25 ±â€¯6.79 to 103.88 ± 6.24; p < 0.0077)], and forced vital capacity (from 91.95 ± 6.81 to 113.17 ± 4.79; p < 0.0183) compared with men. Interestingly, MS + ICS-treated women had significantly lower levels of blood eosinophils (from 5.27 ±â€¯0.30 to 3.30 ±â€¯0.31; p < 0.0449) and exhaled nitric oxide (from 44.70 ± 7.30 to 25.20 ± 3.90; p < 0.0294) compared with men. Conclusion: The treatment with MS, added to ICS, in women leads to better control of symptoms, better management of lung function, and decreased inflammation levels compared with ICS + MS treatment in men.

Recent advances in the search for novel 5-lipoxygenase inhibitors for the treatment of asthma.

The products of 5-lipoxygenase are synthesized and released in the airway when an asthmatic reaction occurs. 5-lipoxygenase via arachidonic acid metabolism produces leukotrienes that mediate bronchoconstriction and inflammatory modifications essential in the pathophysiology of asthma. Until to now, only one approved 5-LO inhibitor, zileuton, can be found as a potential therapy for asthma. With the increasing number of indications for anti-leukotriene (anti-LT) drugs, the development of 5-LO inhibitor agents becomes increasingly important. The present MiniReview reports an update on 5-LO inhibitors currently under clinical investigation. In addition, the latest advances focused on the development of new 5-lipoxygenase inhibitors as asthma anti-inflammatory agents are also discussed.

Nociceptin/Orphanin Fq in inflammation and remodeling of the small airways in experimental model of airway hyperresponsiveness.

It is widely recognized that airway inflammation and remodeling play a key role not only in the central airway but also small airway pathology during asthma. Nociceptin/Orphanin FQ (N/OFQ), an endogenous peptide, and its receptor N/OFQ peptide (NOP) are involved in airway hyperresponsiveness (AHR). We studied a murine model of AHR in order to understand the role of N/OFQ in the inflammation and remodeling of the small airways. Balb/c mice were sensitized to ovalbumin (OVA). At days 0 and 7 (pre-OVA sensitization) or from day 21 to 23 (post-OVA sensitization), the mice were treated intraperitoneally with N/OFQ or saline solution. After the last OVA challenge, all OVA-sensitized mice were aerosol-challenged with 1% OVA in PBS for 48 h, and then euthanized. Small airway compliance (sCaw ) was measured and lung samples were collected for histological and molecular evaluations such as perimeter and diameter of small airway, total wall area, airway smooth muscle (ASM) thickness and number of alveolar attachments. Both pre- and post-OVA sensitization N/OFQ treatments induced: (1) increases in sCaw ; (2) reduction of the bronchial wall thickness; (3) attenuation of the hyperplastic phase of airway smooth muscle mass; and (4) protection against loss of alveolar attachments compared with saline solution treatments. These results suggest that N/OFQ protects against inflammation, and mechanical damage and remodeling of small airways caused by OVA sensitization, suggesting a new potential therapeutic target for asthma.

Lung Mesenchymal Stem Cells Ameliorate Elastase-Induced Damage in an Animal Model of Emphysema.

Pulmonary emphysema is a respiratory condition characterized by alveolar destruction that leads to airflow limitation and reduced lung function. Although with extensive research, the pathophysiology of emphysema is poorly understood and effective treatments are still missing. Evidence suggests that mesenchymal stem cells (MSCs) possess the ability to engraft the injured tissues and induce repair via a paracrine effect. Thus, the aim of this study was to test the effects of the intratracheal administration of lung-derived mouse MSCs in a model of elastase-induced emphysema. Pulmonary function (static lung compliance) showed an increased stiffness induced by elastase, while morphometric findings (mean linear intercept and tissue/alveolar area) confirmed the severity of alveolar disruption. Contrarily, MSC administration partially restored lung elasticity and alveolar architecture. In the absence of evidence that MSCs acquired epithelial phenotype, we detected an increased proliferative activity of aquaporin 5- and surfactant protein C-positive lung cells, suggesting MSC-driven paracrine mechanisms. The data indicate the mediation of hepatocyte growth factor in amplifying MSC-driven tissue response after injury. Our study shed light on supportive properties of lung-derived MSCs, although the full identification of mechanisms orchestrated by MSCs and responsible for epithelial repair after injury is a critical aspect yet to be achieved.