Pathology of asthma

Abstract

Asthma is a serious health and socioeconomic issue all over the world, affecting more than 300 million individuals. The disease is considered as an inflammatory disease in the airway, leading to airway hyperresponsiveness, obstruction, mucus hyper-production and airway wall remodeling. The presence of airway inflammation in asthmatic patients has been found in the nineteenth century. As the information in patients with asthma increase, paradigm change in immunology and molecular biology have resulted in an extensive evaluation of inflammatory cells and mediators involved in the pathophysiology of asthma. Moreover, it is recognized that airway remodeling into detail, characterized by thickening of the airway wall, can be profound consequences on the mechanics of airway narrowing and contribute to the chronic progression of the disease. Epithelial to mesenchymal transition plays an important role in airway remodeling. These epithelial and mesenchymal cells cause persistence of the inflammatory infiltration and induce histological changes in the airway wall, increasing thickness of the basement membrane, collagen deposition and smooth muscle hypertrophy and hyperplasia. Resulting of airway inflammation, airway remodeling leads to the airway wall thickening and induces increased airway smooth muscle mass, which generate asthmatic symptoms. Asthma is classically recognized as the typical Th2 disease, with increased IgE levels and eosinophilic inflammation in the airway. Emerging Th2 cytokines modulates the airway inflammation, which induces airway remodeling. Biological agents, which have specific molecular targets for these Th2 cytokines, are available and clinical trials for asthma are ongoing. However, the relatively simple paradigm has been doubted because of the realization that strategies designed to suppress Th2 function are not effective enough for all patients in the clinical trials. In the future, it is required to understand more details for phenotypes of asthma.

Keywords: Th17 cells; Th2 cells; Th9 cell; asthma; cytokines; epithelial to mesenchymal transition; remodeling.

FIGURE 1

Regulation of ASM contractility. ASM contraction is induced by calcium, regulated two different pathways. First, ASM is evoked by intracellular calcium influx from SR depending on GPCR stimulation or from the extracellular environment through voltage-dependent calcium channel. Second, smooth muscle can be induced calcium sensitivity by RhoA/Rho kinase pathway. RhoA activates Rho-kinase which phosphorylates MLCP. pMLC phosphatase fails to dephosphorylate MLC. KCl, potassium chloride; Ach, acetylcholine; 5-HT, 5-hydroxytryptamine (serotonin); PIP, phosphatidylinositol 4-phosphate; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP5K, 1-phosphatidylinositol-4-phosphate 5-kinase; DG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate.

FIGURE 2

T cell immune response in the asthmatic airways. naїve T cell is received allergen presentation by DCs. The pathway begins with the development of Th2 cells and their production of the cytokines IL-4, IL-5, and IL-13. These cytokines stimulate allergic and eosinophilic inflammation as well as epithelial and smooth-muscle changes that contribute to asthma pathobiology. Th9 cell can be induced and stimulate mast cells by IL-9. naїve T cell is also differentiated to Th1 or Th17 cells depending on the existence of cytokines in the microenvironment. Th1 cell and Th17 cell stimulate and induce neutrophilic inflammation. EMT, epithelial-mesenchymal-myofibroblast transition; MMP, matrix metalloproteinase; MBP, major basic protein; LT, leukotriene.

FIGURE 3

T helper cell subsets and cytokine profiles. Th1, Th2 and Th17 cells are a separate lineage of CD4+ T cells, distinct from other T cell subsets. Every specific T helper cells produce its specific cytokines (Lazarevic and Glimcher, 2011). T-bet, T-box expressed in T cells; FoxP3, forkhead box P3; ROR, retinoid-related orphan receptor.