Standardised Sonneratia apetala Buch.-Ham. fruit extract inhibits human neutrophil elastase and attenuates elastase-induced lung injury in mice

Chronic obstructive pulmonary disease (COPD) along with asthma is a major and increasing global health problem. Smoking contributes to about 80%–90% of total COPD cases in the world. COPD leads to the narrowing of small airways and destruction of lung tissue leading to emphysema primarily caused by neutrophil elastase. Neutrophil elastase plays an important role in disease progression in COPD patients and has emerged as an important target for drug discovery. Sonneratia apetala Buch.-Ham. is a mangrove plant belonging to family Sonneratiaceae. It is widely found in the Sundarban regions of India. While the fruits of this plant have antibacterial, antifungal, antioxidant and astringent activities, fruit and leaf extracts have been shown to reduce the symptoms of asthma and cough. The aim of this study is to find whether hydro alcoholic fruit extracts of S. apetala inhibit neutrophil elastase and thus prevent the progression of neutrophil elastase-driven lung emphysema. The hydroalcoholic extract, ethanol: water (90:10), of the S. apetala Buch.-Ham. fresh fruits (SAM) were used for neutrophil elastase enzyme kinetic assay and IC50 of the extract was determined. The novel HPLC method has been developed and the extract was standardized with gallic acid and ellagic acid as standards. The extract was further subjected to LC-MS2 profiling to identify key phytochemicals. The standardized SAM extract contains 53 μg/mg of gallic acid and 95 μg/mg of ellagic acid, based on the HPLC calibration curve. SAM also reversed the elastase-induced morphological change of human epithelial cells and prevented the release of ICAM-1 in vitro and an MTT assay was conducted to assess the viability. Further, 10 mg/kg SAM had reduced alveolar collapse induced by neutrophil elastase in the mice model. Thus, in this study, we reported for the first time that S. apetala fruit extract has the potential to inhibit human neutrophil elastase in vitro and in vivo

Proinflammatory Role of let-7 miRNAs in Experimental Asthma?

Polikepahad et al. (1) recently reported that let-7 microRNAs have proinflammatory roles because inhibition of let-7a to let-7d alleviated the features of experimental asthma. However, there are serious drawbacks in the study design and interpretations. First, the in vivo findings in an IL-13-driven asthma model are exactly opposite to their in vitro observations where they found that let-7 inhibited IL-13. Although they suggest that this discrepancy could be because of secondary and tertiary effects of let-7 inhibition on the other proinflammatory genes, this is at best speculative and no evidence is provided in support. Second, because there was no change in let-7 in the asthma model, it is unclear why they chose to inhibit only a few selected let-7 members, whereas abundant let-7 members like let-7f were not inhibited. This is worrisome because all let-7 members share the seed region match with IL-13, and a loss of function experiment cannot be properly done unless all members were inhibited. Third, they do not report a more relevant gain-of-function experiment where any of the let-7 members could have been used to inhibit IL-13 in vivo. This is particularly surprising because it would be the logical follow-through of their in vitro data. In absence of this critical experiment, we consider their counterintuitive conclusions to be unreliable and possibly due to existence and/or bystander increase in other let-7 members due to Dicer negative feedback loop (2, 3). Thus the proinflammatory role of Let-7 in asthma is not well justified and further investigations are required to determine the exact role of let-7 in asthma

Mepacrine inhibits subepithelial fibrosis by reducing the expression of arginase and TGF-β<SUB>1</SUB> in an extended subacute mouse model of allergic asthma

Asthma is a dynamic disorder of airway inflammation and airway remodeling with an imbalance in T helper type 1 (Th1)/Th2 immune response. Increased Th2 cytokines such as IL-4 and IL-13 induce arginase either directly or indirectly through transforming growth factor-β1 (TGF-β1) and lead to subepithelial fibrosis, which is a crucial component of airway remodeling. Synthetic antimalarials have been reported to have immunomodulatory properties. Mepacrine is known for its reduction of airway inflammation in short-term allergen challenge model by reducing Th2 cytokines and cysteinyl leukotrienes, which has an important role in the development of airway remodeling features. Therefore, we hypothesized that mepacrine may reduce airway remodeling. For this, extended subacute ovalbumin mice model of asthma was developed; these mice showed an increased expression of profibrotic mediators, subepithelial fibrosis, and goblet cell metaplasia along with airway inflammation, increased Th2 cytokines, allergen-specific IgE, IgG1, increased cytosolic PLA2 (cPLA2), and airway hyperresponsiveness. Presence of intraepithelial eosinophils and significant TGF-β1 expression in subepithelial mesenchymal regions by repeated allergen exposures indicate that asthmatic mice of this study have developed human mimicking as well as late stages of asthma. However, mepacrine treatment decreased Th2 cytokines and subepithelial fibrosis and alleviated asthma features. These reductions by mepacrine were associated with a decrease in levels and expression of TGF-β1 and the reduction in activity, expression of arginase in lung cytosol, and immunolocalization in inflammatory cells present in perivascular and peribronchial regions. These results suggest that mepacrine might reduce the development of subepithelial fibrosis by reducing the arginase and TGF-β1. These effects of mepacrine likely underlie its antiairway remodeling action in asthma

Novel approaches for inhibition of Mucus hypersecretion in asthma

Many obstructive airway disorders such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease (COPD) are characterized by mucous metaplasia of the airway epithelium and chronic mucus hypersecretion. Airway occlusion by mucus plugging has been reported in many cases of fatal asthma and conventional mucolytic therapies have been unable to significantly affect mucus-related airway obstruction. Recently, for the first time, direct evidence was presented for improvement of mucus related airway obstruction in a murine model of asthma, highlighting the potential usefulness of therapeutically targeting mucus hypersecretion. We review the emerging targets for inhibition of mucus hypersecretion and discuss some of the recent published scientific literature and patent applications in this field, to provide a framework for further drug discovery in mucus modulation

Emerging interface between metabolic syndrome and asthma

There is growing epidemiological evidence that obesity increases the risk of developing asthma. In some studies, insulin resistance or metabolic syndrome is a stronger risk factor than body mass. The obese-asthma subphenotype is marked by a paucity of inflammation but also by marked symptoms, poor response to glucocorticoids, and peripheral airway dysfunction. Although obesity may predispose to increased Th2 inflammation or atopic tendencies, other mechanisms that are independent of inflammatory cells need to be considered. There is growing evidence of the influence of hyperglycemia, hyperinsulinemia, and insulin-like growth factors on airway structure and function. Also, studies from mouse models of asthma have highlighted the importance of nitric oxide-arginine metabolism abnormalities and oxonitrosative stress in lungs. Such changes are well established features of the metabolic syndrome and may represent an interface between these diseases that can be therapeutically targeted. Such therapies, including administration of L-arginine or statins, increasing endothelial nitric oxide synthase, or the use of arginase inhibitors, have been successful in experimental models but have not yet translated to the clinical arena. We review the current understanding of the potential mechanistic links between obesity and asthma, emphasizing the potential influence of metabolic abnormalities on asthmatic processes, therapeutic implications, and expected challenges

Mepacrine treatment attenuates allergic airway remodeling segregated from airway inflammation in mice

Asthma is a chronic airway disease characterized by increased airway hyperresponsiveness, airway inflammation, and airway remodeling including collagen deposition in subepithelial regions. We have shown earlier that mepacrine has anti-inflammatory activity and decreased the features of airway remodeling in a subacute model of asthma, when administered during the inflammatory phase. But it was not clear whether the reduction of airway remodeling by mepacrine was a direct effect or indirectly related to the reduction in the airway inflammation. In this study, we determined the effect of mepacrine on airway remodeling and airway hyperresponsiveness (AHR) in a chronic model of asthma which showed the features of airway inflammation in the initial stage (inflammation predominant stage) and airway remodeling with mild airway inflammation in a later stage (remodeling predominant stage). Mepacrine was administered only in the later stage that more accurately simulates human asthma, where airway remodeling already exists at the time of diagnosis. The remodeling predominant stage was associated with high levels of Th2 cytokines like IL-4 and IL-13, increase in the levels of profibrotic mediators such as arginase and TGF-α, and increased collagen deposition. These were efficiently attenuated by mepacrine treatment and led to a significant reduction in AHR. Thus, we conclude from this study that mepacrine has direct effects on established airway remodeling independent of its anti-inflammatory effects

Airway Epithelium: A Neglected but Crucial Cell Type in Asthma Pathobiology

The features of allergic asthma are believed to be mediated mostly through the Th2 immune response. In this Th2-dominant concept, the airway epithelium is presented as the helpless victim of Th2 cytokines. However, this Th2-dominant concept is inadequate to fill some of the vital knowledge gaps in asthma pathogenesis, like the poor correlation between airway inflammation and airway remodeling and severe asthma endotypes, including Th2-low asthma, therapy resistance, etc. Since the discovery of type 2 innate lymphoid cells in 2010, asthma researchers started believing in that the airway epithelium played a crucial role, as alarmins, which are the inducers of ILC2, are almost exclusively secreted by the airway epithelium. This underscores the eminence of airway epithelium in asthma pathogenesis. However, the airway epithelium has a bipartite functionality in sustaining healthy lung homeostasis and asthmatic lungs. On the one hand, the airway epithelium maintains lung homeostasis against environmental irritants/pollutants with the aid of its various armamentaria, including its chemosensory apparatus and detoxification system. Alternatively, it induces an ILC2-mediated type 2 immune response through alarmins to amplify the inflammatory response. However, the available evidence indicates that restoring epithelial health may attenuate asthmatic features. Thus, we conjecture that an epithelium-driven concept in asthma pathogenesis could fill most of the gaps in current asthma knowledge, and the incorporation of epithelial-protective agents to enhance the robustness of the epithelial barrier and the combative capacity of the airway epithelium against exogenous irritants/allergens may mitigate asthma incidence and severity, resulting in better asthma control