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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Aspirin Intolerance: Experimental Models for Bed-to-Bench</title>
<author><name sortKey="Yamashita, Masamichi" sort="Yamashita, Masamichi" uniqKey="Yamashita M" first="Masamichi" last="Yamashita">Masamichi Yamashita</name>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">27719658</idno>
<idno type="pmc">5345322</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345322</idno>
<idno type="RBID">PMC:5345322</idno>
<idno type="doi">10.2174/1389450117666161005152327</idno>
<date when="2016">2016</date>
<idno type="wicri:Area/Pmc/Corpus">000A80</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A80</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Aspirin Intolerance: Experimental Models for Bed-to-Bench</title>
<author><name sortKey="Yamashita, Masamichi" sort="Yamashita, Masamichi" uniqKey="Yamashita M" first="Masamichi" last="Yamashita">Masamichi Yamashita</name>
</author>
</analytic>
<series><title level="j">Current Drug Targets</title>
<idno type="ISSN">1389-4501</idno>
<idno type="eISSN">1873-5592</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
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<front><div type="abstract" xml:lang="en"><p>Aspirin is the oldest non-steroidal anti-inflammatory drug (NSAID), and it sometimes causes asthma-like symptoms known as aspirin-exacerbated respiratory disease (AERD), which can be serious. Unwanted effects of aspirin (aspirin intolerance) are also observed in patients with food-dependent exercise-induced anaphylaxis, a type I allergy disease, and aspirin-induced urticaria (AIU). However the target and the mechanism of the aspirin intolerance are still unknown. There is no animal or cellular model of AERD, because its pathophysiological mechanism is still unknown, but it is thought that inhibition of cyclooxygenase by causative agents leads to an increase of free arachidonic acid, which is metabolized into cysteinyl leukotrienes (cysLTs) that provoke airway smooth muscle constriction and asthma symptoms. As the bed-to-bench approach, to confirm the clinical discussion in experimental cellular models, we have tried to develop a cellular model of AERD using activated RBL-2H3 cells, a rat mast cell like cell line. Indomethacin (another NSAID and also causes AERD), enhances in vitro cysLTs production by RBL-2H3 cells, while there is no induction of cysLTs production in the absence of inflammatory activation. Since this suggests that all inflammatory cells with activation of prostaglandin and cysLT metabolism should respond to NSAIDs, and then I have concluded that aspirin intolerance should be separated from subsequent bronchoconstriction. Evidence about the cellular mechanisms of NSAIDs may be employed for development of in vitro AERD models as the approach from bench-to-bed.</p>
</div>
</front>
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</TEI>
<pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Curr Drug Targets</journal-id>
<journal-id journal-id-type="iso-abbrev">Curr Drug Targets</journal-id>
<journal-id journal-id-type="publisher-id">CDT</journal-id>
<journal-title-group><journal-title>Current Drug Targets</journal-title>
</journal-title-group>
<issn pub-type="ppub">1389-4501</issn>
<issn pub-type="epub">1873-5592</issn>
<publisher><publisher-name>Bentham Science Publishers</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27719658</article-id>
<article-id pub-id-type="pmc">5345322</article-id>
<article-id pub-id-type="publisher-id">CDT-17-1963</article-id>
<article-id pub-id-type="doi">10.2174/1389450117666161005152327</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Aspirin Intolerance: Experimental Models for Bed-to-Bench</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Yamashita</surname>
<given-names>Masamichi</given-names>
</name>
<xref ref-type="corresp" rid="cor1">*</xref>
</contrib>
<aff id="aff1">Laboratory of Food for Health, Department of Bioscience in Daily Life, College of Bioresource Sciences, Nihon University, Kameino, Fujisawa, Kanagawa,<country>Japan</country>
</aff>
</contrib-group>
<author-notes><corresp id="cor1"><label>*</label>
Address correspondence to this author at the Laboratory of Food for Health, Department of Bioscience in Daily Life, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880 Japan; Tel/Fax: +81-466-84-3748; E-mail: <email xlink:href="may@brs.nihon-u.ac.jp">may@brs.nihon-u.ac.jp</email>
</corresp>
</author-notes>
<pub-date pub-type="epub"><month>12</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="ppub"><month>12</month>
<year>2016</year>
</pub-date>
<volume>17</volume>
<issue>16</issue>
<fpage>1963</fpage>
<lpage>1970</lpage>
<history><date date-type="received"><day>28</day>
<month>6</month>
<year>2016</year>
</date>
<date date-type="rev-recd"><day>23</day>
<month>9</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>29</day>
<month>9</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>© 2016 Bentham Science Publishers</copyright-statement>
<copyright-year>2016</copyright-year>
<license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by-nc/4.0/legalcode"><license-p>This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (<uri xlink:type="simple" xlink:href="https://creativecommons.org/licenses/by-nc/4.0/legalcode">https://creativecommons.org/licenses/by-nc/4.0/legalcode</uri>
), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.</license-p>
</license>
</permissions>
<abstract><p>Aspirin is the oldest non-steroidal anti-inflammatory drug (NSAID), and it sometimes causes asthma-like symptoms known as aspirin-exacerbated respiratory disease (AERD), which can be serious. Unwanted effects of aspirin (aspirin intolerance) are also observed in patients with food-dependent exercise-induced anaphylaxis, a type I allergy disease, and aspirin-induced urticaria (AIU). However the target and the mechanism of the aspirin intolerance are still unknown. There is no animal or cellular model of AERD, because its pathophysiological mechanism is still unknown, but it is thought that inhibition of cyclooxygenase by causative agents leads to an increase of free arachidonic acid, which is metabolized into cysteinyl leukotrienes (cysLTs) that provoke airway smooth muscle constriction and asthma symptoms. As the bed-to-bench approach, to confirm the clinical discussion in experimental cellular models, we have tried to develop a cellular model of AERD using activated RBL-2H3 cells, a rat mast cell like cell line. Indomethacin (another NSAID and also causes AERD), enhances in vitro cysLTs production by RBL-2H3 cells, while there is no induction of cysLTs production in the absence of inflammatory activation. Since this suggests that all inflammatory cells with activation of prostaglandin and cysLT metabolism should respond to NSAIDs, and then I have concluded that aspirin intolerance should be separated from subsequent bronchoconstriction. Evidence about the cellular mechanisms of NSAIDs may be employed for development of in vitro AERD models as the approach from bench-to-bed.</p>
</abstract>
<kwd-group kwd-group-type="author"><title>Keywords: </title>
<kwd>Arachidonic acid metabolism</kwd>
<kwd>aspirin intolerance</kwd>
<kwd>aspirin-exacerbated respiratory disease</kwd>
<kwd>aspirin-induced urticaria</kwd>
<kwd>cysteinyl leukotrienes</kwd>
<kwd>food-dependent exercise-induced anaphylaxis</kwd>
<kwd>prostaglandins</kwd>
<kwd>mast cells</kwd>
</kwd-group>
</article-meta>
</front>
<body><sec><label>1</label>
<title>CLINICAL ASPECTS OF ASPIRIN INTOLERANCE</title>
<sec><label>1.1</label>
<title>Aspirin Intolerance and Clinical Aspects of AERD</title>
<p>Aspirin-exacerbated respiratory disease (AERD) is also known as aspirin-induced asthma or aspirin-intolerant asthma (AIA). It is a respiratory disorder that features nasal obstruction, rhinorrhea, and acute asthma attacks with airway constriction, which is induced by non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin (acetylsalicylic acid; Fig. <bold><xref ref-type="fig" rid="F1">1a</xref>
</bold>
) [<xref rid="r1" ref-type="bibr">1</xref>
-<xref rid="r3" ref-type="bibr">3</xref>
] or indomethacin (Fig. <bold><xref ref-type="fig" rid="F1">1b</xref>
</bold>
) [<xref rid="r4" ref-type="bibr">4</xref>
], other medications [<xref rid="r5" ref-type="bibr">5</xref>
] such as sodium succinate-conjugated corticosteroids (<italic>e.g</italic>
. hydrocortisone sodium succinate; Fig. <bold><xref ref-type="fig" rid="F1">1c</xref>
</bold>
) food additives such as tartrazine (a yellow food dye; Fig. <bold><xref ref-type="fig" rid="F1">1d</xref>
</bold>
) or parahydroxybenzoates (antiseptic food additives known as paraben; Fig. <bold><xref ref-type="fig" rid="F1">1e</xref>
</bold>
), and food components such as sulfites, mint, and salicylate (Fig. <bold><xref ref-type="fig" rid="F1">1f</xref>
</bold>
) [<xref rid="r6" ref-type="bibr">6</xref>
, <xref rid="r7" ref-type="bibr">7</xref>
]. Hypersensitivity to NSAIDs and these causative substances is known as aspirin intolerance.</p>
<p>According to the asthma guideline of the US National Heart, Lung and Blood Institute, 21% of adult asthma patients and 5% of pediatric asthma patients have AERD [<xref rid="r8" ref-type="bibr">8</xref>
], while the Japanese asthma guideline [<xref rid="r9" ref-type="bibr">9</xref>
] states that 5-10% of adult asthma patients and 3.6-7.8% of pediatric asthma patients have AERD. According to both guidelines, the majority of AERD patients are adults.</p>
<p>Females are affected twice as often as males, but other factors such as the family history, ethnicity, or geographic region have no influence [<xref rid="r10" ref-type="bibr">10</xref>
], suggesting that genetic disorders are not related to the pathogenesis of AERD. Nasal polyps and dysosmia are frequent in AERD patients [<xref rid="r9" ref-type="bibr">9</xref>
, <xref rid="r11" ref-type="bibr">11</xref>
, <xref rid="r12" ref-type="bibr">12</xref>
].</p>
<p>Asthma attacks triggered by aspirin intolerance can be serious, and it was reported that 40% of patients receiving emergency treatment for asthma have AERD [<xref rid="r13" ref-type="bibr">13</xref>
, <xref rid="r14" ref-type="bibr">14</xref>
]. Since AERD has been reported in patients without known prior exposure to the triggering compound, it seems that the underlying mechanism is not type I allergy [<xref rid="r10" ref-type="bibr">10</xref>
]. Evidence shows that treatment with chromoglycate is effective for AERD [<xref rid="r15" ref-type="bibr">15</xref>
], suggesting that mast cells may play a pivotal role in this condition.</p>
</sec>
<sec><label>1.2</label>
<title>Aspirin Intolerance in Other Diseases</title>
<p>Aspirin intolerance is also observed in a condition called aspirin-induced urticaria (AIU), in which urticaria and/or angioedema develops at 1-6 h after exposure to COX-1-inhibiting NSAIDs in 12% of patients with chronic urticaria [<xref rid="r16" ref-type="bibr">16</xref>
-<xref rid="r18" ref-type="bibr">18</xref>
]. AERD and AIU account for the majority of patients with aspirin intolerance.</p>
<p>Harada <italic>et al.</italic>
[<xref rid="r19" ref-type="bibr">19</xref>
] reported that aspirin intolerance was observed in all of their patients with food-dependent exercise-induced anaphylaxis (FDEIA), a condition combining food allergy and respiratory disorder that is mostly related to wheat or crustaceans. FDEIA differs from AERD, since many patients are teenage boys and 40% of them have atopic diseases, suggesting that FDEIA is associated with type I allergy. While 10% of patients develop asthma attacks with exercise several hours after intake of a causative food, they have no symptoms if they do not exercise [<xref rid="r20" ref-type="bibr">20</xref>
].</p>
<p>These differences between AERD and FDEIA may indicate that the type of allergy (atopic or non-atopic) is not important, or may suggest that non-atopic immune activation underlies the atopic characteristics of FDEIA. Accordingly, it is possible that aspirin intolerance should be separated from the subsequent bronchoconstriction in AERD or FDEIA.</p>
</sec>
</sec>
<sec><label>2</label>
<title>PATHOPHYSIOLOGICAL ASPECTS OF AERD</title>
<sec><label>2.1</label>
<title>Arachidonic Acid Metabolism and AERD</title>
<p>As shown in Fig. (<bold><xref ref-type="fig" rid="F2">2</xref>
</bold>
), the enzyme phospholipase A<sub>2</sub>
releases fatty acids from cell membrane phospholipids. Arachidonic acid is one of the fatty acids released and it is metabolized into various substances, including prostaglandins (PGs), leukotrienes (LTs), and thromboxanes (TXs), which are thought to make a major contribution to the pathogenesis of inflammatory diseases.</p>
<p>PGD<sub>2</sub>
and PGE<sub>2</sub>
are arachidonic acid metabolites produced by cyclooxygenase (COX, also called prostaglandin G/H synthase, PGHS, EC 1.14.99.1) which metabolizes arachidonic acid to PGG<sub>2</sub>
by its cyclooxygenase activity and then metabolizes PGG<sub>2</sub>
to PGH<sub>2</sub>
by its hydroperoxidase activity (Fig. <bold><xref ref-type="fig" rid="F2">2</xref>
</bold>
). Metabolites of COX are known to contribute to inflammation. In 1990s, two subtypes of the COX enzyme were found. One of these was named COX-1 and was found to be constitutively expressed by cells. The other was named COX-2 [<xref rid="r21" ref-type="bibr">21</xref>
, <xref rid="r22" ref-type="bibr">22</xref>
], and this was found to be induced by physiological and experimental inflammatory stimuli, such as the carcinogenic promoter 12-<italic>O</italic>
-tetradecanoylphorbol 13-acetate, thapsigargin, or calcium ionophore A23187 [<xref rid="r23" ref-type="bibr">23</xref>
-<xref rid="r26" ref-type="bibr">26</xref>
]. Transcription of COX-2 protein is controlled by various transcription factors, including nuclear factor-κB (NF-κB) and AP-1 [<xref rid="r27" ref-type="bibr">27</xref>
-<xref rid="r31" ref-type="bibr">31</xref>
], <italic>via</italic>
degradation of the inhibitory protein, IκB [<xref rid="r32" ref-type="bibr">32</xref>
]. Specific COX-2 inhibitors were developed to avoid the side effect of gastrointestinal ulceration, and it was revealed that selectivity is due to difference of tertiary protein structure between COX-1 and COX-2 [<xref rid="r33" ref-type="bibr">33</xref>
-<xref rid="r36" ref-type="bibr">36</xref>
].</p>
<p>Arachidonic acid is also metabolized to leukotriene A<sub>4</sub>
(LTA<sub>4</sub>
) by another pathway involving 5-lipoxygenase (5-LOX), after which LTA<sub>4</sub>
is converted to LTB<sub>4</sub>
and LTC<sub>4</sub>
. Then LTC<sub>4</sub>
is metabolized to LTD<sub>4</sub>
, and LTE<sub>4</sub>
as shown in Fig. (<bold><xref ref-type="fig" rid="F2">2</xref>
</bold>
). LTC<sub>4</sub>
, LTD<sub>4</sub>
, and E<sub>4</sub>
contain cysteine residues, and thus are called cysteinyl leukotrienes (cysLTs). Cysteinyl LTs were originally discovered as slow reacting substance of anaphylaxis (SRS-A), which was extracted from the lung tissues of antigen-sensitized guinea pigs, and was shown to constrict airway smooth muscle from these animals more potently, slowly, and continuously than histamine <italic>via</italic>
an antihistamine- resistant mechanism [<xref rid="r37" ref-type="bibr">37</xref>
].</p>
<p>Urinary concentrations of cysLTs are elevated in AERD patients, even when they have no asthma symptoms [<xref rid="r38" ref-type="bibr">38</xref>
], and cysLT inhibitors, such as 5-LOX inhibitor [<xref rid="r39" ref-type="bibr">39</xref>
], or cysLT receptor blockers [<xref rid="r40" ref-type="bibr">40</xref>
-<xref rid="r42" ref-type="bibr">42</xref>
] are reported to be safe and effective for AERD, indicating involvement of cysLTs in the mechanism underlying this disease.</p>
</sec>
<sec><label>2.2</label>
<title>Target of Aspirin/NSAIDs and Mechanism of AERD</title>
<p>Aspirin is an anti-inflammatory analgesic agent that has been marketed since 1899 and is the oldest chemically synthesized drug (Fig. <bold><xref ref-type="fig" rid="F1">1a</xref>
</bold>
). In the 1970s, it was found that the mechanism of action of aspirin and other acidic NSAIDs involves inhibition of PG production [<xref rid="r43" ref-type="bibr">43</xref>
-<xref rid="r45" ref-type="bibr">45</xref>
]. In the 1990s, the molecular mechanism of aspirin was finally revealed to be irreversible acetylation of Ser-530 on COX [<xref rid="r46" ref-type="bibr">46</xref>
], with inhibition of both COX-1 and COX-2 [<xref rid="r23" ref-type="bibr">23</xref>
], while most NSAIDs such as indomethacin (Fig. <bold><xref ref-type="fig" rid="F1">1b</xref>
</bold>
) reversibly inhibit COX.</p>
<p>Almost all (80-100%) the oral dose of aspirin (100-300 mg) is immediately absorbed from the stomach or upper small intestine and the maximum serum concentration is reached within 35 min. Then it is metabolized into salicylic acid (Fig. <bold><xref ref-type="fig" rid="F3">3a</xref>
</bold>
) and conjugated with a glucuronate or sulfate. A sodium salt of the one of the metabolites, gentisic acid (Fig. <bold><xref ref-type="fig" rid="F3">3b</xref>
</bold>
), is reported to have an anti-inflammatory effect [<xref rid="r47" ref-type="bibr">47</xref>
].</p>
<p>Interestingly, selective COX-2 inhibitors have been reported to be safe for AERD patients [<xref rid="r48" ref-type="bibr">48</xref>
-<xref rid="r51" ref-type="bibr">51</xref>
], indicating the pivotal involvement of COX-1 in the mechanism of AERD.</p>
<p>In 1990s, it was hypothesized that suppression of prostaglandin production <italic>via</italic>
inhibition of COX leads to accumulation of excess arachidonic acid both inside and outside of cells, after which the excess arachidonic acid is metabolized into cysLTs that cause asthma attacks [<xref rid="r38" ref-type="bibr">38</xref>
, <xref rid="r52" ref-type="bibr">52</xref>
-<xref rid="r55" ref-type="bibr">55</xref>
].</p>
</sec>
</sec>
<sec><label>3</label>
<title>BED-TO-BENCH APPROACH OF THE EXPERIMENTAL MODELS WHICH PROPOSING OR CONFIRMING THE PATHOPHYSIOLOGICAL MECHANISMS OF AERD</title>
<p>The pathogenic mechanism of AERD is still not clear. Most of the research performed has been clinical because useful animal or cellular models do not exist. Some attempts to develop experimental models of AERD are ongoing based on clinical information.</p>
<sec><label>3.1</label>
<title>Cellular Model of Arachidonic Acid Metabolism Using a Cultured RBL-2H3 Mast Cell Line</title>
<p>We have tried to develop a cellular model of AERD based on inhibition PG production by NSAIDs, and we previously assessed the effect on cysLT production in the RBL-2H3 mast cell line derived from rat basophilic leukemia [<xref rid="r56" ref-type="bibr">56</xref>
]. We choose indomethacin (≦3 µM, Fig. <bold><xref ref-type="fig" rid="F1">1b</xref>
</bold>
) as the NSAID to avoid unexpected protein acetylation by using aspirin [<xref rid="r57" ref-type="bibr">57</xref>
]. We found that cysLT production increased when RBL-2H3 cells were pretreated overnight with dinitrophenol (DNP)-specific immunoglobulin E (IgE) and then treated with DNP-conjugated human serum albumin, creating a cellular model of type I allergy [<xref rid="r58" ref-type="bibr">58</xref>
-<xref rid="r60" ref-type="bibr">60</xref>
]. Treatment with indomethacin at concentration up to 3 μM did not cause dose-dependent changes of cysLT production, while there was almost 90% inhibition of PGD<sub>2</sub>
production. LTB<sub>4</sub>
production was significantly increased by indomethacin at 1-3 μM. Our observation regarding LTB<sub>4</sub>
is supported by a study of Planaguma <italic>et al.</italic>
[<xref rid="r61" ref-type="bibr">61</xref>
] using rat Kupffer cells; adding aspirin (up to 5 mM) doubled LTB<sub>4</sub>
production while inhibiting PGE<sub>2</sub>
production approximately 60%.</p>
<p>Then we tried adding arachidonic acid (1-10 μM) with DNP-HSA to the culture medium of RBL-2H3 cells. Cysteinyl LT production was significantly increased by adding arachidonic acid combined with allergic stimulation, while there was no significant change without allergic stimulation [<xref rid="r57" ref-type="bibr">57</xref>
].</p>
<p>As mentioned above, AERD is not thought to be a type I allergic disease, so we also tested non-allergic stimulation of RBL-2H3 cells with calcium ionophore A23187 and obtained the similar results.</p>
<p>Our observations indicate that induction of cysLT production by indomethacin may require some inflammatory stimulation of mast cells. If AERD is fundamentally a problem with arachidonic acid metabolism, it leads to another question: “Why don't all patients with type I allergy who show activation of mast cells and increased cysLT production have aspirin intolerant?”</p>
</sec>
<sec><label>3.2</label>
<title>NSAIDs Increase cysLT Production by Mast Cells</title>
<p>In our experiments described above [<xref rid="r57" ref-type="bibr">57</xref>
], we obtained the interesting result that 0.1 μM of indomethacin slightly, but significantly increased the production of LTC<sub>4</sub>
, and LTE<sub>4</sub>
. We also tested indomethacin from another source to avoid the influence of contamination by other factors, and the same result was observed.</p>
<p>Togo <italic>et al.</italic>
[<xref rid="r62" ref-type="bibr">62</xref>
] reported that aspirin and salicylate (both at 100-300 μM) increased LTC<sub>4</sub>
production by the RBL-2H3 mast cell line and mouse bone marrow-derived mast cells, and suggested that the mechanism involved calcium influx following activation of cytosolic phospholipase A<sub>2</sub>
. We cannot conclude whether their observation corresponds with ours or not, and it is also unclear whether the effect of these NSAIDs is related to AERD.</p>
</sec>
<sec><label>3.3</label>
<title>Possible Involvement of Cytokines in PG Production</title>
<p>Liu <italic>et al.</italic>
[<xref rid="r63" ref-type="bibr">63</xref>
] studied mice with knockout of microsomal PGE synthase-1 (mPGES-1), which associates with COX-2 and metabolizes PGH<sub>2</sub>
to PGE<sub>2</sub>
(Fig. <bold><xref ref-type="fig" rid="F2">2</xref>
</bold>
). After pretreatment with dust mite extract and challenge with lysine-aspirin (1.2 mg/12 µL <italic>via</italic>
a ventilator), there was a marked increase of respiratory tract resistance and elevation of the levels of cysLTs, histamine, and MCP-1 (an indicator of mast cell degranulation) in bronchoalveolar lavage fluid. Ketorolac (a selective COX-1 inhibitor) and celecoxib (a selective COX-2 inhibitor) failed to increase respiratory tract resistance in this model. However, an EP2 receptor agonist significantly inhibited these responses, and EP2 receptor knockout mice showed smaller increases than mPGES-1 knockout mice. They recently observed that interleukin (IL)-33, a type 2 helper T (Th2) cytokine released from necrotic cells as “alarmin” [<xref rid="r64" ref-type="bibr">64</xref>
], was highly expressed in the lung epithelium of mPGES-1 knockout mice pretreated with mite extract and in the nasal polyps of AERD patients [<xref rid="r65" ref-type="bibr">65</xref>
, <xref rid="r66" ref-type="bibr">66</xref>
]. It was reported that IL-33 is produced by mast cells and that it increases the production of IL-4, IL-5, and IL-6 by bone marrow-derived murine mast cells and a murine mast cell line (MC/9) when these cells received IgE sensitization followed by antigen treatment. It was also reported that the IL-33 receptor (ST-2) is expressed by mast cells after atopic stimulation [<xref rid="r67" ref-type="bibr">67</xref>
].</p>
<p>Another class of ST-2 positive memory-type Th2 cells, known as pathogenic Th2 cells, was recently proposed to have a role in inflammatory diseases including asthma [<xref rid="r68" ref-type="bibr">68</xref>
]. Though the relationship between the pathogenic Th2 cells and AERD is unclear, T cells or their cytokines could activate mast cells in AERD patients.</p>
<p>The observation that mPGES knockout mice respond to lysine-aspirin [<xref rid="r63" ref-type="bibr">63</xref>
] may indicate that inhibition of cytosolic PGES (cPGES) associated with COX-1 (Fig. <bold><xref ref-type="fig" rid="F4">4</xref>
</bold>
) could be at least partly involved in AERD, suggesting that cPGES activators could be effective for this condition.</p>
<p>Nakatani <italic>et al.</italic>
[<xref rid="r69" ref-type="bibr">69</xref>
] studied the effect of cPGES knockout, and reported that cPGES-null mice undergo perinatal death with low body weight, hypoplastic skin changes, and alveolar collapse in the lungs at 18.5 days post-coitum. In contrast, heterozygous knockout mice seemed normal, apart from the cPGES protein level. They did not provide information about the effect of NSAIDs on cPGES heterozygous knockout animals.</p>
<p>We previously observed that auranofin, a gold compound for rheumatoid arthritis, induced a COX-1-dependent increase of PGE<sub>2</sub>
production without significant induction of COX-1 protein within 4 h after inflammatory treatment of rat peritoneal macrophages, while nitric oxide production was not increased [<xref rid="r25" ref-type="bibr">25</xref>
, <xref rid="r26" ref-type="bibr">26</xref>
, <xref rid="r31" ref-type="bibr">31</xref>
]. It was also reported that auranofin induces p23, a co-chaperone of heat shock protein 90 that was later identified as cPGES (Fig. <bold><xref ref-type="fig" rid="F2">2</xref>
</bold>
) [<xref rid="r70" ref-type="bibr">70</xref>
]. If reduction of PG synthesis <italic>via</italic>
cPGES/COX-1 plays an important role in AERD, auranofin or other cPGES activator(s) could be effective for this condition.</p>
<p>Findings in our cellular model suggested that mast cells may require inflammatory activation for overproduction of cysLTs with COX inhibition. Some classes of T cells and some cytokines may be involved the pathogenesis of AERD by activating mast cells. Therefore, <italic>in vitro</italic>
experiments may be able to identify inflammatory mediators that activate mast cells and PGES activators, with the results having clinical implications.</p>
</sec>
<sec><label>3.4</label>
<title>Other Targets of Aspirin, the Bench-to-Bed Approach</title>
<p>The mechanism through which NSAIDs act on COX is very clear and explains many inflammatory phenomena, but we could not explain all the effects of NSAIDs through inhibition of COX activity.</p>
<p>As described above, some causative substances of AERD may not strongly inhibit COX-1-dependent PG synthesis. We previously observed that the ligands of two well-known nuclear receptors, peroxisome proliferator-activated receptor (PPAR) α and γ, independently reduced cysLT release from stimulated RBL-2H3 mast cell line [<xref rid="r58" ref-type="bibr">58</xref>
-<xref rid="r60" ref-type="bibr">60</xref>
]. This may suggest the possibility of a role of some unknown target(s) of NSAIDs and other causative substances.</p>
<p>Aspirin is reported to be associated with phospholipase A<sub>2</sub>
[<xref rid="r71" ref-type="bibr">71</xref>
], which is the enzyme that liberates arachidonic acid from membrane phospholipids (Fig. <bold><xref ref-type="fig" rid="F2">2</xref>
</bold>
).</p>
<p>Aspirin and other NSAIDs are also reported to affect various mitochondrial enzyme complexes, including NADH-ubiquinone oxidoreductase (complex I), succinate dehydrogenase (complex II), cytochrome bc 1 complex (complex III) and cytochrome c oxidase (complex IV) [<xref rid="r72" ref-type="bibr">72</xref>
, <xref rid="r73" ref-type="bibr">73</xref>
]. Antimycin, a specific complex III inhibitor, is reported to inhibit histamine release from experimentally stimulated human mast cells obtained by bronchoalveolar lavage [<xref rid="r74" ref-type="bibr">74</xref>
]. Antimycin was also reported to increase reactive oxygen species in the mitochondria of a pollen extract-treated A549 human alveolar epithelial cell line and the authors suggested that damage to mitochondrial respiration-related proteins may exacerbate inflammation [<xref rid="r75" ref-type="bibr">75</xref>
].</p>
<p>I found that the amino acid sequence of the acetylated by aspirin in COX (FSLKG from 529 to 533) [<xref rid="r46" ref-type="bibr">46</xref>
], is also in the primary protein structure [<xref rid="r76" ref-type="bibr">76</xref>
] of human corona virus HKU1 near the nonstructural protein (nsp) 4 domain which has a similar amino acid alignment to nsp4 of murine hepatitis virus. I could not find a nomenclature for this 5 amino acid site in HKU1, and I cannot predict whether aspirin and other NSAIDs act <italic>via</italic>
this site in humans.</p>
<p>Salicylic acid (Fig. <bold><xref ref-type="fig" rid="F1">1f</xref>
</bold>
) is secreted by plants in response to pathogens and induces resistance to viruses [<xref rid="r77" ref-type="bibr">77</xref>
]. The salicylate receptors in plants are nonexpressors of PR gene 1 (NPR1), which is a homolog of IκB in mammals [<xref rid="r78" ref-type="bibr">78</xref>
], and has NPR1-like proteins 3, and 4 as paralogues [<xref rid="r79" ref-type="bibr">79</xref>
, <xref rid="r80" ref-type="bibr">80</xref>
]. In tumor necrosis factor-treated COS-1 cells, it has been demonstrated that sodium salicylate (1-20 mM) inhibits the degradation of IκBα, but not IκBβ, <italic>via</italic>
inhibition of IκB kinase activity [<xref rid="r81" ref-type="bibr">81</xref>
, <xref rid="r82" ref-type="bibr">82</xref>
].</p>
<p>Recently, Honjo <italic>et al.</italic>
reported the discovery of 36 genes related to thermal nociception in <italic>Drosophila larvae</italic>
[<xref rid="r83" ref-type="bibr">83</xref>
]. Twenty of 36 genes have human orthologs, and some of them are not known to be related to pain sensation. This is interesting because pain sensation in the respiratory tract may be related to cough in asthma patients. PGE<sub>2</sub>
is known to enhance pain, which is why NSAIDs are analgesics. It is possible that PGE<sub>2</sub>
or aspirin acts directly or indirectly on these gene products to enhance nociceptive sensation in inflammation.</p>
</sec>
</sec>
<sec sec-type="conclusions"><title>CONCLUSION</title>
<p>In traditional Japanese medicine, a disease with a high risk of occurrence in the future, is called “mibyou” [<xref rid="r84" ref-type="bibr">84</xref>
, <xref rid="r85" ref-type="bibr">85</xref>
]. I think that AERD patients who have never experienced an asthma attack could be considered as “mibyou” patients. While asthma attacks associated with AERD are frequently serious, we cannot define whether a person is at risk of AERD or not until asthma occurs following the intake of a causative substance.</p>
<p>If we could determine the mechanism of AERD and identify the risk of asthma during the “mibyou” period, we could prevent AERD and reduce the number of asthma deaths. Further clinical investigations of AERD are needed, and additional basic studies based on the clinical information could also help clinicians to understand the pathophysiological features of this disease.</p>
</sec>
</body>
<back><ack><title>ACKNOWLEDGEMENTS</title>
<p>I wish to thank Dr. Hiroko Watanabe (Kanagawa Prefectural Institute of Public Health) whose lecture on 14 May 2014, proposed the similarity between FDEIA and AERD, and Dr. Kiyoshi Hirahara (Chiba University) whose lecture on 6 October 2015, suggested involvement of IL-33 in non-allergic asthma including AERD.</p>
</ack>
<glossary><title>LIST OF ABBREVIATIONS</title>
<def-list><def-item><term>5-LOX</term>
<def><p>5-lipoxygenase</p>
</def>
</def-item>
<def-item><term>AERD</term>
<def><p>Aspirin-exacerbated respiratory disease</p>
</def>
</def-item>
<def-item><term>AIA</term>
<def><p>Aspirin induced asthma, or aspirin-intolerant asthma</p>
</def>
</def-item>
<def-item><term>AIU</term>
<def><p>Aspirin-induced urticaria</p>
</def>
</def-item>
<def-item><term>COX</term>
<def><p>Cyclooxygenase</p>
</def>
</def-item>
<def-item><term>cPGES</term>
<def><p>Cytosolic PGE synthase</p>
</def>
</def-item>
<def-item><term>cysLT</term>
<def><p>Cysteinyl leukotriene</p>
</def>
</def-item>
<def-item><term>DNP</term>
<def><p>Dinitrophenol</p>
</def>
</def-item>
<def-item><term>FDEIA</term>
<def><p>Food-dependent exercise-induced anaphylaxis</p>
</def>
</def-item>
<def-item><term>IgE</term>
<def><p>Immunoglobulin E</p>
</def>
</def-item>
<def-item><term>IL</term>
<def><p>Interleukin</p>
</def>
</def-item>
<def-item><term>LT</term>
<def><p>Leukotriene</p>
</def>
</def-item>
<def-item><term>mPGES</term>
<def><p>Microsomal PGE synthase</p>
</def>
</def-item>
<def-item><term>NF-κB</term>
<def><p>Nuclear factor-κB</p>
</def>
</def-item>
<def-item><term>NPR-1</term>
<def><p>Nonexpressor of PR gene 1</p>
</def>
</def-item>
<def-item><term>NSAID</term>
<def><p>Nonsteroidal anti-inflammatory drug</p>
</def>
</def-item>
<def-item><term>NSP</term>
<def><p>Nonstructural protein</p>
</def>
</def-item>
<def-item><term>PG</term>
<def><p>Prostaglandin</p>
</def>
</def-item>
<def-item><term>SRS-A</term>
<def><p>Slow reacting substance of anaphylaxis</p>
</def>
</def-item>
<def-item><term>Th2</term>
<def><p>Type 2 helper T</p>
</def>
</def-item>
<def-item><term>TX</term>
<def><p>Thromboxane</p>
</def>
</def-item>
</def-list>
</glossary>
<sec><title>CONFLICT OF INTEREST</title>
<p>The author confirm that this article content has no conflict of interest.</p>
</sec>
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<floats-group><fig id="F1" fig-type="figure" position="float"><label>Fig. (1)</label>
<caption><p>List of causative agents of AERD: (<bold>a</bold>
) acetyl salicylic acid (aspirin), (<bold>b</bold>
) indomethacin, (<bold>c</bold>
) hydrocortisone sodium succinate, (<bold>d</bold>
) tartrazine, (<bold>e</bold>
) parahydroxy-benzoate, and (<bold>f</bold>
) salicylic acid.</p>
</caption>
<graphic xlink:href="CDT-17-1963_F1"></graphic>
</fig>
<fig id="F2" fig-type="figure" position="float"><label>Fig. (2)</label>
<caption><p>Metabolic cascade of arachidonic acid.</p>
</caption>
<graphic xlink:href="CDT-17-1963_F2"></graphic>
</fig>
<fig id="F3" fig-type="figure" position="float"><label>Fig. (3)</label>
<caption><p>Aspirin metabolism in humans.</p>
</caption>
<graphic xlink:href="CDT-17-1963_F3"></graphic>
</fig>
<fig id="F4" fig-type="figure" position="float"><label>Fig. (4)</label>
<caption><p>Diagram of the proposed pathogenesis of AERD. Underlined words indicate tissues or cells. Arrows with a vertical bar () show inhibition, and arrows with a broken line indicate a hypothetical effect.</p>
</caption>
<graphic xlink:href="CDT-17-1963_F4"></graphic>
</fig>
</floats-group>
</pmc>
</record>
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