**5. Structural alterations in asthmatic airway walls**

#### **5.1. Epithelial/subepithelial layer thickening**

Epithelial changes are not unique to asthma, they are also observed, in more or less of similar manner, in lungs of smokers and cancer patients [61]. Epithelial layer damage in asthma includes loss of ciliated cell layer, shedding of the epithelium, goblet cell hyperplasia and growth factors, cytokine and chemokine upregulation [62].

One important feature of asthma, which has been routinely used as an asthma severity index, is the thickening of the subepithelial airways layer. The epithelial and subepithelial layer thickening is caused by the overdeposition of extracellular matrix (ECM) proteins [63]. Roche et al. observed that intensive layers of collagen sedimentation contribute to the thickened subepithelial basement membrane. Through immunohistochemistry, they have shown that the commonly involved collagen types are collagen I, III and V, and fibronectin [64]. Addi‐ tionally, the cells that are responsible for ECM protein production are myofibroblasts and fibroblasts, as both are embedded in the sophisticated ECM which they secrete [65]. Mean‐ while, some inflammatory cells, for example, T cells, mast cells, and eosinophils also accumu‐ late in the submucosal layer [66]. Moreover, transforming growth factor-β (TGF-β), and some similar growth factors, is usually secreted by the lung epithelial cells echoing any ongoing lung injury, and consequently directly impress the matrix proteins' production by fibroblasts/ myofibroblasts. By increasing the airway rigidity, however, Holgate et al. suggested that the airway thickening due to the ECM proteins precipitation may in fact have a remodeling protective effect via postponing long-term bronchoconstriction events [62]. Collectively, the ECM proteins, the lung structural cells (i.e., epithelial cells and fibroblasts), and the immune system inflammatory cells, all interact together and control the overall airway remodeling and fibrosis [67].

#### **5.2. Hyperproliferation of airway smooth muscle mass**

Hyperproliferation of airway smooth muscle mass is a common event in asthma and has been suggested to be implicated in its pathophysiology. Hyperplasia and hypertrophy of the ASM in the bronchial airways of asthmatics can be observed by three-dimensional (3D) morpho‐ metric studies [68]. Airways smooth muscle layer is estimated to be increased by 25–55% in nonfatal asthma and up to 50–200% in fatal asthma [69]. Meanwhile, in response to some growth factors like TGF-β, vascular endothelial growth factor (VEGF), and connective tissue growth factor (CTGF), ASM cells actively participate in the remodeling process through the process of ECM synthesis [70]. ASM cells also express cellular adhesion molecules (CAMs), receptors for cytokines (e.g., tumor necrosis factor-α), Toll-like receptors, and chemokines (eotaxin, macrophage inflammatory protein 1α, and interleukin 8) presenting multiple mechanisms for the inflammatory and remodeling process [71]. Additionally, one character‐ istic event of the airway remodeling is the ASM cells migration toward the epithelium [72]. Since ASM cells are crucial in asthma, Zuyderduyn et al. suggested that these cells should be targeted, rather than targeting inflammation or dealing with the symptoms [73].

#### **5.3. Angiogenesis**

**Figure 2.** Schematic representation of the major events underlying asthma pathophysiology.

142 Asthma - From Childhood Asthma to ACOS Phenotypes

**5. Structural alterations in asthmatic airway walls**

**5.1. Epithelial/subepithelial layer thickening**

not fully clear [60].

Asthma and COPD (chronic obstructive pulmonary disease) are now considered to be discrete respiratory disorders. Although both share several similar underlying mechanisms, driving airway obstruction in COPD, and hyperresponsiveness in asthma, core molecular pathology remains to be mostly different for both [54]. Pauwels et al. [55] defined COPD as "a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of lungs to noxious particles and gases." One important reason of asthma and COPD overlap is the effect of aging. Asthma-COPD overlap syndrome (ACOS) is a medically recognized coexisting syndrome of both asthma and COPD [56]. Some other health conditions may occur more frequently in asthmatic patients. Rhinosinusitis [57], obstructive sleep apnea [58], or GERD [59] are the most common documented comorbidities. Substantially, they can contribute to the same pathophysiological process, which is already triggered by allergic response or alter asthma phenotype detrimentally. The impact of these diseases on asthma is variable and still

Epithelial changes are not unique to asthma, they are also observed, in more or less of similar manner, in lungs of smokers and cancer patients [61]. Epithelial layer damage in asthma Accumulating evidences indicate that there is an abnormal elevation in the size and number of blood vessels, as well as microvessels vascular leakage within the bronchial tissue in remodeled airways [74]. It is assumed that VEGF strongly affects airways remodeling via its angiogenic effects, but the exact molecular mechanism linking the increase in the VEGF expression to remodeling of the airways has not been fully understood [75].

Correlation between angiogenesis and asthma severity has also been documented. Dense vascularity occurs in severe asthmatics, followed by moderate, and then finally mild asthmat‐ ics, who experience less angiogenesis events [76]. This pattern was also observed in fatal asthmatics compared with nonfatal asthmatics [77]. While current asthma therapeutics is not directly targeting vascular remodeling, recent trials investigate some anti-angiogenic therapies as a new approach for asthma. Yuksel et al. showed that Bevucizamab, which significantly neutralizes VEGF, results in a reduced thickening of lung epithelium, a reduced ASM, and a reduced basement membrane thickness compared with untreated ovalbumin (OVA)-chal‐ lenged mice [78].
