Bronchial asthma is a heterogenic disease characterized by persistent inflammation in the respiratory system, airway hyperreactivity, and reversible airflow obstruction, affecting approximately 300 million people worldwide [13,14]. Trends in asthma prevalence have fluctuated throughout the last decades; the overall number of asthma cases has remained consistent, though asthma-related deaths have decreased in recent years, reflecting improved therapeutic control. However, despite advances in modern healthcare, global asthma damage remains high, with about 450,000 asthma-related overall deaths and an economic burden that costs USD 50 billion annually [15,16]. In addition, it is one of the most widespread chronic lung pathology among pediatric patients [17].

At the present time, asthma is considered an “umbrella” diagnosis, unifying several diseases with different clinical manifestations (phenotypes) and pathophysiological mechanisms (endotypes) [18]. According to the Global Initiative for Asthma (GINA) definition, “asthma phenotypes” are recognizable clusters of demographic, clinical, and/or pathophysiological characteristics [19], while the term “endotypes” describes a subset of asthma with distinct molecular mechanisms and treatment response [20]. Today, the best-researched type of asthma is eosinophilic asthma, the most common type of this disease, also called T2-high endotype [21]. The T2-high endotype includes the following phenotypes: early-onset atopic (responsive to steroids), late-onset non-atopic eosinophilic (refractory to steroids), and aspirin-exacerbated respiratory disease (surgical treatment, sensitive to leukotriene modifiers).

Early-onset atopic asthma is the archetypal asthma phenotype, with a well-defined early onset indicated by blood or sputum eosinophil count, serum IgE, high FeNO, and high total IgE, and is sensitive to inhaled corticosteroids (ICS) therapy. It is distinguished from T2-high non-atopic asthma by positive skin prick tests and increased IgE [22].

Late-onset eosinophilic asthma is a subset of T2-high asthma manifesting in adulthood, notable for its higher severity and steroid resistance. The majority of these patients also have comorbid chronic rhinosinusitis with nasal polyps. Generally, this phenotype is characterized by prominent blood and sputum eosinophilia refractory to ICS treatment and normal or slightly elevated serum IgE levels. Additionally, it is believed that inflammation in this phenotype is driven by the production of IL-5 and IL-13 by innate lymphoid cells. Some patients also have sputum neutrophilia, indicating that Th2/Th17 interactions are taking place [23].

Aspirin-exacerbated respiratory disease (AERD) is a subset of late-onset eosinophilic asthma, characterized by dysregulated arachidonic acid metabolism, cysteinyl leukotrienes production, elevated eosinophils in the blood and sputum, high severity from the onset, and frequent exacerbations. Aspirin is a potent cyclooxygenase inhibitor, and it shifts arachidonic acid metabolism from the cyclooxygenase to the 5-lipooxygenase pathway. This leads to the overproduction of cysteinyl leukotrienes, which are potent bronchoconstrictors responsible for the clinical symptoms and resistance to conventional therapy for AERD [24].

Non-eosinophilic asthma, also known as T2-low or non-T2, is a less understood endotype of asthma and is typically defined by the absence of T2-high asthma signs, such as eosinophilia and elevated IgE, the presence of neutrophilic or paucigranulocytic inflammation, and resistance to ICS. Mechanisms underlying the manifestation of T2-low asthma and the maintenance of neutrophilic inflammation are currently unknown, but they have been associated with chronic infection, obesity, smoking, and smooth muscle abnormalities [25]. Therapeutic options are quite limited and consist of tiotropium and macrolides [26].

The etiology of bronchial asthma is currently unknown; however, there are plenty of risk factors, including genetic and environmental conditions [27]. Genetic factors include changes in the expression of several genes responsible for protein folding in the endoplasmic reticulum [27], epithelial [28], and eosinophil dysfunction [29]. Allergic airway diseases (such as allergic rhinitis) are also associated with an increased risk of asthma development [30]. Environmental factors include smoking (both active and passive) [31], air pollution (including automobile associated, such as black carbon and NO₂) [32], obesity [33], and professional risk factors, such as flour dust, animal and plant enzymes, tree resins, tobacco, polyisocyanate, acids, anhydrides, and metals [34,35].

Allergic asthma is considered one of the most widespread asthma types, developing due to sensitization to environmental allergens, mostly house dust, plant pollen, and mushroom spores [36]. After sensitization, asthma symptoms usually develop during second contact with the allergen [37]. Allergic reactions, activating the IgE dependent pathways, are the most common mechanism underlying asthma.

IgE is the main effector of type 1 hypersensitivity, underlying the development of asthmatic inflammation [38]. Its synthesis occurs either by direct class-switch recombination from IgM in germinal centers or through a “sequential” switch from IgM to IgG1 and then from IgG1 to IgE outside of germinal centers. The high-affinity receptor of IgE (FcεRI) is expressed on mast cells and basophils as a tetramer and on monocytes and dendritic cells as a trimer.

During the sensitization step of asthma development, IgE focuses the allergen on the cell surface through FcεRI, leading to the procession of the antigen-IgE complex and presentation through the major histocompatibility complex class II molecules, lowering the threshold for T-cell activation during the allergen challenge [39]. During the next contact with the allergen, inflammation is initiated when the antigen contacts IgE, presenting on all mast cells and basophiles. After contact, cells degranulate, releasing such mediators as histamine, heparin, proteases, and pro-inflammatory cytokines, which are responsible for the chemotaxis of inflammatory cells.

In addition to classic IgE, there is a cytokinergic IgE that facilitates asthmatic inflammation in the absence of allergens, making allergen avoidance an ineffective therapeutic strategy [40].

CD4+ lymphocytes also take part in the development of allergic asthma. After contact with antigen, T helpers type 2 (Th2) secrete pro-inflammatory cytokines, such as IL-4, IL-5, IL-9, and IL-13, which stimulate IgE production and inflammatory cell migration [41,42,43,44,45]. In turn, T helpers type 1 (Th1) start to secrete IL-2 and IFN-γ, activating macrophages and enhancing the cell immune response. T-cell immune response is additionally controlled by IL-1, IL-4, IL-12, and IL-18, secreted by dendritic cells [46]. The cascade of the aforementioned reactions leads to persisting inflammation in the lungs.

About one-third of bronchial asthma patients are believed to have non-allergic asthma, mediated by non-Th2 cytokines, including IL-17 and TNF-α, and characterized by the absence of allergen reactions in the skin prick tests and a decreased or unaffected amount of IgE, contrary to allergic asthma [47,48]. The mechanisms of non-allergic asthma development are currently unknown, but it is supposed that there are two parts to its pathogenesis: dysregulation of the neutrophilic immune response due to lung inflammation [49], and defects in IL-17 mediated signaling pathway [50], leading to the persisting inflammation [51].

Another group of cells that play a significant role in asthma and post-asthmatic fibrosis development are innate lymphoid cells (ILCs). It is a group of loosely related lymphocytes, characterized into five subgroups based on functions, origins, transcription factors, and cytokine expression patterns: natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue-inducer cells [52]. They are abundantly present in the tissue of organs performing barrier functions such as intestines, lungs, and skin. For quite some time, ILC2s have been established as crucial mediators of lung allergy, airway inflammation, and fibrosis, thus affecting the pathogenesis and clinical course of many respiratory diseases, like, for instance, asthma, cystic fibrosis, and chronic rhinosinusitis [53]. More specifically, ILC2s are activated by the alarmin cytokines IL-22 and IL-33, produced by the lung epithelium after contact with allergens, infections, and other injurious stimuli. After activation, ILC2s start producing IL-5, IL-13, and amphiregulin, which in turn recruit and stimulate eosinophils to release profibrotic cytokines such as TGF-β, PDGF, and IL-13, promoting the fibroblast-to-myofibroblast transition [54].

Pathomorphological changes in the bronchial asthma lungs can be divided into two patterns: alterations in bronchial epithelium and smooth muscles, prominent signs of asthma exacerbations, and subepithelial fibrosis, a characteristic of long-term asthma [55]. All these pathological changes lead to bronchial obstruction, which is reversible at the early stages of the disease and irreversible at the later ones.

During acute asthma development, hyperplasia and metaplasia of the goblet and epithelial cells of the bronchial epithelium, leading to mucus hyperproduction, thickening of the airways, and bronchial obstruction, are observed [56]. Moreover, in severe asthma exacerbations, large and small airways are often obstructed by mucus plugs with an admixture of inflammatory cells (mostly eosinophils in the case of allergic asthma) [57]. An additional factor leading to the formation of mucus plugs is the dysfunction of ciliated cells due to airway inflammation, characterized by a decrease in the frequency of its fluctuations as well as dyskinesia and disorientation of the cilia [58].

Spasm of the bronchial smooth musculature—bronchoconstriction—is another factor leading to airway obstruction. Under physiological conditions, bronchial smooth muscles provide mechanical stability to the airways without cartilage. However, hyperreactivity of asthmatic airways decreases smooth muscle sensitivity threshold, following spasm and reversible airway obstruction [59]. The accumulation of smooth muscle cells due to their hypertrophy and hyperplasia is another component of asthma pathomorphological changes, leading to airway thickening [60]. Moreover, it is believed that smooth muscle cells may support airway remodeling through the secretion of pro-inflammatory mediators, matrix and cell adhesion proteins, and other stimulatory molecules, affecting the further migration and activity of inflammatory cells [61].

The major characteristic of chronic asthmatic inflammation is subepithelial airway and, in some cases, lung fibrosis, consisting of connective tissue growth in the basal membrane and submucosal area. However, changes in the airways, leading to lung fibrosis, are present even in the earliest stages of asthma [55,62].