Agaphelin modulates the activation of human bronchial epithelial cells induced by lipopolysaccharide and IL-4.

Sand fly saliva presents molecules with potential to development of compounds for treatment of inflammatory diseases. Agaphelin, isolated from the saliva of the mosquito Anopheles gambiae, demonstrates anti-inflammatory properties such as neutrophils chemotaxis inhibition. Here, we extend these results and evaluated the role of agaphelin (0.1-100 nM) in an in vitro model consisting in the activation of human bronchial epithelial cells (BEAS-2B) by IL-4 (50 ng/mL) or lipopolysaccharide (LPS; 10 ng/mL). Agaphelin is non-cytotoxic for BEAS-2B cells. Notably, agaphelin markedly reduces CCL2 and IL-8 production induced by IL-4 or LPS, without altering the IL-10 production. The TLR4 expression and STAT1 phosphorylation induced by LPS were inhibited by agaphlin. In addition, agaphelin decreased the phosphorylation of STAT6 induce by IL-4, whose effect was independent of IL-4-binding activity. Taken together, these findings identify agaphelin as a potential anti-inflammatory therapeutic agent for airway inflammations.

The anti-inflammatory and pro-resolution effects of aspirin-triggered RvD1 (AT-RvD1) on peripheral blood mononuclear cells from patients with severe asthma.

Asthma is an inflammatory disease that is characterized by a predominance of eosinophils and/or neutrophils in the airways. In the resolution of inflammation, lipid mediators such as resolvin D1 (RvD1) and its epimer aspirin-triggered RvD1 (AT-RvD1) are produced and demonstrate anti-inflammatory and pro-resolution effects. In experimental models such as airway allergic inflammation induced by ovalbumin in mice, RvD1 and AT-RvD1 alleviate some of the most important phenotypes of asthma. Here, we demonstrated the effects of AT-RvD1 on peripheral blood mononuclear cells (PBMCs) from healthy individuals and patients with severe asthma stimulated with lipopolysaccharide (LPS) or Dermatophagoides pteronyssinus (DM). AT-RvD1 (100nM) reduced the concentration of TNF-α in PBMCs from healthy individuals and patients with severe asthma stimulated with LPS or DM. In addition, AT-RvD1 lowered the production of IL-10 only in PBMCs from patients with severe asthma stimulated with LPS. These effects were associated in part with decreasing NF-κB activation. Moreover, AT-RvD1 significantly increased phagocytosis of apoptotic neutrophils by monocytes from patients with severe asthma. In conclusion, AT-RvD1 demonstrated both anti-inflammatory and pro-resolution effects in PBMCs from patients with severe asthma and could become in the future an alternative treatment for asthma.

Anti-inflammatory Effect and Toxicology Analysis of Oral Delivery Quercetin Nanosized Emulsion in Rats.

PURPOSE: This study evaluates the advantage of the quercetin encapsulation in nanosized emulsion (QU-NE) administered orally in rats in order to demonstrate its anti-oedematous and antioxidant effects as well as its toxicity. METHODS: The nanocarriers were prepared using the hot solvent diffusion with the phase inversion temperature methods. The nanocarriers physicochemical properties were then investigated. The anti-edematous activity was tested using paw edema in rats. In addition, NF-kB expression in subcutaneous tissue of the paws was accessed by immunohistochemistry while the lipid peroxidation was analyzed in the liver by malondialdehyde reaction with thiobarbituric acid. Hematological, renal and hepatic toxicity as well as the genetic damage were also evaluated. RESULTS: The results demonstrated that QU-NE exhibited pronounced anti-oedematous property comparable to drug diclofenac. This effect was associated with NF-κB pathway inhibition. The lipid peroxidation was also only reduced in rats treated with QU-NE. Besides this, no genetic damage, hematological, renal or hepatic toxicities were observed after administration of QU-NE. CONCLUSIONS: These results suggest that quercetin nanosized emulsion exhibits anti-oedematous and antioxidant properties and does not demonstrate toxic effects. This indicates that it has a potential application in the treatment of inflammatory diseases.

AT-RvD1 modulates CCL-2 and CXCL-8 production and NF-κB, STAT-6, SOCS1, and SOCS3 expression on bronchial epithelial cells stimulated with IL-4.

Bronchial epithelial cells represent the first line of defense against microorganisms and allergens in the airways and play an important role in chronic inflammatory processes such as asthma. In an experimental model, both RvD1 and AT-RvD1, lipid mediators of inflammation resolution, ameliorated some of the most important phenotypes of experimental asthma. Here, we extend these results and demonstrate the effect of AT-RvD1 on bronchial epithelial cells (BEAS-2B) stimulated with IL-4. AT-RvD1 (100 nM) decreased both CCL2 and CXCL-8 production, in part by decreasing STAT6 and NF-κB pathways. Furthermore, the effects of AT-RvD1 were ALX/FRP2 receptor dependent, as the antagonist of this receptor (BOC1) reversed the inhibition of these chemokines by AT-RvD1. In addition, AT-RvD1 decreased SOCS1 and increased SOCS3 expression, which play important roles in Th1 and Th17 modulation, respectively. In conclusion, AT-RvD1 demonstrated significant effects on the IL-4-induced activation of bronchial epithelial cells and consequently the potential to modulate neutrophilic and eosinophilic airway inflammation in asthma. Taken together, these findings identify AT-RvD1 as a potential proresolving therapeutic agent for allergic responses in the airways.

The effects of proresolution of ellagic acid in an experimental model of allergic airway inflammation.

Asthma is a disease of airway inflammation characterized by airway hyperresponsiveness, eosinophilic inflammation, and hypersecretion of mucus. Ellagic acid, a compound derived from medicinal plants and fruits, has shown anti-inflammatory activity in several experimental disease models. We used the classical experimental model, in BALB/c mice, of sensibilization with ovalbumin to determine the effect of ellagic acid (10 mg/kg; oral route) in the resolution of allergic airways response. Dexamethasone (1 mg/kg; subcutaneous route) was used as a positive control. The control group consisted of nonimmunized mice that received challenge with ovalbumin. Ellagic acid and dexamethasone or vehicle (water) were administered before or after intranasal allergen challenge. Ellagic acid accelerated the resolution of airways inflammation by decreasing total leukocytes and eosinophils numbers in the bronchoalveolar lavage fluid (BALF), the mucus production and lung inflammation in part by reducing IL-5 concentration, eosinophil peroxidase (EPO) activity, and P-selectin expression, but not activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB) pathways. In addition, ellagic acid enhanced alveolar macrophage phagocytosis of IgG-OVA-coated beads ex vivo, a new proresolving mechanism for the clearance of allergen from the airways. Together, these findings identify ellagic acid as a potential therapeutic agent for accelerating the resolution of allergic airways inflammation.

Potential effects of medicinal plants and secondary metabolites on acute lung injury.

Acute lung injury (ALI) is a life-threatening syndrome that causes high morbidity and mortality worldwide. ALI is characterized by increased permeability of the alveolar-capillary membrane, edema, uncontrolled neutrophils migration to the lung, and diffuse alveolar damage, leading to acute hypoxemic respiratory failure. Although corticosteroids remain the mainstay of ALI treatment, they cause significant side effects. Agents of natural origin, such as medicinal plants and their secondary metabolites, mainly those with very few side effects, could be excellent alternatives for ALI treatment. Several studies, including our own, have demonstrated that plant extracts and/or secondary metabolites isolated from them reduce most ALI phenotypes in experimental animal models, including neutrophil recruitment to the lung, the production of pro-inflammatory cytokines and chemokines, edema, and vascular permeability. In this review, we summarized these studies and described the anti-inflammatory activity of various plant extracts, such as Ginkgo biloba and Punica granatum, and such secondary metabolites as epigallocatechin-3-gallate and ellagic acid. In addition, we highlight the medical potential of these extracts and plant-derived compounds for treating of ALI.