frontiers
`in Pharmacology
`
`REVIEW
`published: 29 March 2019
`doi: 10.3389/fphar.2019.00294
`
`Modulation of Allergic Inflammation
`in the Nasal Mucosa of Allergic
`Rhinitis Sufferers With Topical
`Pharmaceutical Agents
`
`Annabelle M. Watts1* , Allan W. Cripps2, Nicholas P. West1 and Amanda J. Cox1
`
`1 Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, QLD, Australia, 2 Menzies
`Health Institute Queensland, School of Medicine, Griffith University, Southport, QLD, Australia
`
`Allergic rhinitis (AR) is a chronic upper respiratory disease estimated to affect between
`10 and 40% of the worldwide population. The mechanisms underlying AR are highly
`complex and involve multiple immune cells, mediators, and cytokines. As such, the
`development of a single drug to treat allergic inflammation and/or symptoms is
`confounded by the complexity of the disease pathophysiology. Complete avoidance
`of allergens that
`trigger AR symptoms is not possible and without a cure,
`the
`available therapeutic options are typically focused on achieving symptomatic relief.
`Topical therapies offer many advantages over oral therapies, such as delivering greater
`concentrations of drugs to the receptor sites at the source of the allergic inflammation
`and the reduced risk of systemic side effects. This review describes the complex
`pathophysiology of AR and identifies the mechanism(s) of action of topical treatments
`including antihistamines, steroids, anticholinergics, decongestants and chromones in
`relation to AR pathophysiology. Following the literature review a discussion on the future
`therapeutic strategies for AR treatment is provided.
`
`OPEN ACCESS
`
`Edited by:
`
`Mauro Maniscalco,
`
`Fondazione Salvatore Maugeri, Telese
`
`(IRCCS), Italy
`
`Reviewed by:
`
`Guy Scadding,
`
`Royal Brompton Hospital,
`
`United Kingdom
`
`Antonio Molino,
`
`University of Naples Federico II, Italy
`
`Keywords: allergic rhinitis, intranasal, antihistamines, steroids, decongestants, anticholinergic, chromones
`
`*Correspondence:
`
`Annabelle M. Watts
`
`a.watts@griffith.edu.au
`
`Specialty section:
`
`This article was submitted to
`
`Respiratory Pharmacology,
`
`a section of the journal
`
`Frontiers in Pharmacology
`
`Received: 31 January 2019
`
`Accepted: 11 March 2019
`
`Published: 29 March 2019
`
`Citation:
`
`Watts AM, Cripps AW, West NP
`
`and Cox AJ (2019) Modulation
`
`of Allergic Inflammation in the Nasal
`
`Mucosa of Allergic Rhinitis Sufferers
`
`With Topical Pharmaceutical Agents.
`
`Front. Pharmacol. 10:294.
`
`doi: 10.3389/fphar.2019.00294
`
`INTRODUCTION
`
`Allergic rhinitis (AR) is estimated to affect between 10 and 40% of the population worldwide
`(Bjorksten et al., 2008; Bernstein et al., 2016) and is associated with significant medical and
`economic burden (Cook et al., 2007; Zuberbier et al., 2014; Marcellusi et al., 2015). AR is classified
`as a chronic upper respiratory disease whereby exposure to allergens induces an IgE mediated
`inflammation of the mucous membranes lining the nose (Bousquet et al., 2008). The disease
`manifests symptomatically as nasal congestion, rhinorrhoea, itchy nose and sneezing. Symptoms
`of post nasal drip, itchy/red eyes also occur in some sufferers. House dust mites, animals, and mold
`spores are major triggers responsible for perennial presentation of symptoms while exposure to
`pollen triggers seasonal symptoms (Cook et al., 2007). Complete avoidance of airborne allergens is
`not possible and without a cure, the available therapeutic options are typically focused on achieving
`symptomatic relief.
`The nasal mucosa is the primary site for allergen exposure and the inflammatory reactions
`that cause AR symptoms. The mechanisms driving AR pathophysiology are multifaceted and
`include activation and migration of effector cells, release of mediators, chemokines and cytokines
`from inflammatory cells, and damage to the nasal epithelium and nerve endings. Oral (systemic)
`
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`Watts et al.
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`Topical Drugs for Allergic Rhinitis
`
`therapies, such as antihistamines, are commonly used to treat
`AR symptoms. However, topical therapies offer many advantages
`over oral
`therapies and are being continuously developed
`to target AR symptoms. Topical therapies allow for higher
`concentrations of drugs to be applied directly to the receptor sites
`at the source of inflammation (nasal mucosa) and carry a reduced
`risk of systemic side effects compared to oral therapies. Current
`therapies target different components of the allergic response,
`and consequently do not always offer full coverage of symptoms.
`Given the numerous immune cells, signaling molecules and
`mediators involved in the allergic response, development of a
`single therapy to rapidly target all components of the allergic
`response represents a significant challenge as a treatment option.
`This review will: (i) consider the immune cells, mediators and
`messenger molecules of the allergic response, (ii) outline the time
`course of the allergic response, (iii) identify the mechanism for
`each topical drug and will indicate which components of the
`allergic response are modulated by the drug mechanism, and
`(iv) highlight the gaps in current therapy and identify future
`therapeutic strategies for the treatment of AR.
`
`PATHOPHYSIOLOGY OF ALLERGIC
`RHINITIS
`
`Atopy occurs as a result of a genetic predisposition to produce IgE
`antibodies and consequently the development of allergic disease.
`The IgE antibody is a fundamental component of the T-helper
`2 (Th2) arm of the immune system, which exists as a means
`for defending the human body against helminth infection or
`other multi-cellular parasites (Allen and Sutherland, 2014). In
`atopic subjects, the Th2 immune pathway is instead promoted
`to produce an immune response to allergenic proteins derived
`from animals, molds and plant pollens. The allergenic proteins
`are processed by specialized cells of the immune system at
`mucosal barriers of the nose, resulting in the production of IgE
`antibodies. These newly produced IgE antibodies interact with
`specific allergens and immune cells (mast cells and basophils)
`situated in the nasal mucosa. The interaction of these antibodies,
`allergens and specialized cells, sets off a series of reactions
`whereby the resident mucosal immune cells such as mast cells,
`eosinophils and basophils to release powerful mediators such
`as histamine as well as chemokines, cytokines and adhesion
`molecules that encourage increased production of leukocytes
`in the bone marrow as well as attracting circulating effector
`leukocytes including neutrophils, Th2 lymphocytes, basophils
`and eosinophils into the nasal epithelium. In a series of time-
`dependent phases including sensitisation, early- and late-phase
`responses, these effector cell types, mediators and cell signaling
`molecules work in a complex network of interactions resulting
`in specific symptoms and the inflammatory morphology of AR
`(Bousquet et al., 2001).
`
`Antigen Presentation and Sensitisation
`Antigen presenting cells (APCs) are located in para- and inter-
`cellular channels neighboring the basal epithelial cells in the nasal
`mucosa (Mandhane et al., 2011). When allergens are deposited in
`
`the mucous layer of the nasopharynx their water soluble proteins
`are taken up by these APCs (dendritic cells and macrophages)
`and processed into short peptides that bind specifically to major
`histocompatibility complex (MHC) class II molecules (MHCII)
`expressed on the APCs surface (Bernstein et al., 2016). The APCs
`migrate to the lymph nodes and present the MHCII peptides
`to the naïve CD4+ T lymphocytes (Th0). CD4+ lymphocyte
`activation requires two distinct signals, contact with the MHCII
`molecules on APCs with specific surface T-cell receptors, and
`ligation of co-stimulatory receptors CD80 and CD86 on APCs
`with CD28 family receptors on T cells (Bugeon and Dallman,
`2000; KleinJan et al., 2006). Under stimulation with the IL-4
`cytokine, activated Th0 lymphocytes are transformed to T helper
`2 (Th2) CD4+ cells. Non-atopic subjects can still mount allergen-
`specific T cell responses to allergen stimulus (Ebner et al., 1995;
`Van Overtvelt et al., 2008), whereby allergen-specific CD4+ T
`cells are mainly transformed into IFN-γ producing Th1 cells
`and IL-10 producing Treg cells (Van Overtvelt et al., 2008). In
`contrast, T cells in atopic patients are mostly transformed into
`allergen-specific Th2 cells (Van Overtvelt et al., 2008) which are
`involved in IgE production. Th2 cells release cytokines IL-4,
`IL-5 and IL-13 to initiate the inflammatory immune response
`(Bernstein et al., 2016). Specific B cell subsets are stimulated
`by IL-4 to differentiate into antibody producing plasma cells.
`In a process termed ‘isotope switching,’ plasma cells switch
`production from IgM to IgE antibodies that specifically recognize
`the allergenic protein. The class switching process is initiated
`by two signals. The first signal is provided by IL-4 and IL-13
`released by T cells (Stone et al., 2010). These cytokines interact
`with receptors on the B-cell surface and signals induction of
`ε-germline transcription of B cells to produce IgE antibodies and
`successive clonal expansion of IgE expressing memory B cells
`(Sin and Togias, 2011). The second signal is a costimulatory
`interaction between CD154 (CD40 ligand) on the surface of
`activated T cells with the CD40 molecule expressed on the surface
`of B cells (Janeway et al., 2001). This second signal stimulates
`B cell activation and class switch recombination to induce IgE
`production (Sin and Togias, 2011).
`IgE antibodies represent a very small fraction of the total
`antibody concentration in human serum (Bernstein et al.,
`2016). However, on binding with specific cell surface receptors
`and cross-linking with antigen,
`IgE can induce powerful
`inflammatory effects. Allergen specific IgE antibodies bind
`strongly with high affinity receptors (FcεRI) expressed on the
`surface of mast cells and basophils (Kraft and Kinet, 2007), which
`are abundant in the nasal mucosa. On re-exposure to allergen,
`the specific allergenic protein is recognized by the IgE antibodies
`bound to FcεRI receptors. On cross-linking of many dimeric
`or higher order oligomeric receptor molecules (Fewtrell and
`Metzger, 1980; Knol, 2006), a sequence of reactions is initiated,
`leading to the degranulation of mast cell and basophil vesicles
`and release of histamine, platelet activating factor and tryptase
`(Norman et al., 1985; Bernstein et al., 2016). Activated mast cells
`also release arachidonic acid from membrane stores, which is a
`precursor to the eicosanoid synthetic pathway, involved in the
`production of cysteinyl leukotrienes (LTC4, LTD4, and LTE4) and
`prostaglandins (primarily PGD2) (Peters-Golden et al., 2006).
`
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`Topical Drugs for Allergic Rhinitis
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`Early Phase Response
`Histamine release from mast cells initiates the early or immediate
`phase response (Figure 1), typically occurs within 1 min of
`allergen exposure, and can last greater than 1 h (Wang et al.,
`1997). The nasal mucosa is innervated by a collection of
`sensory nerve fibers including Aδ and non-myelinated C fibers,
`sympathetic, and parasympathetic nerves. Histamine release
`from mast cells promotes activation of H1 receptors on sensory
`nerves of the afferent trigeminal system (Doyle et al., 1990;
`Bachert, 2002). These activated (depolarized) sensory nerves
`transmit signals to the central nervous system causing itching
`(Schmelz et al., 1997; Andrew and Craig, 2001) and motor reflexes
`such as sneezing. Histamine release also stimulates mucous
`glands to secrete watery discharge, via activation of sensory
`and parasympathetic nerves, which manifests symptomatically as
`rhinorrhoea (Al Suleimani and Walker, 2007). Nasal congestion
`is also caused by histamine release. Histamine stimulates H1
`and H2 receptors of nasal blood vessels causing increased
`vascular permeability and vasodilatation leading to engorgement
`of blood vessels in the nasal mucosa and the sensation of
`nasal congestion (Secher et al., 1982; Wood-Baker et al., 1996;
`Togias, 2003). Histamine release regulates the function of tight
`junctions in the nasal epithelium via coupling of H1 receptors.
`This interaction increases paracellular permeability (Flynn et al.,
`2009; Georas and Rezaee, 2014) which allows APCs to more
`easily penetrate epithelial
`tight
`junctions and augment
`the
`antigen capture and processing abilities of APCs. The other
`mediators released by mast cells and basophils also play a role
`in smooth muscle contraction, mucous secretion and increased
`vascular permeability.
`
`Late Phase Response
`The primary effector cells of the early phase response (mast cells
`and basophils) release cytokines and chemokines which attract
`additional cell types to the nasal mucosa, including eosinophils,
`Th2 cells, group 2 innate lymphoid cells (ILC2s) and neutrophils
`(Sin and Togias, 2011). The late phase response (Figure 2) is
`characterized by an influx of these migratory immune cells and
`the subsequent release of additional cytokines and mediators
`from these cells which sustains inflammation and prolongs
`symptoms (Mandhane et al., 2011; Pawankar et al., 2011). The
`late phase reaction typically occurs between 4 and 5 h after initial
`allergen exposure and can last up to 24 h. Whilst symptoms of
`rhinorrhoea and sneezing persist, ongoing nasal congestion is
`typically indicative of a late phase reaction (Bousquet et al., 2001).
`Nasal biopsy specimens and nasal lavage samples collected during
`the allergy season, or under experimental stimulations using nasal
`allergen provocation tests, have shown that immune cells such as
`basophils, eosinophils, neutrophils, mast cells, CD4+ T cells and
`macrophages (Bascom et al., 1988a,b; Bentley et al., 1992; Fokkens
`et al., 1992; Lim et al., 1995; Durham et al., 1996; Godthelp et al.,
`1996; Pawankar et al., 2011) are increased in the nasal mucosa.
`It is noted that the presence of these immune cells was found to
`vary depending on the method of nasal mucosa sampling and the
`time the samples were taken (i.e., in or out of allergy season and
`timepoint after initial allergen provocation).
`
`The late phase response is a highly complex pathophysiology
`involving various cytokines, chemokines and mediators released
`from different cell types, which interact together to perpetuate the
`allergic response. Mast cells release cytokines such as IL-4, IL-13
`and TNF-α that play a role in activation of endothelial cells and
`upregulate expression of adhesion molecules such as (ICAM-1,
`VCAM-1) to allow eosinophils, T cells, basophils and neutrophils
`to migrate to the nasal mucosa (Okano, 2009; Pawankar et al.,
`2011; Amin, 2012). Release of mediators from mast cells, such
`as leukotrienes, prostaglandins and platelet activating factor,
`are responsible for inducing symptoms as well as possessing
`chemoattractant abilities (Bernstein et al., 2016). In particular,
`cysteinyl leukotrienes and prostaglandin D2 released from mast
`cells are responsible for recruitment and activation ILC2 cells
`(Doherty et al., 2013; Chang et al., 2014). Indeed, elevated
`numbers of ILC2 been identified in peripheral blood (Doherty
`et al., 2014; Lao-Araya et al., 2014) and nasal mucosal samples
`(Dhariwal et al., 2017) from AR subjects during the pollen season
`or following nasal allergen challenge. Upon activation, ILC2 cells
`release large amounts of Th2 cytokines within the mucosal tissue
`which further aids to sustain inflammation (Zhong et al., 2017;
`Doherty and Broide, 2019).
`The role of neutrophils in allergic inflammation is being
`increasingly recognized (Fransson et al., 2004; Hosoki et al., 2016;
`Arebro et al., 2017). Neutrophils recruited to the nasal mucosa,
`produce compounds such as reactive oxygen species, proteases
`such as elastase, and enzymes including metallopeptidase 9
`and myeloperoxidase (MPO) which contribute to epithelial
`damage and recruitment of effector cells to the nasal mucosa
`(Monteseirin, 2009). Recent evidence suggests that neutrophils
`under
`stimulation with cytokines Granulocyte-macrophage
`colony-stimulating factor (GM-CSF), IFN-γ and IL-3 convert to
`functional antigen presenting cells and activate allergen-specific
`effector CD4+ T cells (Polak et al., 2018). The activated T
`cells contribute to allergic inflammation via the release of IL-
`5 which activates and recruits eosinophils to the nasal mucosa
`(Frew and Kay, 1988).
`The influx of activated eosinophils to the nasal mucosa is
`responsible for increased nasal hyperactivity due to exposure
`of nerve fibers following damage to the epithelium (Ayars
`et al., 1989). Epithelial damage results from the toxic effects
`of superoxide anions, hydrogen peroxide production and the
`release of granular products such as eosinophil cationic protein
`(ECP), eosinophil derived neurotoxin and major basic protein
`released from eosinophils (Mandhane et al., 2011). Eosinophils
`also release IL-5, which acts in an autocrine manner to promote
`the activation and survival of eosinophils (Akuthota and Weller,
`2012). T cells and mast cells also contribute to survival of
`eosinophils in the nasal mucosa via release of GM-CSF and IL-5
`(Yamaguchi et al., 1991; Park et al., 1998).
`Direct allergen exposure as well as mediator and cytokine
`release from primary effector cells (mast cells, basophils and T
`cells) can also stimulate structural cells in the nasal mucosa,
`including fibroblasts and epithelial cells, to release additional
`inflammatory chemokines and cytokines (Sin and Togias, 2011).
`Epithelial cells and fibroblasts are stimulated to release cytokines
`and chemokines such as Regulated upon Activation, Normal T
`cell Expressed, and Secreted (RANTES), thymus and activation
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`Topical Drugs for Allergic Rhinitis
`
`regulated chemokine, thymic stromal lymphopoietin, eotaxin, IL-
`33, IL-25, granulocyte colony-stimulating factor and monocyte
`chemoattractant protein 4 (MCP-4). These pro-inflammatory
`molecules act as chemoattractants to augment the Th2 response
`and contribute to the recruitment of eosinophils, basophils and T
`cells to the nasal mucosa (Takahashi et al., 2006; Pawankar et al.,
`2011; Bernstein et al., 2016).
`
`Priming Effect
`Increased nasal symptoms have been reported in subjects at the
`end of the pollen season, despite similar levels of aeroallergens
`(Norman, 1969). This observation is known as the ‘priming
`effect.’ Priming to allergen refers to the occurrence of increased
`nasal reactivity to allergens following repeated allergen exposure
`and has been confirmed under experimental allergen challenge
`models (Connell, 1969; Wachs et al., 1989). It is believed that
`priming to allergen occurs in response to chronic allergen
`exposure, whereby increased numbers of immune cells migrate
`to the nasal mucosa (particularly basophils) providing additional
`sites for IgE – allergen interaction and mediator release (Wachs
`et al., 1989; Bousquet et al., 1996).
`
`Endotypes of Rhinitis
`The assessment of
`the pathophysiology of allergic disease
`has changed from a generic focus on symptoms and tissue
`function, to the recognition of complex immune-regulatory
`networks
`that underpin the unique clinical presentation
`observed between individuals with allergic disease. Rhinitis
`is classically divided into 3 major clinical phenotypes, that
`is, grouping based on distinct clinical observations,
`these
`include: infectious rhinitis, non-infectious, non-allergic rhinitis
`(NAR) and allergic rhinitis with a combination of phenotypes
`present in some patients (Papadopoulos et al., 2015). Disease
`classification based on endotypes, that is, based on a distinct
`pathophysiological mechanism, has been recently proposed
`and is extensively reviewed elsewhere (Papadopoulos et al.,
`2015; Agache and Akdis, 2016; Muraro et al., 2016; Agache
`and Rogozea, 2018). Briefly,
`the endotypes described for
`rhinitis
`include: Type
`two inflammation, associated with
`the presence of eosinophils/ECP release, IgE and cytokines
`IL-5, IL-4 and IL-13 and seen in patients with AR, chronic
`rhinosinusitis and nasal polyposis; Non-type two inflammation,
`associated with neutrophils/ MPO release, cytokines INF-
`γ, TNFα, IL-1P, IL-6 and IL-8 and seen in patients with
`infectious rhinitis; Neurogenic endotype, associated with over
`expression of
`transient receptor potential (TRP) channels,
`nasal hyperactivity and high concentrations of neurokinins
`and substance P, and is seen in patients with idiopathic rhinitis
`and gustatory rhinitis; and Epithelial dysfunction, associated
`with reduced expression of tight junction proteins, enhanced
`subepithelial migration of exogenous antigenic molecules and
`is seen in patients with AR, infectious rhinitis and chronic
`(Agache and
`rhinosinusitis with or without nasal polyps
`Akdis, 2016; Muraro et al., 2016). It has been proposed that
`endotype classification may explain the variation observed
`between patients in clinical presentation and treatment response
`(Papadopoulos et al., 2015).
`
`INTRANASAL PHARMACEUTICAL
`TREATMENT OF ALLERGIC RHINITIS
`
`The presence of AR symptoms is associated with allergen
`exposure. Strategies employed to avoid allergen exposure such
`as staying indoors with closed windows or wearing a mask is
`highly impractical and is not widely practiced (Kemp, 2009).
`The rationale for using intranasal application of medications in
`the treatment of AR, is that high doses of drug can be applied
`directly toward receptor sites at the source of inflammation (nasal
`mucosa) with minimal risk of systemic side effects (Bousquet
`et al., 2008). Many drugs, which act via different mechanisms,
`have been developed for intranasal application. Antihistamines
`and corticosteroids are the most commonly used intranasal
`medications for AR symptoms. Other medications such as
`decongestants, anticholinergics and chromones have also been
`formulated for intranasal application, however they are only
`modestly effective and are recommended as an adjunct therapy
`or for mild symptoms (Bousquet et al., 2008).
`
`INTRANASAL ANTIHISTAMINES
`
`The interaction of histamine with H1 receptors is the primary
`cause for manifestation of early phase allergic responses that
`manifest as rhinorrhoea,
`itch and contraction of bronchial
`smooth muscles (Leurs et al., 2002). Antihistamines act on
`histamine receptors to ameliorate the effects of histamine by
`stabilizing the receptor in an inactive conformation. Azelastine
`hydrochloride and olopatadine hydrochloride are the only
`two intranasal antihistamine (INAH) spray formulations to
`be approved by the Food and Drug Administration for
`relief of AR symptoms.
`The pharmacological profile and clinical efficacy of azelastine
`hydrochloride
`and olopatadine hydrochloride have been
`extensively reviewed elsewhere (Bernstein, 2007; Horak, 2008;
`Berger, 2009; Horbal and Bernstein, 2010; Kaliner et al., 2010).
`Both drugs are classed as second-generation antihistamines
`with high affinities for the H1 receptor and little affinity for
`the H2 receptor (Sharif et al., 1996; Bernstein, 2007). Intranasal
`antihistamines typically have a fast onset of action, demonstrated
`to significantly reduce symptoms within 15 to 30 min (Horak
`et al., 2006; Patel et al., 2007a,b) with effects lasting up to 12 h
`(Greiff et al., 1997; Patel et al., 2007c). INAH are more effective
`at reducing symptoms of itching, rhinorrhoea and sneezing
`compared to oral antihistamines, but are less effective at reducing
`concurrent ocular symptoms (Corren et al., 2005; Bousquet et al.,
`2008). Like an oral antihistamine, INAH therapy typically has
`variable effects on nasal congestion (Golden and Craig, 1999;
`Bousquet et al., 2008).
`
`Mechanisms/Modulation
`The H1 receptor is widely distributed throughout the body.
`Expression of the H1 receptor has been documented in smooth
`muscle, heart, adrenal medulla, sensory nerves, central nervous
`system, epithelial cells and immune endothelial cells (Mahdy
`and Webster, 2011). Histamine receptors are heptahelical
`
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`Watts et al.
`
`Topical Drugs for Allergic Rhinitis
`
`I Re-exposure to aliergen
`
`Cross-linking
`
`Mast cell
`Basophil
`
`0 °o
`0 00
`O O O
`0 0 oo
`0
`
`0
`
`Release of mast cell
`mediators
`- histamine
`- platelet activating factor
`- tryptase
`- leukotrienes
`
`0
`
`0 O O O
`
`NERVES
`
`0 I
`
`GLANDS
`
`Oo oo O l
`
`VESSELS
`
`Stimulation l
`
`vlm;. .... _ou:,
`g lands
`induce
`1:y})e:~t''--..: t: liu,,
`
`Increased
`
`perrrie;:;b!iity
`vasodi!atloi1
`
`Ri 11norri iuea
`
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`
`FIGURE 1 | The early phase response. Crosslinking of FCεR1-bound IgE antibodies on the mast cell surface in response to secondary allergen exposure stimulates
`the degranulation of mast cells. Degranulation induces the release of chemical mediators (primarily histamine) that stimulate sensory nerve endings, mucous glands
`and small vessels of the nasal mucosa to produce classic rhinitis symptoms: sneezing, nasal itching, rhinorrhoea and nasal congestion. The onset of action is
`typically within minutes of exposure and is sustained for 2–3 h forming the early-phase response.
`
`transduce
`G-protein coupled transmembrane receptors that
`extracellular signals through G proteins to intracellular second
`messenger systems (Simons and Simons, 2011). Histamine
`receptors may be considered a ‘cellular switcher,’ functioning
`in equilibrium between two conformation states, active or
`inactive (Figure 3). Antihistamine drugs are classified as
`inverse agonists, as
`they are not
`structurally related to
`histamine and do not antagonize the binding of histamine,
`
`but instead bind to different sites on the receptor (Wieland
`et al., 1999; Gillard et al., 2002). Binding of antihistamines
`to the histamine receptor
`stabilizes
`the receptor
`in the
`inactive state thereby reducing the intrinsic activity of the
`receptor in response to histamine (Mahdy and Webster, 2011;
`Simons and Simons, 2011).
`While histamine is an important mediator involved in
`the pathophysiology of the allergic response, other mediators
`
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`Watts et al.
`
`Topical Drugs for Allergic Rhinitis
`
`EARLY PHASE RESPONSE
`release of mediators,
`cytokines and chemokines
`
`nasal mucosa
`
`[ill]
`
`Release of:
`G-CSF, MCP-4
`RANTES, TARC
`TSLP, EOTAX IN
`IL33, IL25
`
`ICAM1 -0~
`0 CJ()
`
`migration to
`nasal mucosa
`
`Basophils, T-cells,
`
`Eosinophils @j
`
`NASAL CONGESTION
`
`Th2 cells @)
`
`sensory nerve ®
`
`G 1 IL4, IL1 3, ILS
`GM-CSF """Li
`
`✓
`Release of
`neuropeptides ~
`
`1
`
`Activates
`O ' \~osinoph,l s
`
`~ 0~§0 Release of:
`
`oggo0 ECP,MBP
`o O
`superoxide anions
`EPO
`
`FIGURE 2 | The late phase response. Mediators and cytokines released during the early phase response act on various sites including nasal blood vessels, nasal
`epithelial cells, T cells and sensory nerves to initiate the symptoms of an allergic response. The late phase response is characterized by the involvement of key
`immune effector cells including basophils, T cells and eosinophils, which migrate to the nasal mucosa in response to early phase stimulus. The release of cytokines
`and mediators from these effector cells further perpetuates the allergic response and symptom manifestation. (a) Mast cell mediators act on adhesion molecules
`(e.g., ICAM-1 and VCAM-1) on blood vessel endothelial cells increasing vascular permeability thereby allowing effector cells such as eosinophils, T cells and
`basophils to migrate to the nasal mucosa. (b) Nasal mucosal cells are stimulated by mast cell products to secrete cell signaling molecules which further promote
`chemoattraction of effector cells to the nasal mucosa. (c) Nasal edema (congestion) is worsened by the influx of immune cells and their subsequent mediator release.
`(d) Cytokine release from T cells, activates and stimulates eosinophils to release toxic mediators. (e) Eosinophil derived mediators damage the nasal epithelium and
`leave nerve fibers exposed to histamine and other mediators promoting neurogenic inflammation. G-CSF, Granulocyte-colony stimulating factor; MCP-4, Monocyte
`chemotactic protein-4; RANTES, Regulated on activation normal T cell expressed and secreted; TARC, Thymus- and activation-regulated chemokine; TSLP, Thymic
`stromal lymphopoietin, GM-CSF, Granulocyte-macrophage colony-stimulating factor; ECP, Eosinophil cationic protein; MBP, Major basic protein.
`
`0
`
`I RESTING STATE I
`
`~ I AGONIST I
`
`©
`
`I INVERSE AGONIST I
`
`Extracellular
`
`histamine
`
`antihistam ine
`
`'""""'-=. • --=• • =-•
`
`~ p
`
`~G) ® ~ p
`
`~G) ®
`
`Inactive
`
`Active
`
`Inactive
`
`Active
`
`~ p
`
`Inactive
`
`~ G) ®
`
`Active
`
`FIGURE 3 | Molecular model of the histamine 1 (H1) receptor. The H1 receptor is a G protein-coupled transmembrane receptor which acts as a ‘molecular switcher’
`via interactions with their associated intracellular heterotrimeric G proteins (consisting of α, β, and γ subunits). G proteins regulate downstream intracellular signaling
`via their ability to catalyze the exchange of Gα bound GDP to GTP. The H1 receptor complex exists between two conformational states, active and inactive, which
`are directed by specific extracellular ligand binding to the G protein receptor. (a) When the active and inactive state are in equilibrium, the H1 receptor is in a resting
`state. (b) Histamine (an agonist) binds to and stabilizes the receptor in the active conformation which shifts the equilibrium toward the active state. (c) Antihistamines
`(an inverse agonist) binds to and stabilizes the receptor in the inactive conformation which shifts the equilibrium toward the inactive state. Gβ, Guanine
`nucleotide-binding protein beta; Gγ, Guanine nucleotide-binding protein gamma; Gα, Guanine nucleotide-binding protein alpha; GDP, Guanosine diphosphate; GTP,
`Guanosine triphosphate. Modified from Simons and Simons (2011).
`
`Frontiers in Pharmacology | www.frontiersin.org
`
`6
`
`March 2019 | Volume 10 | Article 294
`
`

`

`Watts et al.
`
`Topical Drugs for Allergic Rhinitis
`
`• Hl receptor
`
`(a\/
`Antihistamine
`@
`--..:,)/
`----=-----> e,,
`
`~ I I
`I @/
`j
`®
`enzymes @l-------~ [iTIBJ
`
`Ca'• dependent
`
`/
`
`(P~g))
`Ca"
`
`/
`
`/',,-
`
`-------------
`--........
`Ca lcium ~Y
`ion channel //\~Ca'·
`
`, mast cell
`degranulation
`
`• mediator release
`
`Endoplasmic
`reticulum
`
`Extracellular
`
`Cell membrane
`
`Intracellular
`
`INF-K·B I
`" proinflamm(]tory
`cytokines, chemokines
`mediators
`• adhesion molecules
`
`Nucleus
`
`FIGURE 4 | Anti-inflammatory effects of antihistamines. Binding of antihistamines (an inverse agonist) to the transmembrane H1 receptor prevents the activation of
`intracellular signaling pathways that result in mast cell degranulation and NF-κB activation. Alternatively, when histamine (an agonist) binds to the H1 receptor, this
`signals the associated G protein subunit Gαq to activate the phospholipase C and phosphatidylinositol (PIP2) signaling pathways. (a) Gαq activates phospholipase C
`which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid constituent of the cell membrane, into diacyl glycerol (DAG) and inositol 1,4,5
`triphosphate (IP3). (b) IP3 is then released into the cytoplasm where it binds to IP3 receptors situated in the endoplasmic reticulum (ER). The IP3 receptors are
`intracellular channels that facilitate calcium ion release. On binding with IP3, IP3 receptors are stimulated to release calcium ions from ER stores into the cytosol.
`Mast cell degranulation and subsequent mediator release is dependent on this flux in calcium ion availability in the cytosol. (c) Calcium ions and DAG (cleaved from
`PIP2) activate protein kinase C which is involved in activating the transcription factor NF-κB. (d) Activation of NF-κB results in increased transcription of
`proinflammatory genes. DAG, 1,2-diacyl-glycerol; PLCβ, phospholipase C β, PIP2, phosphatidylinositol 4,5-biphosphate; IP3, Inositol 1,4,5-triphosphate; IR, Inositol
`1,4,5-triphosphate receptor type 1; PKCβ, protein kinase C beta; NADPH, nicotinamide adenine dinucleotide phosphate. Modified from Frolkis et al. (2010); Simons
`and Simons (2011), and Jewison et al. (2014).
`
`released from various immune cells such as leukotrienes,
`prostaglandins, kinins, cytokines, platelet-activating factor (PAF)
`and ECP, are responsible for amplifying and maintaining
`inflammation and therefore prolonging symptoms. There is
`some evidence to suggest that specific antihistamines including
`azelastine hydrochloride and olopatadine hydrochloride can
`exert anti-allergic effects beyond inhibiting the action of
`histamine on histamine receptors (Figure 4).
`
`Action on Histamine Receptors
`In stimulated cell culture models, azelastine hydrochloride
`treatment reduced secretion of pro-inflammatory cytokines TNF-
`α (Hid