Structural Changes and Repair

A repair process that restores the tissue to normal usually follows the acute inflammatory response. This may involve proliferation of damaged cells (e.g., airway epithelial cells) and fibrosis to heal any breach in the mucosal surface. These repair processes may also become chronic in response to continued inflammation, resulting in “exaggerated” structural changes in the airways that are referred to as remodeling. However, the relationship between airway inflammation and remodeling is controversial; the conventional view—that inflammation leads to remodeling—has been challenged by human and animal work, which suggests that they may be parallel processes. These structural changes in asthma and CF may result in irreversible narrowing of the airways, with fixed obstruction to air flow. In asthma, several structural changes are found in the airway wall, including increased thickness of the subepithelial basement membrane, an increased amount of airway smooth muscle, and an increased number of blood vessels (angiogenesis) ( Fig. 7.2 ). There is much debate about the importance of airway remodeling in asthma, as it is not seen in all patients. It may contribute to airway hyperresponsiveness (AHR) in asthma, but it may also have some beneficial effects in limiting airway closure. Details of each of the structural changes seen in children with asthma and their functional relevance, particularly the role of structural airway cells in mediating inflammation, are provided in Chapter 43 .

Diagram illustrating the airway pathological changes in asthma.

Mast Cells

Mast cells are important in initiating the acute bronchoconstrictor responses to allergens and probably to other indirect stimuli such as exercise and hyperventilation (via osmolality or thermal changes). Treatment of asthmatic patients with prednisolone results in a decrease in the number of tryptase-positive mast cells. Furthermore, mast cell tryptase appears to play a role in airway remodeling, as this mast cell product stimulates human lung fibroblast proliferation. Mast cells also secrete cytokines, including IL-4 and eotaxin, which may be involved in maintaining the allergic inflammatory response and the TNF-α. Mast cells are found in increased numbers in airway smooth muscle of asthmatic patients, and this appears to correlate with AHR, suggesting that mast cell mediators may mediate AHR.

However, mast cells may play less of a role in chronic allergic inflammatory events, and it seems more probable that other cells, such as macrophages, eosinophils, and T-lymphocytes, are important in the chronic inflammatory process and in AHR. Classically, allergens activate mast cells through an IgE-dependent mechanism. The importance of IgE in the pathophysiology of asthma has been underscored by recent clinical studies with humanized anti-IgE antibodies, which inhibit IgE-mediated effects. Anti-IgE therapy is effective in patients, including children, with severe asthma who are not well controlled by high doses of corticosteroids; and it is particularly effective in reducing exacerbations. The relationship between IgE and mast cell degranulation in causing acute allergic responses is discussed in Chapter 43 , and the role of omalizumab (anti-IgE monoclonal antibody) in the treatment of severe asthma is discussed in Chapter 48 .

Macrophages

The alveolar macrophage (AM) is the most numerous immune cell present within the respiratory tract. Originally thought to be derived from peripheral monocytes, current knowledge of their function is largely based upon studies of macrophages derived from peripheral precursors. Recent evidence, however, suggests that AMs enter the lungs prenatally and proliferate in situ, suggesting highly specialized functions. It is now apparent that local tissue milieu and regulatory influences result in macrophages that have very specific phenotypes and functions. Bone-marrow derived macrophages have been shown to differentiate to an AM phenotype following pulmonary transplantation, confirming the importance of the local environment in phenotypic development ; however, the mechanisms by which this occurs are poorly understood. Airway macrophages are ideally positioned to dictate the innate defense of the airways ( Fig. 7.4 ). Pulmonary macrophage populations are heterogeneous and demonstrate plasticity, owing to variations in origin, tissue residency, and environmental influences. The diversity of pulmonary macrophages facilitates efficient responses to environmental signals and allows rapid alterations in phenotype and in response to a plethora of cytokines and microbial signals. They express a wide range of receptors, which enable them to regulate their local environment by responding to changes within it. These receptors can be activating, such as TLRs to sense pathogens and cytokine receptors for TNF, IL-1, and IFNγ. Alternatively, the receptors may be suppressive, such as CD200, Triggering Receptor Expressed on Myeloid Cells (TREM), and transforming growth factor-β (TGF-β). The receptors enable high level of engagement and interaction with pulmonary epithelial cells. Indeed, this interaction is crucial for maintenance of immune homeostasis within the respiratory tract. Cooperation between the cells facilitates clearance of cellular debris and particulate matter, as well as directing specific immune responses to pathogens.

Interstitial and alveolar macrophages in airway to maintain immune homeostasis. Immune cells are present in the airways and constantly undertaking immune surveillance to ensure homeostasis and on standby to initiate an inflammatory response to foreign particles when needed. Both interstitial (red) and alveolar (blue) macrophages perform continued immune surveillance in the lungs to maintain immune homeostasis.

Macrophages have the capacity to secrete a large variety of different agents with either proinflammatory or antiinflammatory effects, including cytokines and growth factors, chemotactic factors, lipid mediators, and proteinases. In asthma, macrophages may be activated by allergens via low-affinity IgE receptors (Fcε;RII [Receptor II]). The vast immunologic repertoire of macrophages allows them to produce more than 100 different products, including a large variety of cytokines that may orchestrate the inflammatory response. Macrophages have the capacity to initiate a particular type of inflammatory response via the repertoire of cytokines they release. They may also either increase or decrease inflammation, depending on the activating stimulus. Alveolar macrophages normally have a suppressive effect on lymphocyte function, but this may be impaired in asthma after allergen exposure. In patients with asthma, there is a reduced secretion of IL-10 (an antiinflammatory protein secreted by macrophages) in alveolar macrophages. Macrophages may therefore play an important antiinflammatory role by maintaining tolerance within the respiratory tract. There are subtypes of macrophages that perform different inflammatory, antiinflammatory, or phagocytic roles in airway disease; but at present, it is difficult to differentiate these subtypes in the human airway. There is evidence that alveolar macrophages show reduced phagocytosis of apoptotic cells and carbon particles in severe asthma so that inflammation does not resolve.

Dendritic Cells

Dendritic cells (DC) are specialized innate antigen presenting cells that have a unique ability to initiate and regulate cell mediated and humoral immune responses. DCs can be defined as any mononuclear phagocyte that can take up antigen, process it for presentation on major histocompatibility complex (MHC)-I or II, migrate to the nearest draining lymph node, and efficiently and effectively activate and polarize naïve T cells. Subsequently, with the aid of costimulatory molecules (e.g., B7.1, B7.2, and CD40), they program the production of allergen-specific T cells. People with genetic defects resulting in a lack of DCs, or mice wherein DCs are experimentally depleted, suffer from severely impaired adaptive T and B cell responses. DCs reside beneath the pulmonary epithelium in the lung tissue, and are poised to encounter foreign material (allergen), infections, or tissue damage. They are aided by their ability to actively sample antigens in the airways via cellular extensions that protrude through the epithelial tight junctions. Although their numbers are low in the lung, DCs are highly sensitive to their environment, expressing a variety of pattern recognition receptors (PRRs) including TLRs, C-type lectin receptors, and Nodlike receptors (NLRs). Through these receptors, they can sense a wide range of pathogens, microbes, or damage-associated molecules (DAMPs); these include bacterial, viral, fungal and protozoal pathogens, commensals and allergens, particles, and pollutants. Additionally, the pulmonary environment presents some unique features compared to other barrier sites, such as specific surfactants and mucins, which can influence DC activation and function. Importantly, the combination of PRRs can tailor the developing immune response by directly influencing the activation and function of DCs. A number of DC subpopulations have been defined in the lungs including myeloid DCs (mDCs), conventional DCs that initiate T-cell immunity and antibody production, and plasmacytoid DCs (pDCs) that have an important role in antiviral immunity and immune tolerance. DCs induce a T-lymphocyte–mediated immune response and therefore play a critical role in the development of asthma. Increased numbers of mucosal DCs are present in asthma, and they have been identified in endobronchial biopsies, broncho-alveolar lavage, and induced sputum from patients with asthma. Animal studies have demonstrated that myeloid dendritic cells are critical to the development of T helper type 2 (Th2) cells and eosinophilia.

Eosinophils

Eosinophils form an essential part of the innate immune response against parasitic helminths acting through the release of cytotoxic granule proteins. However, airway eosinophilic inflammation is also a central feature in allergic asthma. Allergen inhalation results in a marked increase in eosinophils in bronchoalveolar lavage fluid, and there is a correlation between eosinophil counts in peripheral blood and bronchial lavage in patients who are not receiving steroid treatment. Eosinophils develop from bone marrow precursors and are recruited to the lung via chemokines and cytokines. Eosinophil recruitment initially involves adhesion of eosinophils to vascular endothelial cells in the airway circulation and then is followed by migration into the submucosa and activation. There have been extensive investigations of the role of individual adhesion molecules, cytokines, and mediators in orchestrating these responses. Adhesion of eosinophils involves the expression of specific glycoprotein molecules on the surface of eosinophils (integrins) and expression of such molecules as intercellular adhesion molecule-1 (ICAM-1) on vascular endothelial cells. The adhesion molecule very late antigen-4 (VLA4) expressed on eosinophils, which interacts with vascular cell adhesion molecule-1 (VCAM-1) and IL-4, increases its expression on endothelial cells. Granulocyte macrophage colony stimulating factor (GM-CSF) and IL-5 may be important for the survival of eosinophils in the airways and for “priming” eosinophils to exhibit enhanced responsiveness.

There are multiple mediators involved in the migration of eosinophils from the circulation to the surface of the airway. The most potent and selective agents appear to be chemokines (e.g., CCL5, CC11, CCL13, CCL24, and CCL26), which are expressed by epithelial cells. There appears to be a cooperative interaction between IL-5 and chemokines so that both are necessary for the eosinophilic response in the airway. Once recruited to the airway, eosinophils require the presence of various growth factors, of which GM-CSF and IL-5 appear to be the most important. In the absence of these growth factors, eosinophils undergo programed cell death (apoptosis).

After humanized monoclonal antibody to IL-5 is administered to asthmatic patients, there is a profound and prolonged reduction in circulating eosinophils and eosinophils recruited into the airway following allergen challenge. However, there is no effect on the response to inhaled allergen and no change in lung function. Recent studies with highly selected patients with persistent sputum eosinophilia despite high doses of inhaled corticosteroids have shown a reduction in asthma attacks following treatment with anti-IL-5 antibody therapy. The selective response in patients with a persistent eosinophilia underscores the importance of understanding the differing inflammatory processes in subgroups of patients with asthma rather than applying the same strategies to all patients (see Chapter 43 ).

Neutrophils

In addition to physical barriers, such as the airway epithelium, neutrophils are part of the first line of immune defense. They can be found in the bloodstream, where they have a lifespan of 6–8 hours, and in tissue, where they can survive for up to 7 days. They are the first cells of the immune system to migrate to a site of inflammation, where they play an important role in pathogen elimination and cytokine production. The mechanisms that neutrophils use for host defense include phagocytosis, degranulation, cytokine production, and the recently described production of neutrophil extracellular traps (NETs). NETs were discovered in 1996 as a pathway of cellular death that was different from apoptosis and necrosis. Neutrophil extracellular traps are DNA structures released due to chromatin decondensation and spreading, and they occupy three to five times the volume of condensed chromatin. NETs arise from the release of granular and nuclear contents of neutrophils in the extracellular space in response to different classes of microorganisms, soluble factors, and host molecules. Several proteins adhere to NETs, including histones and components of neutrophil granules with bactericidal activity such as elastase, myeloperoxidase, cathepsin G (CG), and lactoferrin. The detrimental effect of excessive NET release is particularly important to lung diseases, because NETs can expand in the pulmonary alveoli, causing lung injury. Massive NET formation has been reported in pulmonary diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, respiratory syncytial virus bronchiolitis, influenza, bacterial pneumonia, and tuberculosis. Thus, NET formation must be tightly regulated to avoid NET-mediated tissue damage. Recent approaches to target NETs in pulmonary diseases include DNA disintegration with recombinant human DNase, and neutralization of NET proteins with antihistone antibodies and protease inhibitors.

Neutrophils are the predominant inflammatory cells in patients with CF and chronic suppurative lung diseases such as PCD and bronchiectasis. Studies utilizing bronchoscopy to collect lower airway samples from very young children with CF have identified neutrophilic inflammation both with and without cultured bacterial pathogens. These data suggest that inflammation may develop prior to chronic infection. However, studies using molecular genetic approaches to characterize the airway microbiome have shown numerous microbes present in the CF lung that are not readily cultured under standard conditions. Whether such microbes are pathogenic or proinflammatory is uncertain, but they can be found in very young children and may also help explain why neutrophilic airway inflammation is present when bacteria are not identified by traditional methods. Nebulized hypertonic saline has been shown to improve mucus clearance in CF and impact positively upon pulmonary exacerbations, but there is also increasing evidence to suggest that hypertonic saline is beneficial through its antiinflammatory properties and its ability to reduce bacterial activity and biofilm formation. The specific mechanisms involved include the downregulation of oxidative burst activity and adhesion molecule expression and the suppression of neutrophil degranulation of proteolytic enzymes. In addition, a potential pathogenic role of neutrophilic inflammation in both CF and non-CF bronchiectasis has been shown by interventional studies that have demonstrated improved lung function with the use of antiinflammatory agents such as the macrolide azithromycin, although the exact mechanisms of benefit of macrolides is unclear.

In contrast to CF and non-CF bronchiectasis, the numbers and function of airway neutrophils in asthma remains uncertain. Although they are reported to be increased in severe asthma in adults, numbers in the airway lumen and lung parenchyma are not elevated in children with severe asthma. However, a sub-group of children have increased intraepithelial neutrophils. Intriguingly, these patients have better lung function and asthma control, suggesting the neutrophils may be protective rather than pathogenic. The functional role of neutrophils in asthma has been further questioned by interventional studies that have shown little/no benefit of the antiinflammatory macrolide azithromycin either during infective exacerbations or to prevent exacerbations. Putative causes for airway neutrophilia in asthma are corticosteroid therapy, which inhibits neutrophil apoptosis, chronic infection with atypical organisms such as Chlamydia or Mycoplasma, exposure to passive smoking and other environmental pollutants, and gastroesophageal reflux and aspiration. However, it is still not clear whether neutrophils play a pathophysiologic role in the disease.

T-Lymphocytes

T-lymphocytes play a very important role in coordinating the inflammatory response in asthma through the release of specific patterns of cytokines, resulting in the recruitment and survival of eosinophils and in the maintenance of mast cells in the airways. T-lymphocytes are coded to express a distinctive pattern of cytokines, which are similar to that described in the murine T helper 2 (Th2) type of T-lymphocytes, which characteristically express IL-4, IL-5, IL-9, and IL-13 ( Fig. 7.5 ; see also Fig. 7.3 ). This programming of T-lymphocytes is presumably due to antigen-presenting cells, such as dendritic cells, which may migrate from the epithelium to regional lymph nodes or interact with lymphocytes resident in the airway mucosa. The naïve immune system is skewed to express the Th2 phenotype; data now indicate that children with atopy are more likely to retain this skewed phenotype than normal children. There is some evidence that early infections or exposure to endotoxins might promote Th1-mediated responses to predominate and that a lack of infection or a clean environment in childhood may favor Th2 cell expression and thus atopic diseases. Indeed, the balance between Th1 cells and Th2 cells is thought to be determined by locally released cytokines, such as IL-12, which tip the balance in favor of Th1 cells, or IL-4 and IL-13, which favor the emergence of Th2 cells. There is accumulating evidence that a population of tissue resident memory cells (Trm) are long lived within the lung and facilitate development of T-cell responses upon reencounter with allergen. Although these Trm ensure efficient clearance of viruses, they may exacerbate allergic inflammation. Regulatory T cells (Tregs) suppress the immune response through the secretion of inhibitory cytokines (e.g., IL-10 and TGF-β) (see Fig. 7.3 , Chapter 43 ) and play an important role in immune regulation with suppression of Th1 responses; there is some evidence that Treg function may be defective in asthmatic patients. Details of lymphoid cell responses in children with asthma, including the role of Th17 cells, T regulatory cells and the recently described innate lymphoid cells are discussed in Chapter 43 .

T cell differentiation and cytokine production in pulmonary adaptive immunity following antigen presentation. The pulmonary antigen presenting cell (APC), or dendritic cell, presents antigen via MHC class II to the naïve T cell, and under the influence of the cytokines that have been secreted, the naïve T cell is converted to a T helper cell, which secretes further cytokines. In allergy, these are IL-4, IL-5, and IL-13 from Th2 cells; in infection, Th1 cells secrete IFN-γ and TNF-α; and in both allergy and infection, Th17 cells secrete IL-6, IL-17, or IL-22. CTLA4 , Cytotoxic T-lymphocyte-associated protein 4; IL, interleukin; IFN, interferon; MHC, major histocompatibility complex; TCR , T cell receptor; TGF, transforming growth factor; TNF, tumor necrosis factor.

Patients with CF are known to have an imbalance in the composition of lymphocytic inflammation as well as the presence of neutrophilia. Interestingly, the neutrophilia seems confined to the airway lumen, while the infiltrate in the airway wall in children with CF is predominantly lymphocytic, specifically being composed of IL-17+ CD4+ (Th17) cells and gamma delta T cells. A Th2/Th17 skewed inflammatory response has been associated with increased risk for Pseudomonas aeruginosa infection. Moreover, the numbers of regulatory T cells (CD4+CD25+FoxP3+) in peripheral blood are reduced in patients with CF with chronic P. aeruginosa infection and the reduction correlates with impaired lung function, suggesting immune manipulation of Tregs to try and dampen proinflammatory responses might be a therapeutic strategy in patients with established CF lung disease.

Innate Lymphoid Cells

Innate lymphoid cells (ILCs) are classified into three groups based on their transcription factors and cytokine production patterns, which mirror helper T-cell subsets. Unlike T cells and B cells, ILCs do not have antigen receptors. They respond to innate factors released by the bronchial epithelium, such as cytokines and alarmins, including IL-33, IL-25, and thymic stromal lymphopoietin (TSLP). ILCs produce multiple proinflammatory and immunoregulatory cytokines for the induction and regulation of inflammation. These cells are specifically produced at mucosal surfaces and thus are important in airway inflammation. The role of ILCs, and more specifically type 2 ILCs, in the pathogenesis of allergic airways diseases has been extensively investigated over the last decade, and the evidence for their involvement in pediatric severe asthma has been discussed in Chapter 43 . However, the role of ILCs in infectious and nonallergic airway inflammatory diseases remains largely unknown. Specifically, the role of ILC1 cells, which produce IFNγ and may be important in viral infections and ILC3 cells, which produce IL-17 and may be important in suppurative lung disease such as cystic fibrosis, are unknown.

B-Lymphocytes

In allergic diseases, B-lymphocytes secrete IgE, and the factors regulating IgE secretion are now much better understood. IL-4 is crucial in switching B cells to IgE production, and CD40 on T cells is an important accessory molecule that signals through interaction with CD40-ligand on B cells. There is increasing evidence for local production of IgE, even in patients with intrinsic asthma. For example, a recent clinical trial has shown treatment of adult patients with nonatopic asthma with the anti-IgE antibody omalizumab reduced bronchial mucosal IgE ⁺ mast cells and improved lung function despite withdrawal of conventional therapy.

Basophils

Functionally, basophils are closely related to mast cells. Both cell types express the high-affinity IgE receptor (FcεRI) and rapidly release preformed mediators from intracellular stores upon IgE-mediated activation. However, in contrast to mast cells, basophils mature in the bone marrow and have a lifespan of only 2–3 days. The exact role and importance of basophils in asthma is uncertain, as these cells have been difficult to detect by immunocytochemistry and most studies investigating the mechanistic role of these cells are limited to experimental murine models. However, it appears that basophils have both proinflammatory and antiinflammatory actions. They recruit effector cells such as Th2 cells, ILC2s, eosinophils, and inflammatory macrophages to the site of inflammation; and they are also able to limit inflammation by release of amphiregulin, induction of alternative activation of macrophages, and orchestration of an antiinflammatory Th2 milieu. Using a basophil-specific marker, a slight increase in basophils has been documented in the airways of asthmatic patients, with an increased number after allergen challenge. However, these cells are far outnumbered by eosinophils (approximately 10 : 1), and their functional role is unknown. There is also an increase in the numbers of basophils, as well as mast cells, in induced sputum after allergen challenge.

Cytokines

Cytokines play a significant role in orchestrating the type of inflammatory response seen in airways diseases ( Fig. 7.8 ; see also Fig. 7.3 ). Many cytokines currently form the target for the development of new asthma therapies. Multiple inflammatory cells (macrophages, mast cells, eosinophils, and lymphoid cells) and airway structural cells are capable of synthesizing and releasing cytokines. While inflammatory mediators such as histamine and leukotrienes may be important in the acute and subacute inflammatory responses and in exacerbations of asthma, it is likely that cytokines play a dominant role in maintaining chronic inflammation in airway diseases. The cytokines that appear to be of importance in asthma include the type 2, or Th2 cytokines that are secreted by T-lymphocytes and innate lymphoid cells. These include IL-4, IL-5, and IL-13. Details of the cellular source, functional role, and potential of these cytokines as therapeutic targets in asthma are summarized in Chapter 43 . Other proinflammatory cytokines (e.g., IL-1β, IL-6, TNF-α, and GM-CSF) are released from a variety of cells, including macrophages, epithelial cells, T helper 1, and T helper 17 cells (see Fig. 7.8 ), and may be important in amplifying the inflammatory response. TNF-α may be an amplifying mediator in asthma and is produced in increased amounts in airways of patients with severe asthma. However, blocking TNF-α with a potent antibody had no clinical benefit in patients with severe asthma, and it also led to an increased risk of infections and cancers. TNF-α and IL-1β both activate the proinflammatory transcription factors—nuclear factor-κB (NF-κB) and activator protein-1 (AP-1)—which then switch on many inflammatory genes in the asthmatic airway.

The cytokine network in asthma. Many inflammatory cytokines are released from inflammatory and structural cells in the airway and orchestrate and perpetuate the inflammatory response. CCL, Chemokine; IgE, immunoglobulin E; IL, interleukin; Th0, T helper 0; Th2, T helper 2; TNF, tumor necrosis factor.

Thymic stromal lymphopoietin (TSLP) shows a marked increase in expression in airway epithelium and mast cells of asthmatic patients. TSLP appears to play a key role in programing airway dendritic cells to release CCL17 and CCL22 to attract Th2 cells ( Fig. 7.9 ). A clinical trial of an anti-TSLP antibody in adults with mild allergic asthma showed reduced bronchoconstriction and reduced airway eosinophilic inflammation after an acute allergen challenge in the patients who received the active drug, suggesting that this may be a novel target following an acute allergen induced exacerbation of asthma, but this was a small trial that requires further confirmation.

Thymic stromal lymphopoietin in asthma. TSLP is an upstream cytokine produced by airway epithelial cells and mast cells in asthma that acts on immature dendritic cells to mature and release CCL17, which attracts Th2 cells via CCR4. CCL, Chemokine; CCR, chemokine receptor; IgE, immunoglobulin E; IL, interleukin; Th2, T helper 2.

Lipid Mediators

The cysteinyl-leukotrienes, LTC ₄ , LTD ₄ , and LTE ₄ , are potent constrictors of human airways and may also increase AHR. Leukotriene antagonists have some bronchodilator and antiinflammatory effects but are much less effective than inhaled corticosteroids in the management of childhood asthma. Platelet-activating factor (PAF) is a potent inflammatory mediator that mimics many of the features of asthma, including eosinophil recruitment and activation and induction of AHR; yet even potent PAF antagonists, such as dominant, do not control asthma symptoms, at least in chronic asthma. Prostaglandins (PG) have potent effects on airway function, and there is increased expression of the inducible form of cyclooxygenase (COX-2) in asthmatic airways; however, inhibition of their synthesis with COX inhibitors, such as aspirin or ibuprofen, has no effect in most patients. Prostaglandin D ₂ is a bronchoconstrictor prostaglandin produced predominantly by mast cells; it also activates a novel chemoattractant receptor termed chemoattractant receptor of Th2 cells (CRTh2) or DP ₂ -receptor, which is expressed on Th2 cells and eosinophils and mediates chemotaxis of these cell types. It may provide a link between mast cell activation and allergic inflammation. Several oral CRTh2/DP ₂ antagonists are now in clinical development.

Lipid mediators are also crucial for the resolution of inflammation. Resolvins and protectins are a relatively newly described class of lipids that are thought to be important for the down regulation and resolution of inflammation, thereby leading to restitution of immune homeostasis. Mechanistic data from experimental models show that resolvins can promote clearance of inflammatory cells after allergen exposure, resulting in improved lung function. They have also been described in adult asthmatic patients after allergen challenge.

Chemokines

Both cytokines and chemokines are small proteins made by cells in the immune system. They are important in the production and growth of immune cells and in regulating responses to inflammation and wound healing. The term “cytokines” encompasses all signaling molecules while chemokines are specific cytokines that function by attracting cells to sites of infection/inflammation. Chemokines are defined either according to the pattern of cysteine residues in the ligands (CC, CXC, C, and CX3C) or their function and pattern of expression (homeostatic and inflammatory chemokines). Many chemokines are involved in the recruitment of inflammatory cells to the airways. Over 50 different chemokines are now recognized, and they activate more than 20 different surface receptors. Chemokine receptors belong to the seven-transmembrane receptor superfamily of G-protein–coupled receptors; this makes it possible to find small molecule inhibitors, which has not been possible for classical cytokine receptors. Some chemokine receptors appear to be selective for single chemokines, whereas others are promiscuous and mediate the effects of several related chemokines. Chemokines appear to act in sequence in determining the final inflammatory response, and so inhibitors may be more or less effective depending on the kinetics of the response. T-cell migration in response to G-protein coupled receptor (GPCR)-coupled chemokine receptors plays a prominent role in navigating distinct T-cell subsets at different stages of the immune response to their intended destinations at sites of infection and inflammation ( Fig. 7.10 ).

Chemokine and cytokine interactions on T lymphocytes. Chemokine receptors are g-protein coupled receptors (GPCR) that span the cell membrane of T lymphocytes, and binding of cytokines to these receptors defines the functional phenotype of the T lymphocyte subset. CCR, Chemokine receptor; IL, interleukin; TGF, transforming growth factor.

Several chemokines, including CCL5, CC11, CCL13, CCL24, and CCL26, activate a common receptor on eosinophils termed CCR3. Increased expression in the airways of asthmatic patients is correlated with increased AHR. CCR4 chemokines are selectively expressed on Th2 cells and are activated by the CCL17 and CCL22 chemokines. Epithelial cells of patients with asthma express CCL22, which may then recruit Th2 cells, resulting in coordinated eosinophilic inflammation.

CXC chemokines are involved in the recruitment of neutrophils. CXCL1 and CXCL8 play an important role in neutrophilic inflammation in severe asthma and CF.

Oxidative Stress

As in all inflammatory diseases, there is increased oxidative stress associated with pulmonary inflammation, as activated inflammatory cells, such as macrophages, neutrophils, and eosinophils, produce reactive oxygen species. Evidence for increased oxidative stress in asthma and CF is provided by the increased concentrations of 8-isoprostane (a product of oxidized arachidonic acid) in exhaled breath condensates and increased ethane (a product of oxidative lipid peroxidation) in exhaled breath of asthmatic patients. Increased oxidative stress is correlated with disease severity and may amplify the inflammatory response and reduce responsiveness to corticosteroids, particularly in severe disease and during exacerbations.

Nitric Oxide

Nitric oxide (NO) is generated from various resident and inflammatory cells in the human airway when l -arginine undergoes the process of oxidation by one of three NO synthase (NOS) isoenzymes: endothelial NOS, inducible NOS, and neuronal NOS. The physiologic roles that NO has in the respiratory system are numerous and include neurotransmission, vasodilatation, bronchodilation, and immune augmentation. At the onset of an asthma attack, an enhanced production of NO strongly correlates with increased inducible NOS activity, whereas endothelial NOS and neuronal NOS primarily regulate normal metabolic functions in the central and peripheral airways. During allergic inflammatory responses, NO and superoxide form peroxynitrite, which has deleterious effects in the respiratory tract. The inducible form of NOS (iNOS) shows increased expression, particularly in the airway epithelial cells and macrophages of asthmatic airways. Although the role of NO in the asthmatic airway is not fully understood, the levels of NO are often increased in asthma. This elevation is thought, in part, to reflect increased inducible NOS activity in the airways. Although the cellular source of NO within the lung is not known, inferences based on mathematical models suggest that it is the large airways that are the source of NO; in severe asthma, there is evidence that small airways also produce it. Extended NO analysis is a promising tool in different diseases such as asthma where NO metabolism is altered. One single exhalation cannot give insight to the NO production in the whole respiratory system; the use of multiple exhalation flows has therefore been used to give the alveolar levels (C(A)NO), the airway wall concentration (C(aw)NO), and the diffusion rate of NO (D(aw)NO). Low levels of bronchial NO flux (J'(aw)NO) are seen in cystic fibrosis, PCD and in smoking subjects. However, more studies are needed to evaluate the clinical usefulness of the extended NO analysis; this has been done in systemic sclerosis where a cutoff value has been identified, predicting pulmonary function deterioration.

Growth Factors

Many growth factors are released from inflammatory and structural cells in airway diseases; these may play a critical role in the structural changes that occur in chronic inflammation, including fibrosis, airway smooth muscle thickening, angiogenesis, and mucous hyperplasia. While the role of individual mediators is not yet established, there is evidence for increased expression of TGF-β (a mediator associated with fibrosis), vascular-endothelial growth factor (a mediator associated with angiogenesis), and epidermal growth factor (a mediator that induces mucous hyperplasia and expression of mucin genes) ( Fig. 7.11 ). A key pathological component of asthma is airway remodeling, and it is likely that several growth factors are important in mediating the development of these structural changes; however, to date, there are no specific therapeutics that target airway remodeling.

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