Glucocorticoid and Estrogen Receptors Are Reduced in Mitochondria of Lung Epithelial Cells in Asthma

Mitochondrial glucocorticoid (mtGR) and estrogen (mtER) receptors participate in the coordination of the cell’s energy requirement and in the mitochondrial oxidative phosphorylation enzyme (OXPHOS) biosynthesis, affecting reactive oxygen species (ROS) generation and induction of apoptosis. Although activation of mtGR and mtER is known to trigger anti-inflammatory signals, little information exists on the presence of these receptors in lung tissue and their role in respiratory physiology and disease. Using a mouse model of allergic airway inflammation disease and applying confocal microscopy, subcellular fractionation, and Western blot analysis we showed mitochondrial localization of GRα and ERβ in lung tissue. Allergic airway inflammation caused reduction in mtGRα, mtERβ, and OXPHOS enzyme biosynthesis in lung cells mitochondria and particularly in bronchial epithelial cells mitochondria, which was accompanied by decrease in lung mitochondrial mass and induction of apoptosis. Confirmation and validation of the reduction of the mitochondrial receptors in lung epithelial cells in human asthma was achieved by analyzing autopsies from fatal asthma cases. The presence of the mitochondrial GRα and ERβ in lung tissue cells and especially their reduction in bronchial epithelial cells during allergic airway inflammation suggests a crucial role of these receptors in the regulation of mitochondrial function in asthma, implicating their involvement in the pathophysiology of the disease

Genetics of asthma: a molecular biologist perspective

Asthma belongs to the category of classical allergic diseases which generally arise due to IgE mediated hypersensitivity to environmental triggers. Since its prevalence is very high in developed or urbanized societies it is also referred to as "disease of civilizations". Due to its increased prevalence among related individuals, it was understood quite long back that it is a genetic disorder. Well designed epidemiological studies reinforced these views. The advent of modern biological technology saw further refinements in our understanding of genetics of asthma and led to the realization that asthma is not a disorder with simple Mendelian mode of inheritance but a multifactorial disorder of the airways brought about by complex interaction between genetic and environmental factors. Current asthma research has witnessed evidences that are compelling researchers to redefine asthma altogether. Although no consensus exists among workers regarding its definition, it seems obvious that several pathologies, all affecting the airways, have been clubbed into one common category called asthma. Needless to say, genetic studies have led from the front in bringing about these transformations. Genomics, molecular biology, immunology and other interrelated disciplines have unearthed data that has changed the way we think about asthma now. In this review, we center our discussions on genetic basis of asthma; the molecular mechanisms involved in its pathogenesis. Taking cue from the existing data we would briefly ponder over the future directions that should improve our understanding of asthma pathogenesis

15-Lipoxygenase eicosanoids are the putative ligands for vanilloid receptors and peroxisome proliferator-activated receptors (PPARs)

We read the article by Zhao et al. (1), which showed that epithelial 15-lipoxygenase 1 (15LO1) and its product 15-hydroxyeicosatetraenoic acid phosphatidylethanolamine interact with phosphatidylethanolamine-binding protein (PEBP1) to enhance MAPK signaling (ERK activation) in human airway epithelia. This can then be seen as an internal mechanism in airway epithelium for adjusting the gain settings of critical inflammatory pathways integral to asthma pathogenesis. However, this model rests critically on three assumptions: (i) Epithelial 15LO1 is the major form of 15LO1 and the source of 15S-hydroxyeicosatetraenoic acid (15S-HETE), (ii) metabolites or eicosanoids of 15LO1 such as 15S-HETE are not released extracellularly, and (iii) these eicosanoids do not influence MAPK

CCR5Δ32 deletion and atopic asthma in India

Chemokine receptor 5 (CCR5) contributes to the generation of a Th1 immune response by interacting with agonists such as RANTES, MIP-1α , and MIP-1β .1 A 32 base pair deletion (Δ 32) in CCR5 has been proposed to protect individuals against HIV infection and to bias the immune system towards a Th2-driven response, thus affecting the susceptibility to develop allergic diseases such as asthma. In a study in Scottish children, Hall et al reported an association of CCR5Δ 32 with a reduced risk of asthma2 but found

Glycyrrhizin alleviates experimental allergic asthma in mice

Asthma is a chronic respiratory disease, the incidence of which is increasing globally. The existing therapy is inadequate and has many adverse effects. It needs a better therapeutic molecule preferably of natural origin, which has negligible or no adverse effects. In view of this, we evaluated Glycyrrhizin (GRZ), a major constituent of a plant Glycyrrhiza glabra, for its efficacy on asthmatic features in a mouse model of asthma. BALB/c mice were sensitized and challenged with ovalbumin (OVA) to develop the asthmatic features such as airway hyperresponsiveness: allergen induced airway constriction and airway hyperreactivity (AHR) to methacholine (MCh), and pulmonary inflammation. The mice were orally treated with GRZ (2.5, 5, 10 and 20 mg/kg) during or after OVA-sensitization and OVA-challenge to evaluate its protective or reversal effect, respectively on the above asthmatic features. The status of airway hyperresponsiveness was measured by monitoring specific airway conductance (SGaw) using a non-invasive method and the pulmonary inflammation was assessed by haematoxylin and eosin staining of lung sections. Several other parameters associated with asthma such as interleukin (IL)-4, IL-5 interferon-&#947; (IFN-&#947; ), OVA-specific IgE, total IgG<SUB>2a</SUB> and cortisol were measured by ELISA. GRZ (5 mg/kg) markedly inhibited OVA-induced immediate airway constriction, AHR to MCh (p &lt; 0.01), lung inflammation, and infiltration of eosinophils in the peribronchial and perivascular areas. It prevented the reduction of IFN-&#947; (p &lt; 0.02), and decreased IL-4 (p &lt; 0.05), IL-5 (p &lt; 0.05) and eosinophils (p &lt; 0.0002) in the BAL fluid. Also, it reduced OVA-specific IgE levels (p &lt; 0.01) and prevented the reduction of total IgG<SUB>2a</SUB> (p &lt; 0.01) in serum. We have also showed that it has no effect on serum cortisol levels. Our results demonstrate that GRZ alleviates asthmatic features in mice and it could be useful towards developing a better therapeutic molecule in the future