呼吸系统是执行机体与外界气体交换的主要场所，最易受到病原体的侵袭，在此过程中，机体的免疫系统发挥功能抵御病原体的增殖扩散，但这种能力受诸多因素影响，如营养状况、体况等。肥胖是由多因素引起的体内脂肪堆积过多、脂质异位沉积的一种慢性代谢性疾病，可改变机体的生理条件，包括免疫功能，从而影响呼吸系统对炎症刺激的敏感性。1993年，Hotamisligil等[1]发现，肿瘤坏死因子-α(tumor necrosis factor,TNF-α)在肥胖动物模型的脂肪组织及循环血液中高表达，首次提出肥胖与炎症存在一定的联系。随后大量调查显示，肥胖使肺部处于一种高度促炎状态，不仅增加了肺炎感染的风险[2]，增强了机体的炎症反应[3]，还与死亡率呈正相关[4, 5]，但也有研究报道肥胖虽然提高了肺炎的发病率，却也降低了肺炎患者的死亡率，对机体起到了重要的抗感染作用[6, 7]。目前关于肥胖动物肺脏对病原微生物敏感性的影响鲜有报道，但Gebrehiwot等[8]通过分析1 148只待宰牛肺部眼观病变与年龄和营养状态的关系发现，肥胖牛肺充血、肺脓肿发生的几率较高，肺气肿的几率却明显较低。小鼠试验表明，肥胖可提高肺部感染的严重程度，降低巨噬细胞的吞噬能力，延长机体自然痊愈的时间，增加死亡率[9, 10]，但其具体机制尚不明确。本文就肥胖影响呼吸道抗感染的可能机制作一简要阐述，为深入探究肥胖与肺部感染之间的关系奠定一定的基础，同时为在动物领域的相关研究提供新视角。
1 机械因素肥胖，尤其是腹部肥胖，可机械性地阻碍膈肌和呼吸道平滑肌的运动，使胸腔及肺顺应性下降，气道阻力增加，肺容量受到一定限制，导致通气功能受损[11]，肺脏生理功能的一系列改变增加了肺脏感染的几率。同时，肥胖诱导了支气管周围大量的胶原纤维沉积，基质金属蛋白酶-9(MMP-9)表达增加，从而促进了肺组织纤维化导致气道重塑，影响呼吸系统疾病的严重程度和治疗效果[12]。但国内外学者发现，肥胖患者在减肥等控制体重的过程中，呼吸道症状虽然可以得到一定程度的缓解，但气道高反应性(AHR)却没有明显的减弱[13]，即使在手术解除肺泡负荷的情况下，肥胖动物的AHR依然存在，且明显高于非肥胖动物[14]，均说明机械因素不是肥胖影响呼吸系统炎症效果的主要原因。
2 生物因素 2.1 糖脂代谢紊乱肥胖机体脂肪细胞内甘油三酯(triglyceride,TG)含量超负荷累积，导致脂质储存能力下降，循环血液中TG、游离脂肪酸(free fatty acid,FFAs)含量升高[15]，其中TG作为细胞内的第二信使，可直接激活胞内信号激酶，如蛋白激酶C(protein kinase C,PKC)、c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)、抑制性κB激酶(inhibitor of nuclear factor kappa-B kinase,IKK)等[16]，介导特定因子基因的转录与表达。FFAs是体内Toll样受体4(Toll-like receptors,TLR4)的天然配体[17]，特异性结合后，一方面直接激活下游信号通路，如髓样分化因子(myeloiddifferentiationfactor88,MyD88)和磷脂酰肌醇3-激酶(phosphatidylinositol kinase,PI3K)[18]；另一方面通过活化PKC，间接激活JNKs和IKKs[19]，从而影响免疫细胞的代谢与功能。体内调节脂代谢的重要核受体——过氧化物酶体增殖物激活受体(peroxisome proliferators-activated receptors,PPARs)和肝X受体(liver X receptors,LXRs)，同时也参与了机体的免疫进程和炎症反应。PPARs在巨噬细胞、T细胞、B细胞、树状突细胞等免疫细胞和LXRs在巨噬细胞核内的表达受到机体营养状况的影响，肥胖时FFAs、胆固醇等脂质配体与PPARs、LXRs结合能力及水平提高，PPARs、LXRs被激活，IKKs活性受到抑制，核转录因子kappa B抑制蛋白(inhibitor of NF-κB,IκB)磷酸化水平升高，与DNA结合位点的暴露减少，从而直接抑制核转录因子kappa B(nuclear transcription factor kappa-B,NF-κB)信号通路，导致炎性因子基因表达水平下降，不仅如此，LXRs还能抑制病原体诱导的巨噬细胞凋亡，发挥着重要的抗炎作用[20, 21]。但脂肪组织的代谢产物，如脂肪酸或葡萄糖在线粒体内氧化后产生的活性氧(ROS)也可活化介导炎症发生的蛋白激酶JNKs和IKKs，从而增强NF-κB的转录活性，高水平的ROS还可诱导细胞凋亡，从而诱导炎症的发生[22]。
2.2 炎性细胞浸润脂肪组织是一个复杂的器官，主要由脂肪细胞、胞外基质、血管和神经组织以及前脂肪细胞、成纤维细胞、干细胞和免疫细胞组成。调查研究显示，肥胖机体循环血液中白细胞总数显著升高，中性粒细胞不仅数量明显增加，其活性也显著提高，表明机体的营养状况影响了白细胞的增殖分化[14, 23, 24]。血液中白细胞的增加促进了炎性细胞在肺部的浸润，研究发现，肥胖增加了肺泡灌洗液中白细胞总数，诱导了炎性细胞在气管、支气管周围及肺泡间隔的聚集，其中以中性粒细胞和巨噬细胞为主[12, 25]。脂肪组织中巨噬细胞数量与肥胖指数、脂肪细胞大小有关，缺失巨噬细胞的脂肪组织中TNF-α和其他促炎细胞因子的含量减少，表明巨噬细胞在脂肪组织的浸润是调节肥胖机体炎症反应的中心事件[26, 27]。有学者提出巨噬细胞和脂肪细胞是由相同的前体细胞分化而来，在肥胖机体，巨噬细胞主要聚集在凋亡的脂肪细胞周围，负责清除局部衰老、死亡的细胞，并防止脂肪细胞的过度扩张，在一定程度上控制着机体的肥胖程度。同时肥胖程度也能使巨噬细胞从抗炎M2表型转换成促炎M1表型，从而影响其功能[28]。此外，CD8+ T细胞[29, 30]、CD4+ T细胞[31, 32]、CD3+ T细胞[33]、B淋巴细胞[34, 35]、肥大细胞[36]、嗜酸性粒细胞[37]等炎性细胞在脂肪组织中的募集不仅直接介导了炎症的发生，还促进了巨噬细胞的大量聚集、分化和活化，对炎症的发生过程也发挥着重要作用。其中CD4+ T细胞不同亚群在肥胖机体的脂肪组织中发挥着独立的功效，在营养型肥胖的内脏脂肪组织中Th1细胞数量增加，Th2细胞数量减少，Th1/Th2上升，这种结果即使增加脂肪组织中Th2细胞也不能抑制Th1细胞的募集，从而逐渐形成了促炎状态。此外，Th2细胞还能促进巨噬细胞从M1表型转换成M2表型[31]。
2.3 脂肪细胞因子平衡被破坏脂肪组织组成的复杂性决定了其不仅是机体储存能量的重要仓库，也是一个庞大的高度活化的内分泌器官，能分泌许多种类的生物活性物质，包括脂肪细胞特异分泌的瘦素、脂联素、抵抗素和非特异性分泌的TNF-α、白介素-6(interleukin-6,IL-6)等[38]，这些分子统称为脂肪细胞分泌因子，不仅能通过自分泌或旁分泌作用，与分布于器官和组织中的相应受体结合，影响和调节脂肪组织或其他组织乃至整个动物机体的能量代谢，还能调节机体的炎症水平和免疫功能，在呼吸系统感染的发生发展过程中发挥着重要作用。
2.3.1 非特异性脂肪因子 2.3.1.1 TNF-αTNF-α是一种具有多种生物学功能的细胞因子，主要由激活的单核-巨噬细胞分泌，脂肪组织中巨噬细胞是TNF-α的重要来源。已有研究报道，肥胖机体的循环血液及脂肪组织中TNF-α基因表达及蛋白质水平均显著增加[1, 39]。分离肥胖小鼠脂肪组织中的脂肪细胞和非脂肪细胞检测TNF-α mRNA的丰度，发现脂肪细胞表达TNF-α的能力强于其他细胞(巨噬细胞、肥大细胞等)，是脂肪组织中TNF-α的主要来源[1]。TNF-α的2种结构不同的受体(TNF-RⅠ、TNF-RⅡ)分布在除了红细胞外其他所有细胞的膜上，这2种受体在结合的亲和力和胞内信号通路存在显著的差异，在受到体内外刺激时，TNF-RⅠ与TNF受体相关的死亡结构域(TRADD)结合，通过脂肪酸合成酶相关死亡结构域(FADD)蛋白激活细胞凋亡通路和促炎信号通路，并通过TNF受体相关因子2(TRAF2)和受体作用蛋白共同作用提高NF-κB的转录水平[40]，促进炎症的发生。随后调查呼吸道感染患者发现TNF-α水平在急性下呼吸道感染患者血清中显著上升[41, 42]。动物试验表明，TNF-α能增强肺炎小鼠的抵抗力，降低肺炎小鼠的死亡率，增强机体清除病原菌的能力，增加中性粒细胞的募集，此外TNF-α还与肺脏中病原菌的增殖数量呈正相关[42, 43]。肥胖小鼠感染肺炎后，TNF-α基因表达水平明显上调，但在早期显著低于瘦鼠，而在后期持续升高高于瘦鼠，肥胖对炎症的反应延迟，可能与肺脏局部增加的炎症细胞有关[9]。
2.3.1.2 IL-6IL-6是一种多功能的细胞因子，由众多不同的细胞分泌，如免疫细胞、成纤维细胞、内皮细胞、单核-巨噬细胞及多种内分泌细胞[44]。此外，成熟的脂肪细胞也是IL-6的重要来源[45, 46]。大量调查显示，肥胖机体循环血液中IL-6水平急剧升高，处于异常状态，其水平与肥胖程度呈正相关[39]，且脂肪组织IL-6表达分泌的增加，是血清中IL-6水平升高的主要原因[45, 47]。IL-6与细胞表面的特异性受体IL-6膜结合受体(mIL-6R)结合后，主要通过信号传导及转录激活因子3(signal transducers and activators of transcription-3,STAT3)信号通路抑制细胞凋亡，促进上皮细胞的增殖分化，发挥显著的抗炎功效。但在机体发生感染时，内皮细胞分泌大量的IL-6和趋化因子促使中性粒细胞等炎性细胞在炎症部分大量聚集。当细胞凋亡时，mIL-6R被蛋白酶切脱离胞膜，形成可溶性IL-6受体(sIL-6R)，IL-6与sIL-6R结合后，使趋化因子发生调整(CXC型转化成CC型)，引起单核巨噬细胞和T淋巴细胞的浸润增加，促进淋巴细胞向Th2和Th17亚群分化，抑制Th1和Treg的分化，提高黏附分子的表达，表现出强烈的促炎属性[48, 49]。由于IL-6与sIL-6R和mIL-6R结合的亲和力相当，而mIL-6R只存在于肝细胞和巨噬细胞、中性粒细胞和某些T细胞表面，而信号转导蛋白gp130几乎存在机体的所有细胞表面，IL-6与sIL-6R结合后可与细胞表面的gp130相互作用并激活gp130，从而启动一系列的信号通路，故IL-6的功能主要由其含量决定。低水平的IL-6能增强体内中性粒细胞的杀菌能力、下调各类细胞因子的表达分泌，增强机体抵御感染的能力，但当IL-6升高超过一定范围后，将诱导机体发生一系列的炎症反应[50, 51]。小鼠感染细菌性肺炎后，IL-6 mRNA、蛋白质浓度在局部组织及循环系统中表达分泌水平持续升高，敲除IL-6将导致小鼠死亡速度更快，死亡率更高，肺脏促炎细胞因子(TNF-α、IL-1β、INF-γ)、抗炎因子(IL-10)水平和细菌总数均更高[50, 51]。肥胖小鼠发生肺损伤时较常规小鼠含有更高水平的IL-6，IL-6能促进中性粒细胞募集到肺部，增强上皮细胞损伤程度，从而导致肥胖小鼠肺部炎症反应强于瘦鼠[52]。此外，IL-6在肺组织的长期高表达将引起单核-巨噬细胞在局部的浸润，诱导明显的炎症反应[53]。
2.3.2 特异性脂肪因子 2.3.2.1 瘦素1994年Zhang等[54]通过基因定位克隆获得了小鼠的肥胖基因，其蛋白质产物具有抑制摄食、降低体重的作用，故命名为瘦素，主要由脂肪组织分泌。瘦素能通过结合跨膜功能性受体(Ob-Rb)激活下游JAK-STAT-NF-κB信号通路，广泛参与调控免疫系统动态平衡及免疫细胞的增殖分化，抑制免疫细胞的凋亡，发挥显著的抗炎功效[55, 56]。1998年，Lord等[57]首次提出，瘦素能诱导外周血液中淋巴细胞的增殖，特异性调节初始T细胞和记忆T细胞的活性，促进Th1细胞因子的生成，抑制Th2细胞因子的分泌，并能调节因感染引起的Th1/Th2失衡，缓解因急性饥饿造成的免疫抑制，改善营养缺失引起的免疫功能紊乱。此外，瘦素还能提高促红细胞生成素的活性，刺激红细胞的生成[58]。在肺部，瘦素不仅能作为肺部的生长因子直接影响肺脏的收缩舒张功能，还能通过作用于中枢呼吸调节器间接影响机体的通气机能[59]。在肥胖机体感染细菌性肺炎时，瘦素发挥着重要的抗炎作用，一方面通过增强巨噬细胞的吞噬能力，提高机体清除病原菌的速率，降低感染的死亡率；另一方面，又控制着TNF-α等炎性细胞因子的表达分泌水平，降低肺炎炎症反应强度，抑制炎症的进程[10, 60]。
2.3.2.2 脂联素脂联素是1995年和1996年4个不同研究小组用不同的方法发现的一种由脂肪细胞特异性分泌的激素类蛋白质[61, 62, 63, 64]，在不同组织器官发挥着不同的生理功能。在肝脏，脂联素可通过减少肝脏对脂肪酸的利用，促进FFAs的氧化，间接影响炎症的发生；在血管壁，脂联素不仅能降低黏附因子的表达，抑制单核细胞的黏附，还能通过抑制巨噬细胞表面清道夫受体的表达和TNF-α的合成，干扰TNF-α的信号传导，降低泡沫细胞的水平，直接参与免疫调节过程。在体内脂联素与特异性受体结合后，可直接活化PPAR-α、腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)、分裂原激活的蛋白激酶(mitogen activated protein kinases,MAPK)和NF-κB等信号通路，影响细胞的分化及分泌功能[65, 66]。在支气管哮喘小鼠模型中，脂联素的基因表达和蛋白质分泌水平显著升高，过敏原在健康小鼠和脂联素基因敲除小鼠体内引起的气道高反应性和过敏性炎症反应均可被外源性脂联素显著减弱[67, 68]，因此在呼吸系统疾病发展过程中脂联素表现为明显的抗炎效应。
2.3.2.3 抵抗素抵抗素是2001年发现的一种由脂肪组织特异分泌的小分子蛋白质，因具有显著的胰岛素抵抗作用，故被命名为抵抗素。随后研究表明，抵抗素在骨髓细胞中大量表达[69]，与肺部炎症诱导蛋白炎症区域发现的分子1(FIZZ1)具有同源性[70]，为炎症区域发现的分子3(FIZZ3)，显示抵抗素参与了机体的炎症过程。随后报道称抵抗素主要通过与细胞表面的TLR4相互作用，激活MAPK和NF-κB信号通路，介导相应细胞因子的表达分泌，但抵抗素与TLR4是否是直接特异性结合诱发的细胞反应还尚未可知[71, 72]，Lee等[73]的研究却发现抵抗素直接与单核细胞表面的CAP1结合，激活了PKA和NF-κB信号通路，使促炎细胞因子基因的表达上调，单核细胞的趋化性与迁移率提高。抵抗素能通过PI3K信号传导通路，降低由大肠杆菌引起的多形核白细胞(PMNL)的氧化爆发作用，调节PMNL和CD4+ T淋巴细胞的趋化作用，但抵抗素的这种效果是可逆性的，在一定浓度范围内能促进细胞的迁移，但当浓度过高时，则表现出抑制作用[74]，而抵抗素对黏附分子的诱导作用却是绝对的正相关[75, 76]，并能通过增强内皮细胞中细胞因子信号抑制物3(suppressor of cytokine signaling-3,SOCS-3)的分泌来放大诱导黏附因子表达的效应[77]，促进循环血液中单核细胞与内皮细胞黏附[76]。此外，抵抗素还能通过活化树突状细胞(DCs)诱导Treg细胞的扩增[78]，同时降低DCs递呈抗原和吞噬细菌的能力[79]，表现出明显的促炎属性。
3 小 结肥胖是一种慢性的、系统性的低度炎症，这种炎症导致循环血液中白细胞数量、炎症介质如细胞因子、趋化因子、黏附因子等水平适度上调，这种炎症是可控的，对于维持体内生理平衡和健康很重要，但当肥胖机体受到病原体的侵袭或外界刺激时，炎症过度发展到不可控的地步，机体平衡被破坏，将产生不可修复的损伤。肥胖不仅能机械性地影响肺脏的收缩功能，还能通过体循环将局部增加的炎性介质运送至肺部，从而对肺脏的生理功能及对病原微生物的敏感性产生影响。但目前用于研究肥胖与感染关系的试验模型大多集中在基因敲除小鼠上，不符合人类和动物自然肥胖的生理特征，且动物方面关于肥胖与呼吸系统感染的报道甚少，而饮食诱导的肥胖(DIO)与自然肥胖更接近，未来应更多地使用DIO模型进行相关研究，并对动物的营养状况及发病情况做系统的统计、分析，为肥胖对动物呼吸道感染的影响提供更直接的佐证。
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