關于手足綜合征與皮膚菌群的研究進展文獻綜述1.1手足綜合征概述手足綜合征（Hand-footSyndrome，HFS）是一種以手掌、足跖病變?yōu)樘卣?，伴疼痛、感覺異常的化療相關不良反應ADDINEN.CITE<EndNote><Cite><Author>Nagore</Author><Year>2000</Year><RecNum>136</RecNum><DisplayText><styleface="superscript">[1]</style></DisplayText><record><rec-number>136</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1614254252">136</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Nagore,E.</author><author>Insa,A.</author><author>Sanmartín,O.</author></authors></contributors><auth-address>InstitutoValencianodeOncología,Valencia,Spain.eduyame@meditex.es</auth-address><titles><title>Antineoplastictherapy-inducedpalmarplantarerythrodysesthesia('hand-foot')syndrome.Incidence,recognitionandmanagement</title><secondary-title>AmJClinDermatol</secondary-title><alt-title>Americanjournalofclinicaldermatology</alt-title></titles><periodical><full-title>AmJClinDermatol</full-title><abbr-1>Americanjournalofclinicaldermatology</abbr-1></periodical><alt-periodical><full-title>AmJClinDermatol</full-title><abbr-1>Americanjournalofclinicaldermatology</abbr-1></alt-periodical><pages>225-34</pages><volume>1</volume><number>4</number><edition>2001/11/13</edition><keywords><keyword>AntineoplasticAgents/*adverseeffects</keyword><keyword>Diagnosis,Differential</keyword><keyword>DrugEruptions/diagnosis/epidemiology/*etiology/therapy</keyword><keyword>FootDermatoses/*chemicallyinduced/diagnosis/epidemiology/therapy</keyword><keyword>HandDermatoses/*chemicallyinduced/diagnosis/epidemiology/therapy</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Syndrome</keyword></keywords><dates><year>2000</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>1175-0561(Print) 1175-0561</isbn><accession-num>11702367</accession-num><urls></urls><electronic-resource-num>10.2165/00128071-200001040-00004</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[1]?？ㄅ嗨麨IADDINEN.CITEADDINEN.CITE.DATA[2]（Capecitabine，CAP）、5-氟尿嘧啶ADDINEN.CITEADDINEN.CITE.DATA[3]和多西他賽ADDINEN.CITEADDINEN.CITE.DATA[4]為常見導致HFS發(fā)生的化療藥物。此外腫瘤靶向藥物索拉非尼等同樣會引起HFS的發(fā)生ADDINEN.CITEADDINEN.CITE.DATA[5]。據(jù)文獻報道，HFS的發(fā)病率在6%至64%之間，其中CAP致HFS發(fā)病率可高達50%以上ADDINEN.CITE<EndNote><Cite><Author>Nagore</Author><Year>2000</Year><RecNum>89</RecNum><DisplayText><styleface="superscript">[1]</style></DisplayText><record><rec-number>89</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1614250716">89</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Nagore,E.</author><author>Insa,A.</author><author>Sanmartín,O.</author></authors></contributors><auth-address>InstitutoValencianodeOncología,Valencia,Spain.eduyame@meditex.es</auth-address><titles><title>Antineoplastictherapy-inducedpalmarplantarerythrodysesthesia('hand-foot')syndrome.Incidence,recognitionandmanagement</title><secondary-title>AmJClinDermatol</secondary-title><alt-title>Americanjournalofclinicaldermatology</alt-title></titles><periodical><full-title>AmJClinDermatol</full-title><abbr-1>Americanjournalofclinicaldermatology</abbr-1></periodical><alt-periodical><full-title>AmJClinDermatol</full-title><abbr-1>Americanjournalofclinicaldermatology</abbr-1></alt-periodical><pages>225-34</pages><volume>1</volume><number>4</number><edition>2001/11/13</edition><keywords><keyword>AntineoplasticAgents/*adverseeffects</keyword><keyword>Diagnosis,Differential</keyword><keyword>DrugEruptions/diagnosis/epidemiology/*etiology/therapy</keyword><keyword>FootDermatoses/*chemicallyinduced/diagnosis/epidemiology/therapy</keyword><keyword>HandDermatoses/*chemicallyinduced/diagnosis/epidemiology/therapy</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Syndrome</keyword></keywords><dates><year>2000</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>1175-0561(Print) 1175-0561</isbn><accession-num>11702367</accession-num><urls></urls><electronic-resource-num>10.2165/00128071-200001040-00004</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[1]。此外，接受聯(lián)合化療方案患者HFS的發(fā)病率相對較高，如多柔比星聯(lián)合5-氟尿嘧啶治療患者HFS發(fā)病率高達89%ADDINEN.CITEADDINEN.CITE.DATA[5]。有研究報道，HFS發(fā)病率與化療藥物劑量、累計化療時間相關ADDINEN.CITE<EndNote><Cite><Author>Nagore</Author><Year>2000</Year><RecNum>90</RecNum><DisplayText><styleface="superscript">[1]</style></DisplayText><record><rec-number>90</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1614250817">90</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Nagore,E.</author><author>Insa,A.</author><author>Sanmartín,O.</author></authors></contributors><auth-address>InstitutoValencianodeOncología,Valencia,Spain.eduyame@meditex.es</auth-address><titles><title>Antineoplastictherapy-inducedpalmarplantarerythrodysesthesia('hand-foot')syndrome.Incidence,recognitionandmanagement</title><secondary-title>AmJClinDermatol</secondary-title><alt-title>Americanjournalofclinicaldermatology</alt-title></titles><periodical><full-title>AmJClinDermatol</full-title><abbr-1>Americanjournalofclinicaldermatology</abbr-1></periodical><alt-periodical><full-title>AmJClinDermatol</full-title><abbr-1>Americanjournalofclinicaldermatology</abbr-1></alt-periodical><pages>225-34</pages><volume>1</volume><number>4</number><edition>2001/11/13</edition><keywords><keyword>AntineoplasticAgents/*adverseeffects</keyword><keyword>Diagnosis,Differential</keyword><keyword>DrugEruptions/diagnosis/epidemiology/*etiology/therapy</keyword><keyword>FootDermatoses/*chemicallyinduced/diagnosis/epidemiology/therapy</keyword><keyword>HandDermatoses/*chemicallyinduced/diagnosis/epidemiology/therapy</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Syndrome</keyword></keywords><dates><year>2000</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>1175-0561(Print) 1175-0561</isbn><accession-num>11702367</accession-num><urls></urls><electronic-resource-num>10.2165/00128071-200001040-00004</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[1]。Dranitsaris等ADDINEN.CITEADDINEN.CITE.DATA[6]研究發(fā)現(xiàn)，白細胞計數(shù)、性別及肝轉移等患者自身因素與HFS也存在關系。以上研究表明HFS發(fā)生不僅取決于化療藥物，患者自身情況也是重要因素。1.1.1手足綜合征的表現(xiàn)HFS發(fā)病持續(xù)時間個體之間差異較大，一部分長期接受化療患者發(fā)病持續(xù)時間可長達10個月ADDINEN.CITEADDINEN.CITE.DATA[7,8]。HFS的臨床特征較為顯著，發(fā)病早期表現(xiàn)為手指局部刺痛感，隨后發(fā)展至全手掌燒灼感ADDINEN.CITEADDINEN.CITE.DATA[9]。另外，由于手、足末端存在神經(jīng)病變，使患者病灶部位的痛覺和溫度覺減弱，但觸覺等本體感覺不受影響ADDINEN.CITE<EndNote><Cite><Author>Stubblefield</Author><Year>2006</Year><RecNum>94</RecNum><DisplayText><styleface="superscript">[10]</style></DisplayText><record><rec-number>94</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1614251030">94</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Stubblefield,M.D.</author><author>Custodio,C.M.</author><author>Kaufmann,P.</author><author>Dickler,M.N.</author></authors></contributors><auth-address>*DepartmentofNeurology,MemorialSloan-KetteringCancerCenter,RehabilitationMedicineServicedaggerDepartmentofNeurology,NewYork-PresbyterianHospital,NeurologicalInstitutedoubledaggerMemorialSloan-KetteringCancerCenter,BreastCancerMedicineService,NewYorkCity,NY.</auth-address><titles><title>Small-FiberNeuropathyAssociatedwithCapecitabine(Xeloda)-inducedHand-footSyndrome:ACaseReport</title><secondary-title>JClinNeuromusculDis</secondary-title><alt-title>Journalofclinicalneuromusculardisease</alt-title></titles><periodical><full-title>JClinNeuromusculDis</full-title><abbr-1>Journalofclinicalneuromusculardisease</abbr-1></periodical><alt-periodical><full-title>JClinNeuromusculDis</full-title><abbr-1>Journalofclinicalneuromusculardisease</abbr-1></alt-periodical><pages>128-32</pages><volume>7</volume><number>3</number><edition>2006/03/01</edition><dates><year>2006</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1522-0443</isbn><accession-num>19078798</accession-num><urls></urls><electronic-resource-num>10.1097/01.cnd.0000211401.19995.a2</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[10]。HFS的另外一個特征是患者手指或腳趾掌面以及遠端指節(jié)病變最為明顯，可能與手指腳趾等部位常受外力摩擦、擠壓，皮膚易受損傷有關ADDINEN.CITEADDINEN.CITE.DATA[11]。因腫瘤患者接受化療常導致骨髓抑制，HFS患者可出現(xiàn)紫癜、紅斑，并可逐漸發(fā)展為水泡，隨后出現(xiàn)脫皮、糜爛和潰瘍等嚴重病變ADDINEN.CITEADDINEN.CITE.DATA[12]。部分HFS患者病變可侵及手足背側面，主要表現(xiàn)為表皮營養(yǎng)不良及表皮壞死ADDINEN.CITE<EndNote><Cite><Author>Bolognia</Author><Year>2008</Year><RecNum>96</RecNum><DisplayText><styleface="superscript">[13]</style></DisplayText><record><rec-number>96</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1614251123">96</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Bolognia,J.L.</author><author>Cooper,D.L.</author><author>Glusac,E.J.</author></authors></contributors><titles><title>Toxicerythemaofchemotherapy:ausefulclinicalterm</title><secondary-title>JAmAcadDermatol</secondary-title><alt-title>JournaloftheAmericanAcademyofDermatology</alt-title></titles><periodical><full-title>JAmAcadDermatol</full-title></periodical><alt-periodical><full-title>JournaloftheAmericanAcademyofDermatology</full-title></alt-periodical><pages>524-9</pages><volume>59</volume><number>3</number><edition>2008/08/13</edition><keywords><keyword>Acrodermatitis/chemicallyinduced/pathology</keyword><keyword>AntineoplasticAgents/*adverseeffects</keyword><keyword>AntineoplasticCombinedChemotherapyProtocols/*adverseeffects</keyword><keyword>Diagnosis,Differential</keyword><keyword>DrugEruptions/*classification/etiology/pathology</keyword><keyword>EccrineGlands/pathology</keyword><keyword>Epidermis/pathology</keyword><keyword>Erythema/chemicallyinduced/*classification/pathology</keyword><keyword>Hidradenitis/chemicallyinduced/pathology</keyword><keyword>Humans</keyword><keyword>Paresthesia/*chemicallyinduced</keyword><keyword>Skin/pathology</keyword><keyword>*TerminologyasTopic</keyword></keywords><dates><year>2008</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0190-9622</isbn><accession-num>18694683</accession-num><urls></urls><electronic-resource-num>10.1016/j.jaad.2008.05.018</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[13]。HFS患者的皮膚病理表現(xiàn)為角質(zhì)細胞多發(fā)性壞死伴基底層空泡性改變，隨癥狀加重發(fā)展為表皮壞死，血管周圍炎性細胞浸潤ADDINEN.CITEADDINEN.CITE.DATA[8,14]。美國國家癌癥研究所（NationalCancerInstitute，NCI）依據(jù)臨床表現(xiàn)嚴重程度將HFS分級為三個級別ADDINEN.CITE<EndNote><Cite><Author>Nagore</Author><Year>2000</Year><RecNum>99</RecNum><DisplayText><styleface="superscript">[1]</style></DisplayText><record><rec-number>99</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1614252015">99</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Nagore,E.</author><author>Insa,A.</author><author>Sanmartín,O.</author></authors></contributors><auth-address>InstitutoValencianodeOncología,Valencia,Spain.eduyame@meditex.es</auth-address><titles><title>Antineoplastictherapy-inducedpalmarplantarerythrodysesthesia('hand-foot')syndrome.Incidence,recognitionandmanagement</title><secondary-title>AmJClinDermatol</secondary-title><alt-title>Americanjournalofclinicaldermatology</alt-title></titles><periodical><full-title>AmJClinDermatol</full-title><abbr-1>Americanjournalofclinicaldermatology</abbr-1></periodical><alt-periodical><full-title>AmJClinDermatol</full-title><abbr-1>Americanjournalofclinicaldermatology</abbr-1></alt-periodical><pages>225-34</pages><volume>1</volume><number>4</number><edition>2001/11/13</edition><keywords><keyword>AntineoplasticAgents/*adverseeffects</keyword><keyword>Diagnosis,Differential</keyword><keyword>DrugEruptions/diagnosis/epidemiology/*etiology/therapy</keyword><keyword>FootDermatoses/*chemicallyinduced/diagnosis/epidemiology/therapy</keyword><keyword>HandDermatoses/*chemicallyinduced/diagnosis/epidemiology/therapy</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Syndrome</keyword></keywords><dates><year>2000</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>1175-0561(Print) 1175-0561</isbn><accession-num>11702367</accession-num><urls></urls><electronic-resource-num>10.2165/00128071-200001040-00004</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[1]。I級HFS患者主要表現(xiàn)為手掌、足底部位感覺異常如麻木燒灼感；II級HFS患者疼痛癥狀明顯，顯著影響患者生活質(zhì)量；而III級HFS患者往往需要調(diào)整化療方案甚至停止化療來避免HFS病變進一步發(fā)展。HFS通常不會危及生命，其癥狀在停藥后1個月內(nèi)消失，但部分患者可能出現(xiàn)永久性伴隨癥狀，如表皮損傷導致的指紋丟失、掌跖角化層增厚等ADDINEN.CITE<EndNote><Cite><Author>Wong</Author><Year>2009</Year><RecNum>101</RecNum><DisplayText><styleface="superscript">[15]</style></DisplayText><record><rec-number>101</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1614252098">101</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Wong,M.</author><author>Choo,S.P.</author><author>Tan,E.H.</author></authors></contributors><titles><title>Travelwarningwithcapecitabine</title><secondary-title>AnnOncol</secondary-title><alt-title>Annalsofoncology:officialjournaloftheEuropeanSocietyforMedicalOncology</alt-title></titles><periodical><full-title>AnnOncol</full-title></periodical><pages>1281</pages><volume>20</volume><number>7</number><edition>2009/05/28</edition><keywords><keyword>Antimetabolites,Antineoplastic/*adverseeffects</keyword><keyword>Capecitabine</keyword><keyword>Deoxycytidine/adverseeffects/*analogs&derivatives</keyword><keyword>Dermatoglyphics</keyword><keyword>EmigrationandImmigration</keyword><keyword>Fingers</keyword><keyword>Fluorouracil/adverseeffects/*analogs&derivatives</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>MiddleAged</keyword><keyword>NasopharyngealNeoplasms/*drugtherapy</keyword><keyword>Skin/drugeffects</keyword><keyword>*Travel</keyword><keyword>UnitedStates</keyword></keywords><dates><year>2009</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0923-7534</isbn><accession-num>19470576</accession-num><urls></urls><electronic-resource-num>10.1093/annonc/mdp278</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[15]。1.1.2手足綜合征的治療HFS的治療以控制癥狀為主，包括外用糖皮質(zhì)激素以減少炎癥；定期傷口護理以防止其發(fā)展為潰瘍繼發(fā)感染；外用抗角化劑以減少皮膚過度角化ADDINEN.CITEADDINEN.CITE.DATA[16]。但是，HFS最有效的治療方法為調(diào)整化療用藥劑量，更換化療方案或停止當前化療，隨后HFS癥狀通常在1個月內(nèi)改善ADDINEN.CITE<EndNote><Cite><Author>Saif</Author><Year>2011</Year><RecNum>196</RecNum><DisplayText><styleface="superscript">[17]</style></DisplayText><record><rec-number>196</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1616154290">196</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Saif,M.W.</author></authors></contributors><titles><title>Capecitabineandhand-footsyndrome</title><secondary-title>ExpertOpinDrugSaf</secondary-title><alt-title>Expertopinionondrugsafety</alt-title></titles><periodical><full-title>ExpertOpinDrugSaf</full-title><abbr-1>Expertopinionondrugsafety</abbr-1></periodical><alt-periodical><full-title>ExpertOpinDrugSaf</full-title><abbr-1>Expertopinionondrugsafety</abbr-1></alt-periodical><pages>159-69</pages><volume>10</volume><number>2</number><edition>2010/12/23</edition><keywords><keyword>Administration,Oral</keyword><keyword>Animals</keyword><keyword>Antimetabolites,Antineoplastic/administration&dosage/adverseeffects/metabolism</keyword><keyword>Capecitabine</keyword><keyword>ContinentalPopulationGroups</keyword><keyword>Deoxycytidine/administration&dosage/adverseeffects/*analogs&</keyword><keyword>derivatives/metabolism</keyword><keyword>Diagnosis,Differential</keyword><keyword>Fluorouracil/administration&dosage/adverseeffects/*analogs&</keyword><keyword>derivatives/metabolism</keyword><keyword>FootDermatoses/*chemicallyinduced/diagnosis/physiopathology</keyword><keyword>HandDermatoses/*chemicallyinduced/diagnosis/physiopathology</keyword><keyword>Humans</keyword></keywords><dates><year>2011</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1474-0338</isbn><accession-num>21174613</accession-num><urls></urls><electronic-resource-num>10.1517/14740338.2011.546342</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[17]。研究表明，首次應用多重激酶抑制劑藥物的患者，每天應用尿激酶乳膏2次可以有效預防HFS的發(fā)生ADDINEN.CITEADDINEN.CITE.DATA[18]。一項前瞻性隊列研究發(fā)現(xiàn)，在Ⅰ/Ⅱ級HFS患者中，塞來昔布可以減輕HFS的嚴重程度ADDINEN.CITEADDINEN.CITE.DATA[19]。然而，有研究發(fā)現(xiàn)吡哆醇在預防CAP致HFS方面并無顯著作用ADDINEN.CITEADDINEN.CITE.DATA[20]。激素類藥物如地塞米松可降低脂質(zhì)體阿霉素導致的HFS的發(fā)生率ADDINEN.CITEADDINEN.CITE.DATA[14]。研究發(fā)現(xiàn)，手足局部低溫治療也可有效預防HFS發(fā)生，其原因可能是局部皮膚溫度降低會導致末端血管收縮、血流量減少，進而降低化療藥物在手足部位的濃度，減少藥物對于局部皮膚的損傷作用ADDINEN.CITEADDINEN.CITE.DATA[21]。另有研究指出，應用多西他賽化療的患者，手足局部應用冰凍手套和襪子可降低HFS的發(fā)生率ADDINEN.CITEADDINEN.CITE.DATA[22,23]。此外，常規(guī)護理方案，如避免熱水淋浴、減少劇烈運動、避免在用藥期間穿緊身衣服與鞋子亦可降低HFS的發(fā)生率ADDINEN.CITEADDINEN.CITE.DATA[24]。目前臨床防治HFS的方法效果甚微，多采用綜合對癥等治療措施，未來需要尋找新靶點來開發(fā)針對HFS的有效治療手段。1.1.3導致手足綜合征發(fā)生的可能機制有研究表明，化療藥物的直接毒性作用是HFS發(fā)生的主要原因ADDINEN.CITEADDINEN.CITE.DATA[25]?；颊哽o脈滴注脂質(zhì)體阿霉素后，由于手足部位皮膚具有豐富的汗腺且藥物通過小汗腺管排泄，這使得藥物易滲入手掌和腳底的角質(zhì)層，這是HFS易發(fā)生在手足部位的原因之一ADDINEN.CITEADDINEN.CITE.DATA[25]。另外，手掌和腳底相對于其他部位角質(zhì)層更厚，這會導致藥物排泄延緩，化療藥物會誘導角質(zhì)細胞分泌大量氧自由基，氧自由基大量蓄積和代謝遲緩會誘導局部組織發(fā)生氧化損傷導致HFSADDINEN.CITEADDINEN.CITE.DATA[26]。Yokomichi等ADDINEN.CITEADDINEN.CITE.DATA[27]研究發(fā)現(xiàn)，在HFS的小鼠模型中，阿霉素與銅離子相互作用產(chǎn)生活性氧，通過炎癥信號加速角質(zhì)細胞凋亡，并同時釋放IL-1β、IL-1α和IL-6，從而導致炎癥狀態(tài)。這可能是未來治療HFS的潛在靶點。此外，毛細血管在手、足、腋窩等部位易受到摩擦損傷，而多重激酶抑制劑有抑制血管修復的作用，導致藥物更易滲入周圍組織當中，進一步加重組織損傷，導致HFS的發(fā)生ADDINEN.CITEADDINEN.CITE.DATA[28]。在CAP致HFS中，局部角質(zhì)細胞中胸腺嘧啶磷酸化酶的活性增高，使活化藥物能力提高進而導致HFSADDINEN.CITEADDINEN.CITE.DATA[29,30]?？傊琀FS的發(fā)生機制尚不明確，未來需更多研究來探索其發(fā)病機制。1.2皮膚菌群概述皮膚是人體重要的器官之一，是人體防御的第一道屏障。人體皮膚表面定植著大量的微生物，其中多數(shù)為細菌。機體皮膚表面的菌群構成了機體最龐大且最復雜的微生態(tài)系統(tǒng)ADDINEN.CITE<EndNote><Cite><Author>Kong</Author><Year>2012</Year><RecNum>116</RecNum><DisplayText><styleface="superscript">[31]</style></DisplayText><record><rec-number>116</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1614253047">116</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Kong,H.H.</author><author>Segre,J.A.</author></authors></contributors><auth-address>CenterforCancerResearch,NationalCancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland20892,USA.konghe@maiI.</auth-address><titles><title>Skinmicrobiome:lookingbacktomoveforward</title><secondary-title>JInvestDermatol</secondary-title><alt-title>TheJournalofinvestigativedermatology</alt-title></titles><periodical><full-title>JInvestDermatol</full-title><abbr-1>TheJournalofinvestigativedermatology</abbr-1></periodical><alt-periodical><full-title>JInvestDermatol</full-title><abbr-1>TheJournalofinvestigativedermatology</abbr-1></alt-periodical><pages>933-9</pages><volume>132</volume><number>3Pt2</number><edition>2011/12/23</edition><keywords><keyword>Dermatitis,Atopic/*microbiology/*physiopathology</keyword><keyword>Dermatology/*trends</keyword><keyword>Humans</keyword><keyword>Metagenome/*physiology</keyword><keyword>*SkinPhysiologicalPhenomena</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0022-202X(Print) 0022-202x</isbn><accession-num>22189793</accession-num><urls></urls><custom2>PMC3279608</custom2><custom6>NIHMS337954</custom6><electronic-resource-num>10.1038/jid.2011.417</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[31]，對機體的健康起到不可或缺的作用。人體皮膚菌群可分為常駐菌和暫駐菌。暫駐菌對皮膚健康所造成的影響相對較小。而常駐菌可長期寄居于人體皮膚表面，在皮膚疾病的發(fā)生發(fā)展中發(fā)揮著重要作用，被視為皮膚的核心菌群ADDINEN.CITEADDINEN.CITE.DATA[32,33]。既往研究報道，不同個體的皮膚菌群結構存在差異ADDINEN.CITEADDINEN.CITE.DATA[34]。人體皮膚根據(jù)不同部位可劃分為油脂區(qū)、濕性區(qū)和干性區(qū)。已有文獻報道，油脂區(qū)皮膚菌群多樣性較低，而干性區(qū)皮膚菌群多樣性較高ADDINEN.CITE<EndNote><Cite><Author>Sanford</Author><Year>2013</Year><RecNum>120</RecNum><DisplayText><styleface="superscript">[35]</style></DisplayText><record><rec-number>120</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1614253201">120</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Sanford,J.A.</author><author>Gallo,R.L.</author></authors></contributors><auth-address>DivisionofDermatology,DepartmentofMedicine,UniversityofCalifornia,SanDiego,SanDiego,CA,USA.</auth-address><titles><title>Functionsoftheskinmicrobiotainhealthanddisease</title><secondary-title>SeminImmunol</secondary-title><alt-title>Seminarsinimmunology</alt-title></titles><periodical><full-title>SeminImmunol</full-title><abbr-1>Seminarsinimmunology</abbr-1></periodical><alt-periodical><full-title>SeminImmunol</full-title><abbr-1>Seminarsinimmunology</abbr-1></alt-periodical><pages>370-7</pages><volume>25</volume><number>5</number><edition>2013/11/26</edition><keywords><keyword>Animals</keyword><keyword>Dysbiosis</keyword><keyword>Humans</keyword><keyword>Microbiota/*immunology</keyword><keyword>Skin/*immunology/*microbiology</keyword><keyword>Antimicrobialpeptides</keyword><keyword>Keratinocyte</keyword><keyword>Propionibacteriumacnes</keyword><keyword>Staphylococcus</keyword></keywords><dates><year>2013</year><pub-dates><date>Nov30</date></pub-dates></dates><isbn>1044-5323(Print) 1044-5323</isbn><accession-num>24268438</accession-num><urls></urls><custom2>PMC4219649</custom2><custom6>NIHMS637404</custom6><electronic-resource-num>10.1016/j.smim.2013.09.005</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[35]。油脂區(qū)皮膚菌群中優(yōu)勢菌為丙酸桿菌（Propionibacterium），而濕性區(qū)皮膚菌群中優(yōu)勢菌多為葡萄球菌（Staphylococcus）和棒狀桿菌（Corynebacterium）ADDINEN.CITEADDINEN.CITE.DATA[36]。不同部位的皮膚可呈現(xiàn)出不同的生理特征，如濕度、pH值和粗糙度等ADDINEN.CITEADDINEN.CITE.DATA[37]。既往研究發(fā)現(xiàn)不同解剖部位皮膚的差異對菌群結構的影響大于其他因素，如年齡、性別等ADDINEN.CITEADDINEN.CITE.DATA[38]。然而，隨著年齡的增長，同一個體皮膚菌群狀態(tài)也發(fā)生變化，如在65歲以上的人群中，奇異變形桿菌（

Proteusmirabilis）和銅綠假單胞菌（Pseudomonasaeruginosa）的皮膚定殖率比年輕人增加了約25%（LaubeS.Skininfectionsandageing）。皮膚酸堿度也是影響菌群結構的因素之一。H.Lambers等ADDINEN.CITE<EndNote><Cite><Author>Lambers</Author><Year>2006</Year><RecNum>125</RecNum><DisplayText><styleface="superscript">[39]</style></DisplayText><record><rec-number>125</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1614253432">125</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Lambers,H.</author><author>Piessens,S.</author><author>Bloem,A.</author><author>Pronk,H.</author><author>Finkel,P.</author></authors></contributors><auth-address>SaraLeeHouseholdandBodyCareResearch,Fruitweg,TheHague,TheNetherlands.</auth-address><titles><title>NaturalskinsurfacepHisonaveragebelow5,whichisbeneficialforitsresidentflora</title><secondary-title>IntJCosmetSci</secondary-title><alt-title>Internationaljournalofcosmeticscience</alt-title></titles><periodical><full-title>IntJCosmetSci</full-title><abbr-1>Internationaljournalofcosmeticscience</abbr-1></periodical><alt-periodical><full-title>IntJCosmetSci</full-title><abbr-1>Internationaljournalofcosmeticscience</abbr-1></alt-periodical><pages>359-70</pages><volume>28</volume><number>5</number><edition>2008/05/21</edition><dates><year>2006</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0142-5463</isbn><accession-num>18489300</accession-num><urls></urls><electronic-resource-num>10.1111/j.1467-2494.2006.00344.x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[39]研究發(fā)現(xiàn)皮膚的pH值一般在5.0以下，金黃色葡萄球菌（Staphylococcusaureus，S.aureus）會隨著pH值的增加逐漸成為優(yōu)勢菌種。總之，皮膚菌群結構是相對穩(wěn)定的，同時也會隨解剖部位、個體生理狀態(tài)的差異而展現(xiàn)出不同的結構特性。1.2.1皮膚菌群與疾病皮膚菌群與皮膚疾病之間的關系仍處于探索階段。鑒于皮膚生理環(huán)境的復雜性，二者之間的作用可能是相互的ADDINEN.CITE<EndNote><Cite><Author>Grice</Author><Year>2011</Year><RecNum>201</RecNum><DisplayText><styleface="superscript">[40]</style></DisplayText><record><rec-number>201</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1616155029">201</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Grice,E.A.</author><author>Segre,J.A.</author></authors></contributors><auth-address>GeneticsandMolecularBiologyBranch,NationalHumanGenomeResearchInstitute,NationalInstitutesofHealth,Bethesda,Maryland20892-4442,USA.</auth-address><titles><title>Theskinmicrobiome</title><secondary-title>NatRevMicrobiol</secondary-title><alt-title>Naturereviews.Microbiology</alt-title></titles><periodical><full-title>NatRevMicrobiol</full-title><abbr-1>Naturereviews.Microbiology</abbr-1></periodical><alt-periodical><full-title>NatRevMicrobiol</full-title><abbr-1>Naturereviews.Microbiology</abbr-1></alt-periodical><pages>244-53</pages><volume>9</volume><number>4</number><edition>2011/03/17</edition><keywords><keyword>AdaptiveImmunity</keyword><keyword>Humans</keyword><keyword>Immunity,Innate</keyword><keyword>*Metagenome</keyword><keyword>Skin/anatomy&histology/immunology/*microbiology</keyword><keyword>SkinDiseases,Infectious/immunology/microbiology</keyword></keywords><dates><year>2011</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1740-1526(Print) 1740-1526</isbn><accession-num>21407241</accession-num><urls></urls><custom2>PMC3535073</custom2><custom6>NIHMS424100</custom6><electronic-resource-num>10.1038/nrmicro2537</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[40]。皮膚生理狀態(tài)的變化誘發(fā)皮膚菌群結構改變；皮膚菌群結構的變化又影響到皮膚生理狀態(tài)，如經(jīng)皮失水率、皮脂分泌量等。皮膚的附屬器也會對皮膚菌群結構產(chǎn)生重要的影響。皮膚的小汗腺和皮脂腺可為皮膚菌群提供營養(yǎng)成分ADDINEN.CITE<EndNote><Cite><Author>Sanford</Author><Year>2013</Year><RecNum>126</RecNum><DisplayText><styleface="superscript">[35]</style></DisplayText><record><rec-number>126</rec-number><foreign-keys><keyapp="EN"db-id="ew90evvzx5zdf8erppyxzepptzf5arx0dw5w"timestamp="1614253577">126</key></foreign-k