Asthmatic Inflammation

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Asthma is a chronic inflammatory disease of the airways. Asthmatic inflammation involves complex interactions between the cytokines and signaling pathways of many cell types. In adults and children, T cells are known to be integrally involved in this process (Azzawi et al. 1990; Corrigan and Kay 1990; Wardlaw et al. 1988). The maintenance of airway inflammation is attributed, in adults, to chronically activated memory T cells sensitized against a variety of allergens (Corrigan and Kay 1990) and, in children, to elevated soluble IL-2 receptor levels (Warner et al. 1998). In general, asthma is associated with cytokines secreted by TH2 cells; for instance, IL-5 is involved with the recruitment and activation of eosinophils, while IL-4 plays a role in programming B cells to secrete IgE. It should be noted, however, that CD8+ T cells have also been implicated in IgE class switching through the actions of IL-13 (rather than IL-4) (Punnonen et al. 1997). Moreover, TH1 cytokines such as IL-2, interferon g (IFNg), TNFa, and IL-15 have been reported to promote allergic airway inflammation (Donovan and Finn 1999; Hessel et al. 1997; Krug et al. 1996), of COPD Pb TNF-a -Induces Eotaxin on Eosinophils

Eotaxin Tnf

of COPD Pb TNF-a -Induces Eotaxin on Eosinophils and asthma

Figure 14.1

and asthma

Figure 14.1

so ultimately, all T cell subsets probably contribute to the disease process of asthmatic inflammation. In a study to elucidate how circulating lymphocytes infiltrate into the airways of asthmatic patients, Tsumori and colleagues transplanted human bronchial xenografts into asthmatic huPBMC-SCID mice and found that the number of CD3-, CD4-, and CD8-positive cells in the xenografts of these mice was higher than those of dermatitis, rheumatic, and normal huPBMC-SCID mice (Tsumori et al. 2003). Moreover, expression of the mRNA of IL-4 and IL-5, but not of IL-2 or IFNg, were significantly elevated in the xenografts of asthmatic huPBMC-SCID mice compared to those in the xenografts of normal huPBMC-SCID mice. Together, these results suggest that in asthmatics, T cells, especially TH2-type T cells, preferentially infiltrate into human bronchi.

It is pertinent at this point to discuss a relationship between leukocyte infiltration in asthmatics and circulating platelets. Platelet-leukocyte interactions have been demonstrated in cardiovascular disease (Ehlers et al. 2003), culminating in enhanced

Figure 14.1 (See figure facing page.) The cell-cytokine networks and immune deviation of asthmagenesis. Each T cell subset can contribute to disease, but the cytokines from the TH2 subset dominate. Naïve CD4+ T cells (THP) differentiate upon Ag-specific recognition into TH1 or TH2 cells under the influence of interleukin(IL)-12 or IL-4, respectively. The originating source of IL-4 may be from CD4+ NKT cells, which also secrete asthma-associated IL-13. Va14i a/p NKT cells have been shown to be required for allergen-induced airway hyperresponsiveness (AHR) in mice, in a process that is inhibited by Vg4 g/8 T cells. Macrophage-derived IL-12 is inhibited by prostaglandin E2 (PGE2), which signals through cAMP-elevating Gs-protein coupled receptors. Macrophages and NK cells secrete and are activated by TNFa. Macrophage-derived IL-12 causes NK cells to secrete IFNg, which restimulates macrophages in a THI-amplifying positive feedback loop. tHi cells secrete IL-2 to assist Ag-recognizing precursor cytotoxic T cells (pCTL) to become activated CTL, the effectors of cell-mediated immunity (CMI). TH1 cells also secrete IFNg, which synergizes with macrophage-derived iL-18 to inhibit TH2 responses to allergenic challenge, including allergen-induced airway eosinophilia and airway epithelial cell-derived secretion of eotaxin. TH2 cells secrete IL-4, -5, -9, and -13, among other cytokines. IL-4 and IL-13 synergize to cause Ag-stimulated B cells to switch from producing immunoglobulin M (IgM) molecules to IgE, the Ig isotype associated with mast cell degranulation, asthma, and allergy. TH2 cytokine secretion is inhibited by IL-10, although the source of IL-10 may come from TH2 cells themselves as well as from regulatory T cells. IL-10 induces long-term hypore-sponsiveness of allergen-specific CD4+ T cells, decreases circulating numbers of mast cells and eosinophils, and in a rat model of asthma has been shown to inhibit the late-phase response as well as the influx of eosinophils and lymphocytes to airways. Other regulatory T cells include TH3 cells secreting Transforming Growth Factor-beta (TGF-beta), which inhibits cytokine secretion from both TH1 and TH2 cells. IL-4 stimulates TH2 cells to self-amplify in a positive feedback loop. TH2 cells bind to circulating platelets via CD11b, a component of Mac-1 (CD11b/CD18) that is upregulated under inflammatory conditions. TH2/platelet aggregates are recruited to sites of inflammation, including sites of allergen-induced degranulation of mast cells, basophils, and eosinophils. IL-5 and IL-9 synergize to mobilize and differentiate eosinophils from the bone marrow. TNFa from TH1, NK, cells, and macrophages primes neutrophils for activation by IL-6 or platelet activating factor (PAF). Neutrophil-derived elastase, as well as its activity in asthma and chronic obstructive pulmonary disease (COPD), are inhibited by heparin and other IP3 receptor antagonists. The immunotoxic effects of lead (Pb) may be related to its ability to support TH1-derived TNFa secretion, which is known to induce the CC chemokine eotaxin on eosinophils. Lead is also shown to induce TH2-derived secretion of the asthma-associated cytokines, IL-4 and IL-13.

leukocyte recruitment. Circulating platelet-leukocyte aggregates have been observed in the blood of allergic asthmatic patients during the allergen-induced late asthmatic response and in sensitized mice after allergen exposure (Pitchford et al. 2003a). Because of these observations, Pitchford and coworkers conducted a study that demonstrated that leukocyte infiltration was reduced in the airways of allergen-challenged mice that had been depleted of platelets (Pitchford et al. 2003b). Airway infiltration was restored following adoptive transfer of platelets from allergic animals. Moreover, using blood taken at various time points from asthmatic patients to document the degree of leukocyte activation and the presence of platelet-leukocyte aggregates before and after allergen exposure, these authors confirmed an essential role for platelets in leukocyte recruitment. These researchers also demonstrated an upregulation of CD11b, a subunit of the Mac-1 molecule, on leukocytes that were involved in aggregates with platelets and not on free leukocytes. The results suggest an essential role for platelets in the recruitment of leukocytes in allergic inflammation (Figure 14.1).

Interestingly, a biochemical explanation for the participation of platelets in the activity of neutrophils in asthmatic lungs may be available. Heparin is known to not only inhibit the generation of thrombin but the enzymatic activity of elastase as well. Neutrophil-derived elastase is an enzyme implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD) (Ohbayashi 2002) and asthma (Monteseirin et al. 2003). However, a recent report demonstrated that heparin can inhibit the release of elastase from TNFa-primed human neutrophils (Brown et al. 2003). The authors of this study speculated that because IP(3) receptor antagonist 2-aminoet-hoxydiphenylborate (2-APB) mimicked the effects of heparin, itself an established IP(3) receptor antagonist, perhaps IP(3) antagonism inhibits the release of elastase from TNFa-primed human neutrophils. Because of the role platelets have been shown to play in the recruitment of leukocytes to asthmatic airways, it is interesting that heparin inhibits the generation of thrombin, which is known to activate platelets, and that heparin inhibits the receptor for IP(3), which is also thought to be involved in the upregulation of the CD11b molecule central to platelet-mediated leukocyte trafficking (Klos et al. 1992). Perhaps IP(3) pathway dysregulation will be found to be a marker in future asthma immunotoxicant studies.

The physiologic response of asthma, however, begins with the generation and activity of immunoglobulin E. Although IgE synthesis directed by TH2-derived IL-4 helps to initiate the asthmatic response, it is the allergen-mediated cross-linking of IgE/FceR complexes on mast cells that leads to the physiologic response: Upon mast cell degranulation, release of inflammatory mediators causes bronchoconstric-tion, shortness of breath, lowered blood pressure, edema, and recruitment of inflammatory cells (Cookson 1999; Corry and Kheradmand 1999; Fallon et al. 2001). Some of the mediators released by mast cell degranulation include the three cysteinyl leukotrienes C4, D4, and E4 (Drazen et al. 1999), although eosinophils, macrophages, and monocytes are also important sources of these mediators (Holgate, 1999) (Figure 14.2). These leukotrienes bind to specific receptors and are responsible for the contraction of smooth muscles, vasodilation, increased vascular permeability, and the hypersecretion of mucus associated with asthma (Drazen et al. 1999). Since many of the leukotrienes are known to generate cAMP via activation of G protein-

Bronchoconstriction, Shortness of breath,

Lowered BP, Edema A

Activation of Protease-Activated Receptors on Endothelial Cells

Recruitment of inflammatory cells

Tryptase

Degranulatio inflammatory

Degranulatio inflammatory

Trimeric Fceri Eosinophils
FceRI

Bind to GsPCR on CD4+ T cells

IgE from IL-4/13-stimulated B cells

Figure 14.2 Mast cell degranulation. Armed with B cell-derived allergen-specific IgE molecules bound to cell surface-associated, high-affinity FceRI receptors, mast cells degranulate upon secondary and subsequent exposures to the same allergen in a process involving activation of the protein tyrosine kinase Syk. Upon degranulation, inflammatory mediators including histamine and cysteinyl leukotrienes B4, C4, and D4 (LTB4, LTC4, and LTD4) are released. These mediators recruit inflammatory cells, including circulating TH2/platelet aggregates, to sites of allergen-induced mast cell degranulation. Tryptase released during degranulation is responsible for activating endothelial receptors necessary for the recruitment of eosino-phils to sites of inflammation. The entire process results in the bronchoconstriction, shortness of breath, lowered blood pressure, and edema associated with asthma.

coupled receptors (GPCR), and cAMP levels are regulated by the hydrolytic activity of phosphodiesterases (PDEs), it is interesting to note that PDE type IV inhibitors are showing promise as antiasthmatics. These agents have recently been shown to generate good efficacy against guinea pig respiratory tract inflammation and bronchoconstriction (Kim et al. 2003) (Figure 14.3).

Another mast cell-derived effector molecule released in response to IgE-crosslinking is tryptase, which is responsible for activation of the protease-activated receptors on endothelial and epithelial cells; this activation eventually leads to the upregulation of adhesion molecules that selectively attract basophils and eosinophils to the site of inflammation (Holgate 1999) (Figure 14.4). Importantly, eosinophilic inflammation is intimately involved in the inflammatory response of asthma (Robinson et al. 1992) and is driven by the TH2-derived cytokines IL-5 and IL-9, as well as by the chemotactic cytokine, or chemokine, eotaxin (Figure 14.5).

Mature and immature eosinophils are released from the bone marrow under the control of IL-5 (Palframan et al. 1998), which is also responsible for regulating the expression of the transmembrane isoform of its own receptor (Tavernier et al. 2000)

Stimulation of TH2 cytokines Resulting from f presentation of Ag by APC/B cell

CD28

Cysteinyl LTs B4, C4, & D4 from degranulated Mast cells

GsPCR

TH2 Cell

SOCS-3 expression in TH2 cells is strongly correlated with onset and maintenance of asthma

^cAMP Q

J MAPK

1 CD40L Cell activation

PDE-4

Type IV PDE inhibitors shown to improve respiratory tract inflammation & bronchoconstriction in guinea pigs

Figure 14.3 The intracellular signaling of a TH2 cell participating in asthmagenesis. Cysteinyl leukotrenes released during mast cell degranulation bind to cAMP-elevating Gs-protein coupled receptors on TH2 cells and recruit those cells to sites of asthmatic inflammation. Elevated cAMP levels result in diminished T cell receptor (TCR)-induced mitogen-activated protein kinases (MAPKs) activation in a process countered by asthma-associated elevations in TH2 phosphodiesterase 4 (PDE4) levels. Type IV PDE inhibitors have been shown to be particularly promising in improving respiratory tract inflammation and bronchoconstriction in guinea pigs. Activation of the TH2 cells results from cognate interaction with an antigen presenting cell (APC) such as a B cell, macrophage, or dendritic cell, causing the release of asthma-associated TH2 cytokines.

and terminal differentiation of committed eosinophil precursors (Clutterbuck et al. 1989). After leaving the bone marrow and following a gradient of one or more chemokines, eosinophils migrate into the asthmatic airways via the bronchial post-capillary endothelium (Figure 14.4 and Figure 14.5). It is interesting to note that Katoh and coworkers have recently shown in a murine model of pulmonary eosino-philia that eosinophil and lymphocyte accumulation in the lung, as well as antigen-induced airway hyperresponsiveness, are completely prevented by treatment with anti-CD44 monoclonal antibodies (Katoh et al. 2003). The authors demonstrated that intraperitoneal administration of anti-CD44 antibodies inhibited the increased levels of hyaluronic acid (HA, hyaluronan) and leukotrienes in the bronchoalveolar lavage fluid (BALF) that typically result from antigen challenge. CD44 (also known as ECMR III; H-CAM; HUTCH-1; Hermes; Lu, In-related; Pgp-1; and gp85) serves as a recyclable receptor for hyaluronan and is involved in the homing of leukocytes to sites of inflammation (Liao and Patel 1999). Katoh's observation that CD44 blockade interferes with HA accumulation in BALF and inhibits eosinophil and lymphocyte accumulation in the lung confirms known biochemical and cellular activities of the CD44 hyaladherin molecule (Figure 14.5).

Following their migration into asthmatic airways, interactions with selective adhesion molecules (a4pj integrin and VCAM) (Denburg 1998) allow eosinophils

Site of Inflammation rETV Degranulation jj^l^

Eo's migrate along a chemotactic gradient to the site of inflammation

Toxic Basic Proteins (MBP, EPO, ECP, & EDN) Cysteinyl LTsj^

• Fibrogenic GFs

• MMPs (MMP-12 required for airway eosinophilia surfaces Asthmatic airway remodeling a

Eo's enter lung tissue by diapedesis

Eo's enter lung tissue by diapedesis

Upregulation of adhesion molecules selective for slowing eosinophils & basophils (o401 & VCAM)

Activation of protease-activated

Receptors on endothelial cells

Tryptase from degranulated Mast cells

Upregulation of adhesion molecules selective for slowing eosinophils & basophils (o401 & VCAM)

Activation of protease-activated

Receptors on endothelial cells

Tryptase from degranulated Mast cells

Figure 14.4 Eosinophil (Eo) adhesion, diapedesis, and degranulation. Tryptase, released when mast cells degranulate, activates protease-activated receptors on vascular endo-thelium near sites of asthmatic inflammation. Activation of these receptors leads to an upregulation of the a4p1 and VCAM adhesion molecules, which selectively slow the circulation of eosinophils and basophils. Eosinophils, mobilized from the bone marrow by IL-5, follow a CC chemokine gradient by virtue of their CCR3 receptors. Within the vasculature they are slowed by a4p1 and VCAM but become firmly adhered to inflammatory site endothelium by the adhesion molecules b2-integrin and VLA-4. Eosinophils then enter lung tissue by diapedesis where they continue to migrate along a chemotactic gradient until they degranulate at the site of asthmatic inflammation. Mediators such as toxic basic proteins, cysteinyl leukotrienes, and platelet activating factor (PAF) are released and are known to cause injury of mucosal surfaces. Fibrogenic growth factors and matrix metallo-proteinases (MMP), also released when eosinophils degranulate, lead to asthmatic airway remodeling.

to slow to a roll on blood vessel surfaces until they recognize eotaxin (or other chemokine) on the endothelial cell surface (Wardlaw 1999). Ligation of a class of chemokine receptors, called "CC" receptors, by eotaxin and other CC chemokines activates eosinophils, firmly adheres them to the vascular endothelium via adhesion molecules such as p2-integrin and very late activation antigen-4 (VLA-4), and allows them to enter bronchial tissue in a process known as diapedesis. Once in the bronchial tissue, eosinophils migrate along a chemotactic gradient to the site of allergic inflammation where they degranulate (Wardlaw 1999), presumably in response to

IFN-y —| allergen-induced Homes to from airway eosinophilia and noninflamed

IFN-y —| allergen-induced Homes to from airway eosinophilia and noninflamed

Homes to inflamed tissue from Th2 cells

Figure 14.5 Eosinophil mobilization from the bone marrow. Under the influence of TH2-derived

Homes to inflamed tissue

Chemokine Gradient from Th2 cells

Figure 14.5 Eosinophil mobilization from the bone marrow. Under the influence of TH2-derived

IL-5 and IL-9, immature eosinophils are released from the bone marrow in a process requiring a GATA transcription (abbreviated as XSCn in the figure) factor. Mature eosinophils upregulate eotaxin-binding CCR3 receptors in response to IL-5. CCR3 allows the eosinophil to follow an eotaxin gradient to sites of asthmatic inflammation in a process that is inhibitable with antibodies to CD44. However, mature eosinophils upregulate CXCR4 chemokine receptors in response to TH1-derived IFNg, and it is thought that these receptors compete with the CCR3 receptors to hold eosinophils in noninflamed tissue.

reaching a threshold eotaxin concentration. Proteins released during degranulation include major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN) (reviewed in: Menzies-Gow and Robinson 2001). The release of toxic basic proteins by eosinophils can injure mucosal surfaces, as can the release of cysteinyl leukotrienes and platelet activating factor (PAF). Interestingly, repair of these surfaces also comes from eosinophils, since they produce fibrogenic growth factors and matrix metallopro-teinase (MMP), both of which play roles in asthmatic airway remodeling (Levi-Schaffer et al. 1999). MMPs, however, appear to play multiple roles in airway remodeling. A novel role for one MMP has recently been demonstrated by Pouladi and colleagues, where, using MMP-12-deficient and IL-13-deficient mice, MMP-12 was shown to be required for the development of airway eosinophilia in mice in a process that was dependent on IL-13 (Pouladi et al. 2003) (Figure 14.4).

Eotaxin and other chemokines have been implicated in eosinophil accumulation and activation within the bronchial mucosa of asthmatics, primarily due to the tissue-specific expression of their G-protein coupled receptors through which all chemo-kines signal (Zlotnik et al. 1999). Whereas the TH2 cytokines IL-4 and IL-13 have been shown to induce eotaxin expression by several cell types (including airway epithelial cells, endothelial cells, and fibroblasts (Gangur and Oppenheim 2000; Li et al. 1999; Menzies-Gow and Robinson 2001), the TH1 cytokine IFNg has been demonstrated to inhibit eotaxin synthesis in vitro (Miyamasu et al. 1999). Within

M0's T cells Eo's Mast cells

Neuropeptides:

• Calcitonin-gene-related-peptide

4 Vasodilation | Vascular permeability

• Contraction of HASMC

• Hypersecretion mucus

Zinc Chelators

Human Airway Epithelial Cell: the main source of Eotaxin in the respiratory tract

TH1-derived IFN-y

Eotaxin -

Fibroblasts

Antioxidants f P38 MAPK A ERK MAPK

in HASMC

Figure 14.6 The role of the human airway epithelial cell (HAEC) in asthmagenesis. The HAEC is the major source of eotaxin in the respiratory tract. Release of eotaxin from HAEC is inhibited by TH1-derived IFNg, but it is induced by TH2-derived IL-4 and IL-13, which, like RANTES, also induce eotaxin release from airway fibroblasts. HAEC-derived eotaxin is also induced by the inflammatory cytokines IL-1 and TNFa that also induce the zinc-dependent release of the chemokines MCP-1 and RANTES, as well as reactive oxygen species (ROS) from HAEC. HAEC-derived ROS have been shown to induce activation of both p38 and ERK MAPK in human airway smooth muscle cells (HASMC). Within asthmatic bronchial airways, other cells also participate in asthmatic inflammation, including macrophages, T cells, eosinophils, and mast cells. Mediators released from these cells during asthmagenesis include the neuropeptides substance P, neurokinin A, and calcitonin-gene-related peptide. Release of these neuropeptides from the inflammatory cells of asthmatic bronchial airways results in an orchestration of increased vasodilation and vascular permeability, contraction of HASMC, and the hypersecretion of mucus.

the respiratory tract, the major source of eotaxin is the airway epithelial cell, where eotaxin mRNA and protein expression are increased by TNFa, IL-1, and IL-4 (reviewed in: Menzies-Gow and Robinson 2001) (Figure 14.6). The mechanism of action of IL-1 with respect to eotaxin expression has recently been investigated. In a report by Wuyts and colleagues (Wuyts et al. 2003), interleukin-1p (IL-1p)-induced chemokine release in human airway smooth muscle cells were shown to be inhibited by the antioxidative agent N-acetylcysteine (NAC). Both the expression and production of eotaxin and monocyte chemotactic protein 1 (MCP)-1 were inhibited by NAC. (As will be discussed further in the section on the transcription factor GATA-1, both eotaxin and MCP-1, as well as "regulated upon activation normal T cell expressed and secreted" [RANTES], have also been shown to be induced by TNFa.) Understanding that mitogen-activated protein kinases (MAPK) are often activated by reactive oxygen species (ROS), the authors investigated and determined that IL-1 p-induced production of the ROS 8-isoprostane, as well as activation of p38 MAPK,

HASMC

©I Adenosine

Isoproterenol ROS from Human ^ Airway Epithelial Cells

P-arrestin-2 regulates & is required for manifestation of allergy & asthma in an IL-4Ra polymorphism-dependent manner

Chemokine TARC

(Upregulated in airways of -«-asthmatic pts)

Ado A3R

Anti-I oxidants

Eotaxin

(polymorphism-dependent)

p38 MAPK*

MAPK

PKA*

Changes in PKC, TK, PI3K (regulates adhesion, contraction, proliferation, & cell survival)

TARC release

Recruits TH2 Cells to asthmatic airways

Calcium entry PW consistent with TRP family member

Calcium entry PW consistent with TRP family member

Cell

Positive

Feedback Loop

Figure 14.7 The role of the human airway smooth muscle cell (HASMC) in asthmagenesis.

Eotaxin derived from any number of sources stimulates the HASMC to produce more eotaxin, as well as to activate histamine H1 receptors leading to activation of a calcium entry pathway consistent with members of the transient receptor potential (TRP)-c family. Calcium then enters the HASMC, causing changes in PKC, TK, and PI3K. TH2-derived IL-4 or IL-13 synergize with TNFa presumably derived from macrophages, TH1 cells, or NK cells to induce the release of the chemokine "thymus- and activation-regulated chemokine" (TARC), which is upreg-ulated in the airways of asthmatic patients. TARC, in turn, recruits more TH2 cells to asthmatic airways, which continue to secrete more IL-13 and IL-4 in a positive feedback loop. IL-13 also upregulates extracellular adenosine, which binds to Gi-protein coupled adenosine A3 receptors, themselves upregulated in response to IL-13 in another positive feedback loop. IL-13 receptors share the IL-4Ra subunit with IL-4 receptors, and IL-13-dependent upregulation of Adenosine A3 receptors is regulated by p-arrestin-2. p-arrestin-2 regulates, and is required for manifestation of allergy and asthma in an IL-4Ra polymorphism-dependent manner. IL-13-induced adenosine, in signaling through A3 receptors, decreases intracellular levels of the second messenger cAMP, which may serve to inhibit TARC release from HASMC. Conversely, cAMP levels are amplified in response to stimulation of Gs-coupled beta adrenergic receptors (p-AR) in a polymorphism-dependent manner. Elevated cAMP causes activation of cAMP-dependent protein kinase A (PKA), which has been shown to inhibit the release of TARC from HASMC.

were inhibited in a dose dependent manner by NAC (Figure 14.6 and Figure 14.7). The reduction of chemokine release by antioxidative agents via inhibition of p38 MAPK in human airway smooth muscle cells may have implications for the introduction of antioxidants during gestation.

Eosinophilic inflammation is directly tied to signaling through the CC chemokine receptors, and the biochemical events involved in this signaling are known to include intracellular calcium transients, pertussis toxin sensitive Grproteins, protein kinase C, tyrosine kinase, and phosphatidylinositol-3-kinase (PI3K) (Zlotnik et al. 1999). Indeed, the elevations of intracellular free calcium ([Ca(2+']i) induced by CC receptors are known to regulate many functional responses in airway smooth muscle, including contraction, proliferation, adhesion, and cell survival. Because entry from the extracellular environment, as opposed to release from intracellular stores, had been suggested, Corteling and coworkers (Corteling et al. 2003) sought to find the source of calcium. Using HASM and human bronchial epithelial cells (HBEC), the authors found a histamine H1 receptor-activated Ca(2+) entry pathway with characteristics typical of transient receptor potential (TRP)C family members. This led the researchers to demonstrate the expression of a range of TRP family homologues in the airway. As environmental toxicants are studied in the future for their effects on childhood asthma, it may be important to look at specific effects on chemokine receptor-associated pathways and second messengers, including calcium transients and TRP family members (Figure 14.7).

Although eotaxin was discovered in guinea pig studies (Jose et al. 1994), human eotaxin has since been cloned (Ponath et al. 1996). Eotaxin-2 (Forssmann et al. 1997) and eotaxin-3 (Kitaura et al. 1999) have been identified, shown to act on the same receptor (CCR3, expressed predominantly on eosinophils), and recognized as possessing the same cellular specificity. The importance of the CCR3 receptor cannot be overemphasized regarding its role in asthmagenesis. In support of the potential for inhibition of the eotaxin-CCR3 binding interaction as an anti-inflammatory treatment for asthma, Warrior and colleagues have recently reported identifying two compounds specifically inhibiting this interaction that also inhibit eosinophil chemo-taxis in both in vitro and in vivo assays (Warrior et al. 2003). Besides eotaxin, other CC chemokines reported to recruit eosinophils in vivo are RANTES, monocyte chemoattractant protein-3 (MCP-3), MCP-4, and macrophage inflammatory protein-1a (MIP-1a) (Menzies-Gow and Robinson 2000; Menzies-Gow and Robinson 2001).

In addition to recruiting, activating, and degranulating eosinophils at sites of allergic inflammation, eotaxin is also known to recruit TH2 cells and basophils through the CCR3 receptor (Devouassoux et al. 1999). Moreover, eotaxin causes IgE-independent degranulation of basophils (Uguccioni et al. 1997a) and potentiates their production of IL-4 (Devouassoux et al. 1999). At the same time, IL-4 has been shown to induce eotaxin-3 expression in vascular endothelial cells (Shinkai et al. 1999). In this way, it appears that eotaxin may positively feedback to continue T cell-driven allergic inflammation in vivo. Sources of the chemokine eotaxin include not only T cells, alveolar macrophages, bronchial smooth muscle cells, cartilage chondrocytes, CD68+ macrophages within the subendothelium and endothelial cells, but also eosinophils themselves (Rankin et al. 2000). Eotaxin expression can be upregulated by IL-3, IL-5, and TNFa (Rothenberg 1999) (Figure 14.8). Moreover, disparate chemokine receptors expressed on eosinophils may play functionally opposite roles regulating eosinophil trafficking in asthma. A model has been proposed that expression of the chemokine receptor CXCR4 holds eosinophils at noninflamed tissues, while CCR3 allows the cells to respond to eotaxin. The crux of the model is that TH1 cytokines such as TNFa and IFNg induce CXCR4 expression, while TH2 cytokines such as IL-5 induce the expression of CCR3 (Nagase et al. 2000)

(Sources include macrophages, HASMC, T cells, cartilage

(Sources include macrophages, HASMC, T cells, cartilage

Feedback Loop Asthma

Figure 14.8 The integral role of eotaxin in the positive feedback loops of asthmagenesis.

Eotaxin as well as eotaxin-2 and eotaxin-3 stimulate the cells of asthmatic inflammation through CCR3 or other CC chemokine receptors. Eosinophils secrete eotaxin in response to IL-3, TNFa, and IL-5. Blocking the interaction of eotaxin with CCR3 receptors has been shown to be effective as an anti-inflammatory treatment for asthma, leading to reduced eosinophil chemotaxis both in vitro and in vivo. Eotaxin stimulates TH2 cells and basophils to secrete IL-4, in addition to causing basophils to degranulate. IL-4 stimulates vascular smooth muscle cells (VSMC) to secrete eotaxin-3, which in turn stimulates eosinophils and TH2 cells in a positive feedback loop. Other CC chemokines known to recruit eosinophils include RANTES, MCP-3, MCP-4, and MIP-1a. Other sources of eotaxin include macrophages, HASMC, T cells, cartilage chondrocytes, and endothelial cells.

Figure 14.8 The integral role of eotaxin in the positive feedback loops of asthmagenesis.

Eotaxin as well as eotaxin-2 and eotaxin-3 stimulate the cells of asthmatic inflammation through CCR3 or other CC chemokine receptors. Eosinophils secrete eotaxin in response to IL-3, TNFa, and IL-5. Blocking the interaction of eotaxin with CCR3 receptors has been shown to be effective as an anti-inflammatory treatment for asthma, leading to reduced eosinophil chemotaxis both in vitro and in vivo. Eotaxin stimulates TH2 cells and basophils to secrete IL-4, in addition to causing basophils to degranulate. IL-4 stimulates vascular smooth muscle cells (VSMC) to secrete eotaxin-3, which in turn stimulates eosinophils and TH2 cells in a positive feedback loop. Other CC chemokines known to recruit eosinophils include RANTES, MCP-3, MCP-4, and MIP-1a. Other sources of eotaxin include macrophages, HASMC, T cells, cartilage chondrocytes, and endothelial cells.

(Figure 14.5). This model illustrates the complex nature of the regulation of eosinophil trafficking. Although complicated, the fact that eotaxin itself is upregulated by the TH1 cytokine TNFa (Figure 14.8) suggests that asthmagenesis may depend in part on the TH1 pathway as well as the TH2 pathway. Exactly how a balance between TH1- & TH2-derived cytokines affects eosinophil response remains to be seen. If such a balance is shown to be critical to the regulation of eosinophil trafficking, then the disruption of normal G-protein coupled receptor systems may be important endpoints to examine in the pathogenesis of asthma. Understanding the complexity of multiple redundant chemokines recruiting eosinophils, basophils, and TH2 lymphocytes to sites of allergic inflammation—i.e., when these cells secrete more TH2 cytokines that induce the synthesis of more eosinophil chemotactic factors—is just one of the challenges facing researchers trying to decipher or manip ulate the mechanisms of asthmatic inflammation. In preparation for a discussion on how maternal-fetal interactions might sensitize a child for asthmatic responses to allergenic challenges, the soluble factors, receptors, and signaling pathways that mediate the cell-to-cell interactions and alterations in tissue architecture associated with asthma will be described next.

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