Pathogenesis of asthma

INTRODUCTION — The "classic" signs and symptoms of asthma are intermittent dyspnea, cough, and wheezing. This well-recognized syndrome is characterized by variable airflow limitation and by airway hyperresponsiveness, which represents an exaggerated contractile response of the airways to a variety of stimuli.

The inflammatory, physiologic, and structural factors that contribute to the pathogenesis of asthma will be reviewed here, focusing on aspects that aid in the understanding of the clinical presentation of asthma and its treatment.

Discussions of the genetics, clinical risk factors (eg, atopy, allergen exposure, viral illness, gender, and smoking), diagnosis, and management of asthma are provided separately. (See "Genetics of asthma" and "Risk factors for asthma" and "Asthma in adolescents and adults: Evaluation and diagnosis" and "Asthma in children younger than 12 years: Initial evaluation and diagnosis" and "An overview of asthma management".)

ATOPY — Atopy, or the genetic predisposition to develop specific immunoglobulin E (IgE) antibodies directed against common environmental allergens, is the strongest identifiable risk factor for the development of asthma [1]. While the association of asthma and atopy is undisputed, the pathways by which atopy is expressed as clinical asthma and by which asthma occurs in the absence of atopy are not as clearly defined [1].

Intrinsic abnormalities in airway smooth muscle function, airway remodeling in response to injury or inflammation, and interactions between epithelial and mesenchymal cells appear to modulate and add to the effects of airway inflammation in creating the clinical presentation of asthma. Different phenotypes of asthma that can be defined clinically reinforce the notion that asthma is really a syndrome with multiple underlying mechanisms [2].

AIRWAY INFLAMMATION — Airway biopsies obtained by bronchoscopy have demonstrated that inflammation in asthma generally involves the same cells that play prominent roles in the allergic response in the nasal passages and skin, whether the individual is atopic or not. This supports the belief that the consequences of mast cell activation, mediated by a variety of cells, cytokines, and other mediators, are key to the development of clinical asthma. (See "Pathogenesis of allergic rhinitis (rhinosinusitis)".)

Mast cell activation by allergen provides a good model for asthma and will be described in this section. Accumulated evidence suggests that the following sequence of events explains how inhalation of allergen leads to the early, or immediate, phase of airway inflammation, which is followed about six hours later by a late phase reaction.

●Initial allergen exposure is followed by elaboration of specific IgE antibodies. Regulation of specific IgE production appears related to an overexpression of Th2 type T cell responses relative to the Th1 type; this overexpression is likely due to a combination of genetic and environmental influences. (See "The adaptive cellular immune response: T cells and cytokines".)

●After allergen specific IgE antibodies are synthesized and secreted by plasma cells, they bind to high-affinity receptors on mast cells (and basophils). (See "The biology of IgE".)

●When an allergen is subsequently inhaled and comes into contact with mucosal mast cells, it cross links allergen-specific IgE antibodies on the mast cell surface; rapid degranulation and mediator release follow in a calcium dependent process. This is known as the early or immediate phase reaction, which is described in the next section. (See "Mast cell-derived mediators".)

Early and late phase reactions

●Early phase reactions – In human studies of allergen bronchoprovocation, allergen inhalation by a sensitized individual leads to bronchoconstriction within several minutes. This is called the early response and correlates with the release of mast cell mediators during the immediate hypersensitivity reaction detailed above [3]. These mediators, including histamine, prostaglandin D2, and cysteinyl leukotrienes (LTC4, D4, and E4), contract airway smooth muscle (ASM) directly, and may also stimulate reflex neural pathways [3,4].

●Late phase reactions – This early phase reaction is sometimes followed by a late phase recurrence of bronchoconstriction several hours later. The late phase response coincides with an influx of inflammatory cells, including innate immune cells such as monocytes, dendritic cells, and neutrophils, and cells associated with adaptive immunity such as T lymphocytes, eosinophils, and basophils. The mediators released by these cells also cause ASM contraction that is largely reversible by beta-agonist administration [5]. However, the observation that beta-agonists do not completely reverse airflow obstruction caused by allergen inhalation is evidence that the late phase reaction is more complex than just ASM contraction.

The late phase response is characterized by recruitment of inflammatory and immune cells, particularly the eosinophil, basophil, neutrophil, and helper, memory T-cells to sites of allergen exposure [3]. Monocytes and dendritic cells are also recruited to inflammatory sites and likely play important roles in mediating or modulating the response to allergen exposure [6]. The roles of these various inflammatory cells are described in the next sections.

Eosinophils — The eosinophil is the most characteristic cell that accumulates in asthma and allergic inflammation. While the presence of eosinophils is often related to disease severity, some patients with asthma do not have eosinophilic infiltration of the airways [7]. (See 'Clinical correlation' below.)

Activated eosinophils produce lipid mediators, such as leukotrienes and platelet activating factor, that mediate smooth muscle contraction; toxic granule products (eg, major basic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, or eosinophil cationic protein) that can damage airway epithelium and nerves; and cytokines, such as granulocyte-macrophage colony stimulating factor (GM-CSF), transforming growth factors (TGF)-alpha and beta, and interleukins that may be involved in airway remodeling and fibrosis.

Eosinophils are recruited or activated by the hematopoietin interleukin 5 (IL-5), by the eotaxin family of chemokines via the eosinophil-selective chemokine receptor CCR3, and by Toll-like receptors (TLR) [8].

Mast cells — Mast cells are increased in number in asthmatic airways and may be found in close association with airway smooth muscle cells [9]. In addition to producing bronchoconstricting mediators (eg, histamine, certain prostaglandins, and leukotrienes), mast cells also store and release tumor necrosis factor (TNF)-alpha, which is important in the recruitment and activation of inflammatory cells and in altered function and growth of ASM [10-13]. (See "Mast cell-derived mediators" and "Mast cells: Surface receptors and signal transduction".)

Th2 lymphocytes — The T cell population infiltrating the asthmatic airway is characterized by the T-helper 2 subset (Th2) of lymphocytes that produces a restricted panel of cytokines, including interleukin (IL)-3, IL-4, IL-5, IL-13, and GM-CSF, but not interferon gamma, when stimulated with antigen [14]. Th2 lymphocytes also express the chemokine receptors (CCR4 and CCR8) and the chemoattractant receptor (CR)-like molecule (CRTH2), a receptor for prostaglandin D2 (PGD2), suggesting potential interactions between the mast cell and chemotactic signals that target eosinophils and Th2 cells and that sustain airway inflammation [15-17]. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytokine profiles and functions of CD4+ T helper cell subsets'.)

The actions of the following cytokines produced by Th2 lymphocytes strongly suggest that they play critical roles in asthma and allergic responses.

●IL-3 is a survival factor for eosinophils and basophils.

●IL-4 helps in the differentiation of uncommitted T cells into Th2 cells, switch of B-lymphocyte immunoglobulin synthesis to IgE production, and selective endothelial cell expression of vascular cell adhesion molecule-1 (VCAM-1) that mediates eosinophil, basophil, and T cell specific recruitment.

●IL-5 is the major hematopoietic cytokine regulating eosinophil production and survival.

●IL-13 appears to contribute to airway eosinophilia, mucous gland hyperplasia, airway fibrosis, and remodeling [18,19].

●GM-CSF is also a survival factor for eosinophils.

The anti-IL-5 monoclonal antibodies (benralizumab, mepolizumab, and reslizumab) and the anti-IL-4 receptor alpha antibody (dupilumab) that interrupts both IL-4 and IL-13 signalling are in widespread use for severe uncontrolled asthma, demonstrating the important role that these cytokines play in asthma pathogenesis. Clinical studies have not, however, documented a benefit to the anti-IL-13 monoclonal antibodies, lebrikizumab and tralokinumab. These agents are described in greater detail separately. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-IL-5 therapy' and "Treatment of severe asthma in adolescents and adults", section on 'Anti-lL-4 receptor alpha subunit antibody (dupilumab)' and "Investigational agents for asthma", section on 'Anti-IL-13 antibodies'.)

NKT cells — It is hypothesized that invariant natural killer T (iNKT) cells direct or modulate asthma inflammation. iNKT cells express a conserved T-cell receptor (V[alpha]24–J[alpha]18), which is capable of recognizing glycolipid antigens, such as those from plant pollens. They rapidly produce both IL-4 and IL-13, which are involved in airway inflammation and IgE production.

In one study, 63 percent of the CD4+ T lymphocytes in the airways of 14 patients with severe asthma were iNKT cells, compared to less than 1 percent in normal controls [20]. However, this finding was not confirmed in another study [21].

Basophils — While Th2 lymphocytes are a major source of the cytokines thought to participate in asthma, the basophil, in addition to producing histamine and leukotrienes, is a potent producer of IL-4 and IL-13, exceeding levels produced by T cells [22].

Innate immunity — The innate immune system appears to play an important role in the development of allergic airway inflammation [23]. Evidence for this includes the following key observations:

●Airway epithelial cells express TLR on their surface, including TLR 4, a receptor that recognizes lipopolysaccharide (LPS). In addition to being a constituent of gram negative bacteria, LPS is a contaminant of inhalational allergens like house dust and animal dander. In a mouse model of asthma, inhalation of house dust extract appears to trigger airway epithelial cell TLR 4, leading to elaboration of the proallergenic cytokines IL-5, IL-13, IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) [24].

●Innate lymphoid cells Type 2 (ILC2) are a group of innate immune cells that are potent producers of Th2 cytokines, particularly IL-5 and IL-13, as well as IL-4 under certain conditions. They are directly activated by the epithelial cytokines IL-25, IL-33, and TSLP; lipid mediators from mast cells, such as PGD2 and cysteinyl leukotrienes; and by viruses and allergens. These features suggest an important role for ILC2 in Th2 inflammation that is non-allergic [25-27].

●Dendritic cells, which form a network of innate immune cells within the airway, are increased in asthma and after allergen challenge [6,28]. These cells are essential, not only to the initial induction of specific or adaptive immunity due to their role in antigen processing and presentation, but also in the effector phase of response to allergen following host sensitization [29].

●Neutrophils are the predominant granulocyte in the airways of some patients with severe, glucocorticoid-dependent asthma, sudden fatal asthma, and asthma exacerbations [30-32]. Their exact role in the pathogenesis of severe asthma is not known.

Clinical correlation — In general, there is some correlation between intensity of airway inflammatory changes (eg, airway eosinophils) and disease severity. However, in certain circumstances, the intensity of allergic type inflammatory changes does not correlate with disease severity. For instance, in severe asthma, defined in part by its poor response to glucocorticoid therapy, neutrophil-predominant inflammation may play a role [30]. (See "Severe asthma phenotypes".)

Studies of which medications are effective or ineffective as treatments for asthma also enhance our understanding of the role of airway inflammation and mast cell mediators in the pathophysiology of asthma. (See "Anti-IgE therapy" and "Treatment of severe asthma in adolescents and adults", section on 'Persistently uncontrolled asthma'.)

As examples:

●Pharmacologic studies have clearly confirmed important roles for IgE and leukotrienes in the physiologic changes that occur during both the immediate and late phase asthma responses.

●Clinical treatment with anti-IgE monoclonal antibodies, antihistamines, and leukotriene modifying agents blocks significant portions of both early and late phase responses to allergen [33,34].

●Treatments that target asthma inflammation (eg, glucocorticoids, anti-IgE) block the late phase response and improve control of asthma [1,35-37]. (See "Anti-IgE therapy".)

●The success of leukotriene-modifying therapies for asthma management provides validation that mast cells, basophils, and leukotrienes participate in chronic asthma [38,39].

●The fact that dramatic reductions in eosinophils with monoclonal antibodies to interleukin 5 did not lead to improved asthma control in initial trials underscores the complexity of asthma pathogenesis [40-42]. The subsequent success of several anti-IL-5 therapies in patients with severe eosinophilic asthma uncontrolled by standard therapies highlights the importance of patient selection for targeted therapeutic trials. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-IL-5 therapy'.)

●Similarly, biologic agents targeting the IL-4/IL-13 receptor pathway have demonstrated efficacy in severe uncontrolled asthma, providing further confirmation of the role of the Th2 pathway and associated cytokines in selected asthma patients. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-lL-4 receptor alpha subunit antibody (dupilumab)'.)

●The importance of the cytokine thymic stromal lymphopoietin (TSLP) in the pathogenesis of asthma inflammation is supported by clinical trials showing a reduction in exacerbations in patients with uncontrolled asthma, independent of baseline eosinophil counts, treated with the anti-TSLP agent tezepelumab. (See "Treatment of severe asthma in adolescents and adults", section on 'Persistently uncontrolled asthma' and "Treatment of severe asthma in adolescents and adults", section on 'Anti-thymic stromal lymphopoietin (tezepelumab)'.)

EPITHELIAL-MESENCHYMAL CONTRIBUTION — An alternate paradigm for asthma pathogenesis has been proposed in which the "epithelial-mesenchymal trophic unit" plays a central role in inflammation and remodeling [43]. According to this theory, structural cells, particularly bronchial epithelial cells, fibroblasts, smooth muscle, and vascular endothelial cells, elaborate mediators and cytokines that contribute to inflammation and/or airway remodeling. In this view, epithelial dysfunction and Th2 mediated inflammation serve as parallel pathways for proliferative signals to smooth muscle, fibroblasts, vessels, and nerves that collaborate to cause airway remodeling via interconnected chemokine and cytokine signals.

Evidence for epithelial-mesenchymal communication in asthma includes the following:

●Release of pro-fibrogenic and proliferative growth factors by bronchial epithelial cells is increased in asthma; these factors (eg, fibroblast growth factor (FGF-2), insulin-like growth factor (IGF-1), platelet-derived growth factor (PDGF), endothelin (ET-1), and transforming growth factor (TGF)-beta2) act on smooth muscle cells and fibroblasts to enhance matrix deposition (figure 1) [44].

●In an animal model, IL-13 caused enhanced production of TGF-beta2 by epithelial cells [45]. TGF-beta2 may promote fibroblast to myofibroblast differentiation, collagen production, and elaboration of additional growth factors [45,46].

●Epidermal growth factor receptor (EGFR) expression is increased in asthmatic airway epithelium and correlates with subbasement membrane thickness [47].

●Matrix metalloproteinase-9 expression is enhanced in the sub-basement membrane in patients with severe asthma and support ongoing damage and repair responses contributing to airway remodeling [47,48].

●The finding of increased mast cells within airway smooth muscle in asthma suggests that the asthmatic smooth muscle itself may promote mast cell proliferation. Both airway smooth muscle cells and fibroblasts can produce c-kit ligand or stem cell factor (SCF), a growth factor for mast cells [49].

●The Th2 cytokines, IL-4 and IL-13 may also influence mesenchymal function by increasing release of TGF-beta2 from the epithelium [43,50].

PHYSIOLOGY OF AIRFLOW OBSTRUCTION — Variable narrowing of the airway lumen causing variable reductions in airflow is a pathognomonic feature of asthma. Mechanisms causing airflow limitation include contraction of airway smooth muscle, thickening of the airway wall due to edema or cellular components, plugging of airways with mucus or cellular debris, and airway remodeling. (See 'Airway remodeling' below.)

Smooth muscle — Contraction and relaxation of airway smooth muscle (ASM) accounts for much of the rapid changes in airflow limitation characterizing asthma and is the basis for beta-agonist therapy that directly relaxes ASM. Bronchoconstriction may be due to direct effects of contractile agonists released from inflammatory cells or reflex neural mechanisms. As an example, mast cell and eosinophil mediators, such as leukotrienes C4, D4, and E4 and histamine, are potent bronchoconstrictors.

Airway inflammation occurs throughout the tracheobronchial tree; varying degrees of obstruction of different diameter airways may determine disease physiology. In theory, obstruction in large airways leads to airflow limitation and decreased flow rates, while obstruction in small airways (ie, diameter less than 2 mm) leads to airway closure at low lung volumes, air trapping with an increase in residual volume, and in many cases, dynamic hyperinflation [51]. Hyperinflation may compensate for airway narrowing by increasing the tethering forces of the lung parenchyma that oppose airway narrowing at increasing lung volumes, a phenomenon known as airway-parenchymal interdependence [52].

If airway obstruction is widespread, dynamic hyperinflation is more likely to lead to increases in total lung capacity (TLC); less widespread obstruction is less likely to increase TLC, but may cause local areas of hyperinflation. Much of the chest tightness and discomfort of an asthma attack may be due to air trapping and breathing at higher lung volumes to maintain airway patency and sustain adequate ventilation (figure 2).

The relative contributions of small and large airways to airflow obstruction have also been evaluated. Marked (sevenfold) increases in resistance in small airways have been documented in patients with mild asthma, despite normal spirometry; the small airways appear to be a key site of airway closure due to ASM contraction [51,53].

However, the notion that the small airways are the predominant site of airway narrowing in asthma has been challenged by imaging studies in patients with asthma. These studies suggest that even large airways can close with ASM contraction [54]. Studies using high resolution computed tomography (HRCT) in patients with asthma found heterogeneous narrowing of large airways often with recurring patterns of airway narrowing within individuals [55]. By hyperpolarized helium nuclear magnetic resonance imaging of asthmatic lungs, wedge-shaped ventilation defects were demonstrated consistent with narrowing or closure of segmental or subsegmental airways. The extent of these defects correlated with asthma severity and spirometry [56].

Studies of bronchial thermoplasty, a technique that applies radiofrequency waves to the airways during bronchoscopy to decrease large airway smooth muscle mass, provide another line of evidence supporting a central role for ASM in large airways in the pathogenesis of asthma. Preliminary evidence suggests that reducing ASM mass by this technique improves asthma control. (See "Treatment of severe asthma in adolescents and adults", section on 'Bronchial thermoplasty'.)

Mucus plugging — Mucus plugs appear to contribute to airflow limitation in chronic severe asthma [57]. CT scans have demonstrated mucus plugs in at least 1 of 20 lung segments in 58 percent of subjects with asthma [58,59]. In addition, high mucus plug scores (plugs in ≥4 segments) on CT scans correlate with airflow limitation on spirometry and sputum eosinophilia.

Bronchial hyperresponsiveness — Bronchial hyperresponsiveness (BHR) is another defining feature of asthma and is a manifestation of reversible airflow obstruction due to smooth muscle contraction. BHR represents an exaggerated constrictor response to a variety of physical, chemical, or environmental stimuli. BHR can be quantitated by the dose response to pharmacologic agents such as methacholine or histamine, causing a 20 percent fall in forced expiratory volume in one second (FEV₁). While BHR is not specific for asthma, patients with asthma typically demonstrate BHR to much lower doses (eg, 10- to 100-fold) of these agents than normal or allergic individuals [60]. (See "Bronchoprovocation testing".)

While ASM is clearly involved in BHR, the precise mechanism that causes ASM to become hyperresponsive is not known. Possible explanations for BHR include alterations in smooth muscle function or mass, loss of airway-parenchymal interdependence, loss of a bronchodilating effect of deep breaths, enhanced sensitivity of neural pathways leading to bronchoconstriction, and exaggerated airway narrowing from smooth muscle contraction as a consequence of remodeling and structural abnormalities of the airway.

Evidence that BHR in asthmatics is not due to altered ASM function or sensitivity, but rather to the breathing pattern in which the smooth muscle contracts, comes from studies that reproduce BHR in normal individuals simply by prohibiting deep breaths during methacholine challenge [61]. Under these conditions, the dose response to methacholine of normals was identical to that of asthmatics, indicating that the defect in asthma was loss of smooth muscle relaxation associated with deep inspiration. Acute airway narrowing in normal subjects could be demonstrated by HRCT [62]. Further, HRCT imaging of airways revealed equal bronchodilation in normals and asthmatics with deep inspiration. However, after airway constriction with methacholine, normal subjects maintained bronchodilation after a deep breath, while asthmatics constricted further [63].

A possible clinical manifestation of the loss of bronchodilator effect from deep inspiration is the bronchoconstriction that occurs during exercise in patients with asthma. (See "Exercise-induced bronchoconstriction".)

Clinical correlation — BHR presents clinically with the sudden onset of shortness of breath following inhalation of irritants or cold air. Patients may describe the sensation that their airways feel "twitchy", meaning that minor changes in the inhaled air can lead to need for their beta agonist inhaler. Beta agonists cause smooth muscle relaxation at least temporarily. This sensation of "twitchiness" may occur when airway inflammation is present and may be improved by allergen and irritant avoidance or treatment of inflammation with glucocorticoids. Better understanding of the physiology of this response may lead to better methods for treatment and prevention.

AIRWAY REMODELING — While many patients have intermittent asthma symptoms and normal physiologic testing between asthma episodes, increasing evidence suggests that a subset of patients with asthma have irreversible airflow obstruction, which is believed to be caused by airway remodeling [64]. Airway remodeling refers to structural changes in the airways that may cause irreversible airflow limitation, superimposed on the effects of inflammation and smooth muscle contraction described above (figure 1).

Histopathology — The histopathologic changes of airway remodeling include damage or loss of the normal pseudostratified structure of airway epithelium, an increase in the proportion of mucus-producing goblet cells, fibrotic thickening of the sub-epithelial reticular basement membrane or "lamina reticularis", increased numbers of myofibroblasts, increased vascularity, increased airway smooth muscle mass, and increased extracellular matrix.

Such structural changes contribute to bronchial wall thickening, alterations in the physiologic consequences of smooth muscle contraction, or loss of airway-parenchymal interdependence (ie, the tethering forces exerted by the lung parenchyma that maintain airway patency). (See 'Smooth muscle' above.)

Contribution of airway remodeling to bronchial hyperresponsiveness — Structural narrowing of airways associated with remodeling appears to increase bronchial hyperresponsiveness (BHR). This was examined in a study that correlated pulmonary function test parameters with the dimensions of small, medium, and large airways measured by high resolution computed tomography (HRCT) in 21 subjects with moderate or severe asthma (baseline forced expiratory volume in one second (FEV₁) was 64 percent of predicted) [65]. Airway dimensions, measured at total lung capacity (TLC) and functional residual capacity (FRC), were analyzed for relationships to lung volumes at baseline and after intensive bronchodilator treatment. The change between findings at baseline and after albuterol was felt to reflect the effect of airway smooth muscle tone and structure, respectively. The following findings suggest that dynamic hyperinflation caused by narrowing of large airways (ie, remodeling) is a major determinant of bronchial hyperresponsiveness in asthma:

●Baseline smooth muscle tone was associated with an increased residual volume (RV) that was threefold greater than the decrease in forced vital capacity (FVC) due to a simultaneous increase in TLC.

●The increase in RV correlated inversely with the relaxed luminal diameter of medium airways and directly with the wall thickness of large airways under conditions where smooth muscle tone was absent, not with the degree of smooth muscle tone or dimensions of small airways.

●Decreased FVC was the major determinant of baseline FEV₁. Whether or not TLC increased and FVC fell, was also dependent on the dimensions of relaxed large airways, with narrower large airways correlating with larger falls in FVC and FEV₁.

Clinical correlation — Airway remodeling is thought to be an early feature of asthma based on the description of sub-basement membrane thickening in the airways of children with asthma [66]. In adults, evidence for remodeling comes from the observation that many adults with asthma have an irreversible component to their disease [67]. The importance of this feature of asthma is that remodeling may be an early component of asthma pathogenesis and patients who are prone to remodeling may need a different approach to treatment than those who are not.

The general consensus is that patients with more severe and earlier onset asthma experience accelerated loss of lung function due to airway remodeling; however, the extent of progression and loss of lung function is highly variable. Longitudinal studies have demonstrated progressive loss of lung function in subjects with asthma compared to normals [68,69]. However, other studies have suggested that this decline in lung function depends on the severity of asthma; patients with mild asthma were less likely to manifest airway remodeling/worsening airflow limitation, whereas those with severe asthma were more likely to show evidence of airway remodeling [70,71]. As an example, a study from Melbourne, Australia, that followed a large cohort of asthmatic and control subjects for 35 years, did not find accelerated average decline in lung function with asthma; however, those with severe asthma had progressive disease through childhood [70]. Adults with low lung function had developed low lung function in childhood, suggesting that the abnormality was present early and persisted over time. In a study that used computed tomography (CT) to assess airway wall thickness, patients with severe asthma had thicker airway walls than those with mild asthma [71].

MODULATORY FACTORS — A variety of factors appear to influence whether susceptible individuals progress to overt asthma. These include:

Genetic factors — Modern genetic techniques have identified genes that may contribute to the pathogenesis of asthma through the above described mechanisms or through unidentified pathways. (See "Genetics of asthma".)

Environmental factors — Environmental exposure to air pollution, allergens (eg, dust mite, occupational allergens), cigarette smoke, and endotoxin have all been associated with an increased risk of asthma. (See "Risk factors for asthma".) It is hypothesized that interactions between genetic susceptibility and exposure to certain inflammatory, infectious, or irritant agents determine who will develop symptomatic asthma.

Infectious agents — Both bacterial and viral respiratory tract infections have been associated with increased risk of asthma [72]. This is discussed in more detail separately. (See "Risk factors for asthma", section on 'Respiratory infections'.)

The exact mechanisms by which these factors increase the risk of asthma are still under investigation.

SUMMARY AND RECOMMENDATIONS

●While the clinical syndrome of asthma is common and easily recognized, the pathogenesis of asthma involves complex interactions between inflammatory and resident airway cells. (See 'Introduction' above.)

●Mast cells, eosinophils, lymphocytes, dendritic cells and their associated products appear especially prominent in the airways of patients with asthma. Inflammatory events and associated alterations in airway smooth muscle function result in asthma symptoms, and also in structural changes, particularly within the epithelium, subepithelium, fibroblasts, and smooth muscle. (See 'Airway inflammation' above.)

●Bronchial hyperresponsiveness (BHR) is a defining feature of asthma and is a manifestation of exaggerated reversible airway obstruction due to smooth muscle contraction. Several theories are being explored to explain this phenomenon. (See 'Bronchial hyperresponsiveness' above.)

●Structural cells, particularly the epithelium, fibroblasts, smooth muscle, and endothelium, may contribute to inflammation or airway remodeling through elaboration of mediators and cytokines. (See 'Airway remodeling' above.)

●A variety of genetic, environmental, and infectious factors appear to modulate whether susceptible individuals progress to overt asthma. (See 'Modulatory factors' above.)

●Improved understanding of these relationships will lead to new interventions for asthma by targeting key components of airway inflammation and remodeling.