综述：肥大细胞在过敏及其他疾病中的病理生理作用

REVIEW Mast cells: an expanding pathophysiological role from allergy to other disorders Preet Anand & Baldev Singh & Amteshwar Singh Jaggi & Nirmal Singh Received: 16 December 2011 /Accepted: 17 April 2012 /Published online: 6 May 2012 # Springer-Verlag 2012 Abstract The mast cells are multi-effector cells with wide distribution in the different body parts and traditionally their role has been well-defined in the development of IgE- mediated hypersensitivity reactions including bronchial asthma. Due to the availability of genetically modified mast cell-deficient mice, the broadened pathophysiological role of mast cells in diverse diseases has been revealed. Mast cells exert different physiological and pathophysiological roles by secreting their granular contents, including vasoac- tive amines, cytokines and chemokines, and various pro- teases, including tryptase and chymase. Furthermore, mast cells also synthesize plasma membrane-derived lipid medi- ators, including prostaglandins and leukotrienes, to produce diverse biological actions. The present review discusses the pathophysiological role of mast cells in different diseases, including atherosclerosis, pulmonary hypertension, ischemia-reperfusion injury, male infertility, autoimmune disorders such as rheumatoid arthritis and multiple sclerosis, bladder pain syndrome (interstitial cystitis), anxiety, Alz- heimer’s disease, nociception, obesity and diabetes mellitus. Keywords Mast cells . Male infertility . Cancer . Ischemia- reperfusion injury . Irritable bowel disorder Introduction The mast cells were first described in 1876 by Paul Ehrlich, who designated them as “Mastzelle”. Mast cells are long- lived, highly granulated, FcεRI-bearing cells that are de- rived from the hematopoietic stem cells and circulate as immature progenitors and get matured in the tissues where they enter (Galli and Tsai 2010). Mast cells are highly granulated cells and these are partially or completely degra- nulated by a wide range of immunological as well as non- immunological stimuli. The granules of these inflammatory cells contain histamine, heparin, serotonin, chemotactic fac- tors and various proteases such as peroxidase, tryptase, chymase, carboxidase, beta glucuronidase as primary medi- ators (Schwartz and Austen 1980). Moreover, activation of mast cells generates secondary mediators such as prosta- glandins, leukotrienes, platelet activating factor (PAF) and various cytokines, such as interleukin (IL)-1, IL-3, IL-4, IL-5, IL-6, granulocyte macrophage colony stimulating factor (GM- CSF), macrophage inflammatory protein (MIP)-1β, MIP-1α and TNF-α (Plaut et al. 1989). Due to synthesis and release of diverse types of inflammatory mediators, mast cells may produce pathophysiological changes in various organs, lead- ing to the development of different diseases (Fig. 1). Mature mast cells show a strong species and organ-specific heteroge- neity related to morphology and function. Their functional reactivity is also critically dependent on the microenviron- ment. Thus, according to local tissue conditions, mast cells adapt and release mediators according to tissue conditions (Lowman et al. 1988). Mast cells are composed of two phe- notypes: mucosal mast cells, which contain tryptase but not chymase, and connective tissue type mast cells, which contain both proteases (Galli 1990). Mast cells are part of the innate immune system and participate in the first line of defense against pathogens such P. Anand : B. Singh Department of Chemistry, Punjabi University, Patiala 147002, India A. S. Jaggi :N. Singh (*) Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India e-mail: nirmal_puru@rediffmail.com Naunyn-Schmiedeberg's Arch Pharmacol (2012) 385:657–670 DOI 10.1007/s00210-012-0757-8 as bacteria and parasites, and release their granules after activation of mast cell receptors. Traditionally, mast cells are considered as major effectors in IgE-associated immedi- ate hypersensitivity and in allergic responses such as asth- ma. However, recent research has broadened the functions of mast cells and their pathophysiological roles in various diverse diseases have been recognized. The findings related to the role of mast cells in different diseases have been due to the availability of mast cell-deficient mouse models, includ- ing KitW/Wv (WBB6F1-KitW/W v or W/W-v) (Kitamura et al. 1978), KitW-sh/W-sh (Lyon and Glenister 1982) and SJL-KitW/ W-v (Sayed et al. 2011). KitW/Wvmice have a mutation in the c- kit gene that encodes the transmembrane receptor with intrin- sic tyrosine kinase activity for stem cell factor (SCF). SCF is a major migration, proliferation, maturation and survival factor, and is important for efficient mast cell development. These mice have a defect in the cell surface expression of kit (CD117) and are severely mast cell-deficient (∼1% of nor- mal). But their major limitation is that they are sterile. The KitW-sh/W-sh mice are having an inverted segment of chromo- some 5 in the regulatory element of the c-kit gene, which reduces its expression in the form of reduced CD117 (kit) on the surface of mast cells. However, these mice are fertile compared with KitW/W-v mice. SJL-KitW/W-v mice are mast cell deficient in all the tissues but have relatively normal thymic T cell compartments. These animals have been created by transferring the c-KitW/Wv mutation on the SJL back- ground, a strain that is susceptible to remitting relapsing multiple sclerosis (Sayed et al. 2011). The availability of different mast cells stabilizers such as sodium cromoglycate, nedocromil sodium and ketotifen has also helped to identify the role of mast cells in the patho- physiology of different diseases. Sodium cromoglycate is widely employed as mast cell stabilizer and clinically employed for the management of bronchial asthma (Alton and Norris 1996; Parnham 1996), allergic rhinitis (Pedinoff 1996) and allergic conjunctivitis. There have been several reports documenting the strain-specific variability in number of mast cells and variation in response to distinct activation signals and inhibitors including sodium cromo- glycate in mice (Johnson et al. 1991; Yong et al. 1994; Bebo et al. 1996; Sayed et al. 2011). Accordingly, sodium cromo- glycate may not act as a mast cell stabilizer in some mast cell populations due to species-related heterogeneity of mast cells. This may be responsible for variability of response observed in different studies especially using different strains of mice. The present review discusses the pathophys- iological role of mast cells in different diseases, including atherosclerosis, pulmonary hypertension, ischemia- reperfusion injury, male infertility, nociception, anxiety, Alzheimer’s disease, auto-immune diseases, obesity, and diabetes. Atherosclerosis There have been extensive studies suggesting the pro- atherogenic potential of mast cells (Bot and Biessen 2011). Mast cells have been localized in the vessel walls, particu- larly in perivascular tissue which may point to their role in pathogeneses of atherosclerosis. Earlier clinical studies demonstrated the abundant presence of mast cells in the intima and perivascular tissue (adventitia) of atherosclerotic plaques in the diseased coronary arteries (Kaartinen et al. 1994; Kovanen et al. 1995; Jeziorska et al. 1997) and the increase in numbers was correlated with the disease progres- sion. Furthermore, the clinical studies also demonstrated the co-localization of mast cells with intraplaque neovessels, suggesting the role of mast cells in intraplaque hemorrhage and plaque destabilization (Kaartinen et al. 1996; Lappalainen et al. 2004). In advanced atherosclerotic lesion, adventitial mast cells have been shown to co-localize with nerve fibers and thereby suggesting a correlation between neuronal factors, mast cells and atherosclerosis. It has been proposed that neurogenic stimulation might degranulate mast cells in peri- vascular coronary artery tissue and release pro-inflammatory Fig. 1 The possible inter- linked mechanisms involved in mast cells mediated pathophys- iological changes in different diseases. Ang angiotensin, MMP matrix metalloproteinase, ECM extracellular matrix, NO nitric oxide, 5-HT 5-hydroxy tryptamine, RASF rheumatoid arthritis synovial fibroblasts, JNK c-Jun N-terminal kinase, WBC white blood cells 658 Naunyn-Schmiedeberg's Arch Pharmacol (2012) 385:657–670 mediators that may be responsible for plaque destabilization (Laine et al. 2000). The clinical data has also shown increased levels of IgE (mast cell activator) in dyslipidemia (Kovanen et al. 1998) and histamine (biomarker of mast cells) in coronary artery disease patients (Clejan et al. 2002). Along with clinical reports, experimental studies have also documented the pro-atherogenic role of mast cells. Earlier studies showed that mast cell-derived heparin binds to low-density lipoprotein (LDL) particles, implying that mast cell granules may help in retaining LDL in the blood vessels (Kokkonen and Kovanen 1987a). Furthermore in the in vitro system, stimulation of mast cells has also been shown to cause cholesterol accumulation in macrophages by an increased uptake of LDL molecules (Kokkonen and Kovanen 1987b). On the other hand, the oxidized LDL molecules have been shown to induce mast cell degranu- lation and leukocyte adhesion, which may further exacer- bate the atherosclerotic process (Paananen and Kovanen 1994). In more recent studies, it was conclusively demonstrated that systemic mast cell activation aggravates the atheroscle- rotic lesion formation in apoE-deficient mice (Tang et al. 2009) and mast cell stabilizers prevent this effect. Further- more, it has also been shown that mast cell activation in perivascular tissue of advanced atherosclerosis in apoE- deficient mice leads to plaque instability, indicated by plaque hemorrhage, apoptosis and leukocyte recruitment (Guo et al. 2009; Bot et al. 2011). Activation of mast cells is associated with the release and secretion of proteolytic enzymes, including chymase, tryptase, and metalloprotei- nases, that may degrade the various components of pericel- lular and extracellular matrices, including collagen (main protein of the fibrous cap of atherosclerotic plaque) to render plaque destabilization (Bot et al. 2011; Czyzewska- Buczyńska and Witkiewicz 2011). In mast cell-deficient W- sh/W-sh mice, the reduced atherogenesis in the aorta has been demonstrated (Sun et al. 2007). The key role of mast cell- derived pro-inflammatory cytokines such as IL-6, interferon (IFN)-γ, TNF-α induced up-regulation adhesion molecules such as VCAM-1, intercellular adhesion molecule-1 (ICAM-1), and P- and E-selectin in atherosclerotic progres- sion has been defined (Sun et al. 2007). It has been sug- gested that mast cell-dependent lipoprotein modification, lipoprotein-mediated mast cell activation and subsequent leukocyte recruitment may be a vicious cascade by which mast cells contribute to the progression of atherosclerosis. The studies have suggested that identifying the endogenous triggers of mast cell degranulation followed by their block- ade may attenuate the progression of cardiovascular dis- eases. The endogenous triggers particularly related to atherosclerosis include oxidized LDL molecules (Kelley et al. 2006), microbes residing in the plaque such as Chlamyd- ia pneumoniae (Hauer et al. 2006), C3a and C5a as complementary factors (Oksjoki et al. 2007), and neuropep- tides such as neuropeptide P (Bot et al. 2010). Pulmonary hypertension There has been evidence documenting the critical role of mast cells in the development of pulmonary hypertension as a consequence of tissue remodeling (Hoffmann et al. 2011). Mast cell inhibition attenuates pulmonary vascular remodel- ing in pulmonary hypertension in rats and a lower chymase activity correlates with more favorable hemodynamics and pulmonary vascular remodeling (Bartelds et al. 2012). Ear- lier studies demonstrated an increased number of mast cells in the primary plexogenic pulmonary arteriopathy (Heath and Yacoub 1991), pulmonary hypertension (Mitani et al. 1999) and congenital heart diseases associated with early pulmonary vascular diseases (Hamada et al. 1999). Further- more, it has also been described that a large number of mast cells accumulate around the vessels in monocrotaline- induced pulmonary hypertension (Miyata et al. 2000), par- ticularly around the pulmonary vessels in rats with severe pulmonary hypertension. A recent finding has demonstrated that the majority of the perivascular mast cells are in a degranulated state in an experimental model of pulmonary hypertension (Dahal et al. 2011). Banasova et al. (2008) demonstrated that mast cell de- granulation plays an important role in initiating hypoxic pulmonary vascular remodeling as administration of sodium cromoglycate in an early phase of isobaric hypoxia effec- tively prevented the development of pulmonary hyperten- sion. However, delayed administration of cromoglycate was not found to be effective in preventing hypertension in pulmonary blood vessels. Therefore, it may be deduced that an inhibition of mast cell degranulation impairs the devel- opment but does not affect the established pulmonary hy- pertension in rats. On the contrary, it has been shown that prevention of mast cell degranulation by disodium cromo- glycate delays the regression of hypoxic pulmonary hyper- tension following chronic hypoxia in rats, suggesting that mast cell degranulation plays a role in the regression of pulmonary hypertension during the early phase of recovery from chronic hypoxia (Maxová et al. 2010). The products of mast cell degranulation, i.e., serotonin, cytokines (IL-6, IL-13), chymase, and matrix metalloprotei- nase (MMP 13), are known to act as important mediators in the pathogenesis of pulmonary hypertension and pulmonary vascular remodeling (Mitani et al. 1999; Hassoun et al. 2009). A clinical study has documented the presence of chymase positive mast cells in vascular lesions with intimal fibrosis in pulmonary hypertensive patients suggesting the role of chymase in the fibrous changes of the neointima (Mitani et al. 1999). It has been proposed that chymase is Naunyn-Schmiedeberg's Arch Pharmacol (2012) 385:657–670 659 involved in pulmonary hypertension indirectly by convert- ing angiotensin I to angiotensin II, whose role in pulmonary hypertension and its vascular changes in chronically hypox- ic rats has been very well described (Morrell et al. 1995). The serotonin also plays a key role in pulmonary arterial vasoconstriction and smooth muscle cell proliferation (MacLean and Dempsie 2009). The production and secretion of mast cell mediators is regulated by mast cell growth factor, also referred to as stem cell factor or kit ligand (Bischoff and Dahinden 1992). The cytokines are the representative ligands of the kit tyrosine kinase receptor (clustered as CD117) and kit is employed as a marker for bone marrow-derived hemopoietic stem cells and mast cells. However, kit expression is downregulated on maturation of all hemopoietic lineages, except mast cells that retain high levels of expression (Miettinen and Lasota 2005). The critical role of kit in the development of pulmo- nary hypertension has been reported. It has been described that kit helps in promoting perivascular mast cell accumu- lation and degranulation in the lungs (Dahal et al. 2011). A recent study has shown that kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hyper- tension (Montani et al. 2011). Tyrosine kinase inhibitors (imatinib) has been shown to reduce perivascular accumu- lation of kit+ cells in pulmonary arteries of mice exposed to chronic hypoxia along with improvement in pulmonary vascular remodeling (Gambaryan et al. 2010; 2011). Ischemia-reperfusion injury Mast cells are localized in the heart as resident cardiac mast cells mainly in perivascular areas along small veins and capillaries (Sperr et al. 1994). The preliminary suggestion given by Jolly et al. (1982) that cardiac mast cells may be associated with ischemia-reperfusion-induced myocardial injury was well supported by other reports (Keller et al. 1988). It has also been reported that mast cells accumulate in the heart after ischemia and reperfusion (Frangogiannis et al. 1998). The studies from our laboratory as well from others have reported that the stabilization of resident cardiac mast cells with ketotifen, disodium cromoglycate and lodox- amide provide myocardial protection against ischemia- reperfusion injury (Parikh and Singh 1998; Jaggi et al. 2007). The mast cell degranulation-induced release and syn- thesis of cytotoxic mediators may produce myocardial injury (Singh and Saini 2003). Furthermore, the mast cell-derived mediators may also cause recruitment of leukocytes (Kubes and Granger 1996) and inflammatory reactions may contrib- ute significantly in causing myocardial injury (Frangogiannis et al. 2002; Ren et al. 2003). A recent study has suggested that extravasated plasmin mediates neutrophil recruitment via ac- tivation of perivascular mast cells and secondary generation of lipid mediators. The plasmin inhibitors such as tranexamic acid and ε-aminocaproic acid interfere with this inflammatory cascade and effectively prevent postischemic neutrophil responses as well as remodeling events within the vessel wall (Reichel et al. 2011). The studies have shown that perivascularly located cere- bral mast cells participate in acute blood–brain barrier dis- ruption and expansive brain edema in an experimental transient cerebral ischemia (Strbian et al. 2009). Our own study has shown the critical role of cerebral mast cells in mediating neuronal damage in an experimental model of ischemia (Rehni et al. 2008). Mast cells release cytotoxic mediators that act on the basal membrane to promote blood– brain barrier damage, brain edema, prolonged extravasation and hemorrhage (Lindsberg et al. 2010). A recent study has shown that activated mast cells show secretion of gelatinase- positive granules, suggesting that cerebral mast cells regu- late activation of proteolytic microvascular gelatinase to participate in blood–brain barrier disruption following tran- sient cerebral ischemia (Mattila et al. 2011). The studies have also suggested the role of mast cells in ischemia- reperfusion-induced intestinal injury (Sand et al. 2008). Administration of ketotifen and sodium cromogycate is shown to decrease the multi-organ injury induced by intestinal ischemia reperfusion and increase the survival rates (Hei et al. 2008). Mast cells secrete CXC chemokines and promote leukocyte rolling and adhesion in the colonic microvascular bed that in turn initiates cascade of inflammatory reactions to promote intestinal injury (Santen et al. 2008). Male infertility There have been a number of studies documenting an in- creased number of mast cells in the testes, epididymis and seminal fluid of males exhibiting infertility with oligosper- mia or/and azoospermia (El-Karaksy et al. 2007; Haidl et al. 2011; Menzies et al. 2011) along with beneficial effects of treatment with mast cell blockers on impaired male fertility (Hibi et al. 2002). A mast cell blocker such as ketotifen has been documented to improve semen parameters, chromatin integrity and pregnancy rates as in infertile males following post-varicocelectomy (Azadi et al. 2011) and in male patients with leukocytospermia and unexplained infertility (Oliva and Multigner 2006). Using the testicular biopsies of patients with infertility, a positive relationship was estab- lished between expression of iNOS score and mast cell accumulation, suggesting the critical role of mast cell- derived nitric oxide in producing damage of the germ cell and eventually infertility (Sezer et al. 2005). Mast cell- derived mediators affect sperm funct