Clinica Chimica Acta 433 (2014) 272–277
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Invited critical review
Matrix metalloproteinases in pneumonia☆ Ting-Yen Chiang a, Shih-Ming Tsao a,b, Chao-Bin Yeh a,c, Shun-Fa Yang d,e,⁎ a
School of Medicine, Chung Shan Medical University, Taichung, Taiwan Division of Infectious Diseases, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan c Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan d Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan e Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan b
a r t i c l e
i n f o
Article history: Received 19 January 2014 Received in revised form 25 March 2014 Accepted 26 March 2014 Available online 8 April 2014 Keywords: Pneumonia Matrix metalloproteinase
a b s t r a c t Pneumonia is a worldwide infectious disease that is associated with significant morbidity and mortality and is the most common fatal infection acquired in hospitals. Despite advances in preventive strategies, such as antibiotic therapies and intensive care, the mortality rate still requires substantial improvement. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases, which are known as the major enzymes responsible for the proteolytic degradation of proteinaceous components of the extracellular matrix (ECM). Although the main function of MMPs is the removal of the ECM during tissue resorption and progression of various diseases, MMPs also interact with multiple cytokines, participating in the pathology of infection and inflammation. This review presents a schematic overview of the different MMPs expressed in pneumonia. MMPs are key factors in the pathogenesis of various types of pneumonia, such as community-acquired pneumonia, hospital-acquired pneumonia, and ventilator-associated pneumonia. Here, we review the pathological roles of various MMPs in pneumonia. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction to pneumonia . . . . . . . . . . . . . Three types of pneumonia . . . . . . . . . . . . . . Matrix metalloproteinases participating in the pathology of inflammation . . . . . . . . . . . . . . . . . . 4. Role of matrix metalloproteinases in pneumonia . . . . References . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction to pneumonia Pneumonia is associated with significant morbidity and mortality, causing the deaths of 3.2 million people in 2011 and ranking third among the 10 most common causes of death worldwide [1]. The primary method for diagnosing pneumonia is the identification of a microbiological pathogen isolated directly from lung tissue; however, this invasive procedure is not routinely performed. Performing clinical evaluations followed by chest radiography can help physicians to preliminarily ☆ The authors have declared no conflicts of interest. ⁎ Corresponding author at: Institute of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo N. Road, Taichung, Taiwan. Tel.: +886 4 24739595x34253; fax: +886 4 24723229. E-mail address: [email protected] (S.-F. Yang).
http://dx.doi.org/10.1016/j.cca.2014.03.031 0009-8981/© 2014 Elsevier B.V. All rights reserved.
determine pneumonia impressions [2], and laboratory techniques, such as Gram's stain, sputum cultures, blood cultures, antigen tests, polymerase chain reaction, and serology, can be used to determine the potential etiology [3]. Biological markers are occasionally used to evaluate pneumonia [4]. Thus, developing a biomarker for performing rapid and reliable diagnoses would be beneficial.
2. Three types of pneumonia Pneumonia is defined as an infection of the pulmonary parenchyma that develops from the proliferation of microbial pathogens at the alveolar level of the respiratory track and the response of the host itself [5]. Because the epidemiology, pathogenesis, and risk factors for infection of pneumonia patients are different, the American Thoracic Society
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and Infectious Diseases Society of America have developed guidelines for distinguishing among three types of pneumonia. Communityacquired pneumonia (CAP) is defined as pneumonia acquired from the community. Hospital-acquired (or nosocomial) pneumonia (HAP) is defined as pneumonia that occurs 48 h or more after hospital admission and does not appear to be incubating at the time of admission. Among HAP patients, those who develop pneumonia after more than 48 to 72 h of endotracheal intubation are classified as having ventilatorassociated pneumonia (VAP) [6,7]. The etiology of pneumonia includes bacteria, viruses, fungi, and protozoa [8]. Generally, two groups of pathogens that potentially cause pneumonia exist: “typical” bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and gram-negative bacilli, such as Klebsiella pneumoniae and Pseudomonas aeruginosa; and “atypical” organisms, including Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella species, and respiratory viruses, such as influenza viruses, adenoviruses, and respiratory syncytial viruses. Determining whether a case is typical or atypical pneumonia is imperative because this diagnosis provides considerable implications for therapy. However, 11–20% of pneumonia cases are polymicrobial, and the etiology often includes a combination of typical and atypical pathogens [9]. 3. Matrix metalloproteinases participating in the pathology of inflammation Matrix metalloproteinases (MMPs), which are also called matrixins, are a large family of zinc-dependent endopeptidases that are known Table 1 Classification of MMPs.
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as the major enzymes responsible for the proteolytic degradation of proteinaceous components of the extracellular matrix (ECM) [10], which are essential for embryonic development, morphogenesis, reproduction, tissue homeostasis, tumorigenesis, and organ fibrogenesis [11, 12]. Excreted MMPs contain 23 proteases in humans and are categorized into four classes based on their substrate specificity (Table 1): collagenases (MMP-1, -8, and -13); gelatinases (MMP-2 and -9); stromelysins (MMP-3, -10, and -11); and a heterogeneous group that includes matrilysin (MMP-7), metalloelastase (MMP-12), enamelysin (MMP-20), endometase (MMP-26), and epilysin (MMP-28). The membrane MMPs (MMP-14, -15, -16, -17, -24, and -25) are anchored to the cell surface. An alternate classification system that categorizes the MMPs based on domain structure is also used [13]. MMPs typically consist of four domains: the propeptide domain, which contains a cysteine-switch motif for ligating catalytic zinc to maintain the latency of the inactive form of MMPs [14]; the catalytic domain, which contains two zinc ions that coordinate with the zincbinding motif HEXXHXXGXXH and a conserved methionine, which forms a unique Met-turn structure for stabilization [15]; and the cysteine residue in the propeptide domain interacts with the catalytic zinc ion, which prevents its association with water molecules until the propeptide domain is removed [16]. Except for MMP-7, MMP-23, and MMP-26, MMPs have C-terminal hemopexin-like domains that are recognized by substrates. The hemopexin domain consists of a four-bladed propeller structure and confers substrate specificity to the MMPs; thus, degradation of the triple-helical collagens is absolutely necessary [17].
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Each type of MMP contains a linker region that varies in length, and several MMPs possess slight structural differences. The gelatinases (MMP-2 and -9) contain three repeats of a fibronectin type II inserted into the catalytic domain for binding to gelatin and collagen [18]. MMP-23 contains a cysteine-rich region and an immunoglobulin domain instead of the hemopexin domain [19]. Finally, membrane-type MMPs contain a transmembrane domain or a glycosylphosphatidylinositol anchor [16, 20]. MMP function is regulated at several levels. The first level of control of MMP production is transcriptional regulation. The induction of gene expression is controlled by effectors, including growth factors, cytokines, chemical agents, physiological stress, and oncogenic cellular transformation. In addition, enhanced MMP gene expression may be downregulated by suppressive factors, such as transforming growth factor b, retinoic acids, or glucocorticoids. Moreover, specific signaling pathways result in the expression of particular MMP genes [11]. For example, activation of the Rho family guanosine triphosphatase (GTPase) pathway increased the expression of MMP-1 [21]; ultraviolet B (UVB) irradiation mediated signaling pathway up-regulates MMP-1 and MMP-3 expression [22]. Moreover, activation of the ceramide signaling pathway inhibits MMP-1 gene expression [23]. Most MMPs are translated into an inactive zymogen form. Secreted zymogens are activated either intracellularly by zymogen convertases, such as furin, in the normal secretory pathway, at the cell surface, or extracellularly by other proteases [16]. In all cases, activation requires the disruption of the Cys–Zn2+ (cysteine switch) interaction [24]. For example, in neutrophils, specific MMPs (MMP-8 or MMP-9) can be stored as proenzymes in intracellular granules, and their exocytosis is stimulated by external signals (including cytokine signaling or CD40 signaling) [16]. Finally, active MMP proteins are naturally inhibited by tissue inhibitors of metalloproteinases (TIMPs) in extracellular environments [16]. Although the main function of MMPs is the removal of the ECM during tissue resorption and the progression of various diseases, MMPs also interact with numerous cytokines, participating in the pathology of infection and inflammation [11,25]. In the pathology of pneumonia, an infectious disease, MMPs are understandable and have been shown to play a role.
4. Role of matrix metalloproteinases in pneumonia The first line of defense against invasive respiratory pathogens is the airway epithelium, and the mechanisms include the prevention of bacterial colonization and infection in the airways. Epithelial cells maintain a barrier to the environment, and provide enzymes (such as lysozyme, β-defensins, cathelicidin, and other enzymes [26]) and an airway mucus layer for physical protection [27]. In addition, they regulate inflammation as a secondary line of defense in response to infection by secreting factors that recruit inflammatory cells to attack invasive pathogens; MMPs are components of these factors [28], and several reports have described the presence of an increased epithelial MMP
expression in response to bacterial infection, such as those of MMP-7 [29], MMP-10 [28], and MMP-28 [30] (Table 2). MMP-7 and MMP-28 are constitutively expressed in low concentrations by bronchial epithelial cells and are induced by bacterial infections [30–32]. Previous studies have reported that MMP-7 has several functions involved in immune responses, which include re-epithelializing airways by cleaving E-cadherin [33,34], processing antibacterial peptides [35], regulating acute alveolar neutrophil transepithelial migration by shedding syndecan-1/KC complexes [31], clearing pathogens [36] by promoting apoptosis through the generation of soluble Fas (CD95) ligands [36,37], and regulating growth factor signaling through epidermal growth factors and insulin-like growth factors [38]. MMP-28 has been shown to control neutrophil recruitment into the lung in a P. aeruginosa pneumonia model [30]. Most MMPs play roles in maintaining immunity by cleaving specific proteins, which increases the activity of the target substrates [39]. For example, MMP-2, MMP-3, and MMP-9 can activate IL-1β [40], and MMP-7 and MMP-12 can activate latent TNFα [41–43]. In addition, MMP-28 restrains macrophage recruitment by retarding the chemotaxis of these cells [30]. Moreover, Kassim et al. demonstrated that MMP-10 restrains the inflammatory response and controls apoptosis [28]. In the lung, neutrophils are located in the vascular bed. Neutrophils are recruited to pulmonary capillaries by inflammatory cytokines, such as interleukin-8 (IL-8) and leukrotrien B4 in patients with pneumonia [44]. Subsequently, the activated MMPs contribute to neutrophil migration into the alveolar compartment [45]. The release of MMP-8 and MMP-9 [44,46] is speculated to result in a disruption of basement membrane components, which facilitates the neutrophil invasion of extravascular tissue [47]. However, Rosendahl et al. proposed that bacteria can exploit MMP-9 to open tissue barriers and cause its own dissemination from the local site of infection using an S. pneumonia-infected model [48]. In the role of degrading the tissue barriers, MMPs have two aspects in the pathology of pneumonia, it benefits the inflammatory cells to infiltrate to the infected site; simultaneously, it results in the dissemination of the pathogen. The alveolar compartment is the location where neutrophils degranulate with the exocytosis of MMPs, such as MMP-8, MMP-9 [49], as well as other types of neutrophil granules and reactive oxygen species, which can execute antimicrobial functions [50]. In pneumonia patients, compared with peripheral neutrophils, pulmonary neutrophils are highly stimulated during infections to release MMPs [51]. Released MMPs are activated by bacterial MMPs [52], plasmin [53], or other neutrophil products such as myeloperoxidase and neutrophil elastase [44,54]. Oggioni et al. discovered that a pneumococcal zinc metalloproteinase can cleave and activate MMP-9 in a murine model of pneumonia [44]. MMP-9 and MMP-2 play key roles in the migration of various leukocytes, such as T cells and neutrophils [47]. MMP-2 and, to a lesser degree, MMP-9 were observed to efficiently cleave and inactivate IL-17A, which is a pathogen-associated proinflammatory molecule that induces the recruitment of activated neutrophils to infection sites [55].
Table 2 Role of MMPs in pneumonia. MMPs
Pneumonia
MMP-2, MMP-9 MMP-2, MMP-9 MMP-7 MMP-7, MMP-10 MMP-8, MMP-9 MMP-8, MMP-9 MMP-8, MMP-9 MMP-8, MMP-9, TIMP-1 MMP-9 MMP-9, TIMP-1 MMP-9, LCN2 MMP-28
S. pneumoniae pneumonia in murine model M. pneumoniae CAP Airway epithelial cells infected with P. aeruginosa in vivo P. aeruginosa pneumonia in murine model HAP HAP with high-risk bacteria VAP P. aeruginosa VAP CAP CAP CAP P. aeruginosa pneumonia in murine model
References MMPs serves in the early host immune response MMP-9 activity elevated in M. pneumoniae CAP patients Infection induced MMP-7 expression Infection induced MMP expression MMP levels are increased in HAP patients MMP activities are elevated in HAP patients MMPs elevated in VAP patients Higher MMP-9/TIMP-1 ratio determine poor outcome MMP-9 elevated in CAP patients MMP-9/TIMP-1 ratio elevated in CAP patients LCN2/MMP-9 correlated with the CAP severity MMP-28 negative regulates macrophage recruitment
Hong et al. [57] Puljiz et al. [77] Lopez-Boado et al. [29] Kassim et al. [28] Hartog et al. [51] Schaaf et al. [44] Wilkinson et al. [68] El-Solh et al. [61] Yang et al. [69] Chiang et al. [72] Yeh et al. [75] Manicone et al. [30]
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High levels of MMP-9 in the lungs were reported to promote the infiltration of inflammatory cells [56]. Furthermore, MMP-9 is critical for effective bacterial phagocytosis and the generation of reactive oxygen species in neutrophils [57]. In addition, MMP-2 and MMP-9 have been reported to play roles in regulating adaptive immune processes by degrading ECM proteins and modifying chemokines [57]. Hong et al. elaborated that MMP-2 and MMP-9 serve as anti-inflammatory mediators by avoiding excess neutrophil recruitment to the lung, and MMP-9 is essential to neutrophil-mediated bacterial killing as well as phagocytosis. Thus, the mortality rate increased in S. pneumoniae-infected MMP-2, 9−/− mice [57]. MMPs were reported to contribute to the innate immune and adaptive immune systems. Furthermore, they were shown to be crucial factors in eliminating pathogen and protecting the host itself from its own immune system. A positive feedback loop exists between cytokines and MMPs. For example, MMP-9 cleaves IL-8 into an active form, which increases MMP-9 levels, resulting in a potent IL-8 [49]. This type of positive feedback may maintain excessive MMP activity, such as the degradation of ECM, which eventually leads to severe ECM destruction and alveolocapillary leakage accompanied by an increased risk of developing acute respiratory distress syndrome (ARDS), which is the most severe complication of pneumonia [49]. The local production of MMPs can directly alter the local tissue architecture by degrading proteins of the ECM [58]. The evidence suggests that MMPs in the lung control the pathogenesis of ARDS by disrupting structures of the basement membrane. Torii et al. reported that in ARDS patients, MMP-9 levels were correlated with 7S collagen, a marker of basement membrane disruption [59]. In such cases, inhibition of MMP activity may attenuate several crucial pathogenetic steps in the inflammatory cascade, such as preventing an acute lung injury from severe infection [60]. In the pathology of pneumonia, MMPs might have a dual effect involving the ultimate outcome, duration of exposure, site of release, and characteristics of the defending pathogen [61]. HAP is the leading cause of death among hospital-acquired infections [62]. Various bacterial species differentially affect MMP secretion and activation. Clinically, infections with P. aeruginosa, S. aureus, and Stenotrophomonas maltophilia are associated with the most severe form of HAP [63]. In HAP patients, high-risk pathogens appear to induce the release of strong neutrophil MMPs. In addition, Schaaf et al. observed higher MMP-8 and MMP-9 levels in the lungs, and an increased MMP-9/TIMP-1 molar ratio and MMP-9-activity compared with HAP patients with low-risk bacteria and control patients [44]. HAP patients exhibited a close correlation between pulmonary MMP levels and the laboratory parameters of systemic inflammation, such as high-serum C-reactive protein, high white blood cell counts, and high body temperature [44]. Hartog et al. observed increased levels and activity of MMP-8 and MMP-9 in plasma and in the minibronchoalveolar lavage fluid (mini-BALF) of patients with HAP, which correlated with systemic signs of inflammation [51]. MMP activation in HAP patients might be necessary for bacterial clearance, but unresolved infections might trigger ongoing MMP activation and tissue destruction [64,65]. In intensive care units, 15% to 30% of patients who are intubated and mechanically ventilated develop VAP as a complication [66]. VAP patients are known to possess dysfunctional neutrophils, which are less capable of phagocytosis and cytotoxicity, and once recruited, they can easily damage pulmonary epithelial membranes [67]. Wilkinson et al. suggested that excessive dysfunctional neutrophils are recruited to the lungs of VAP patients and active proteolytic enzymes are secreted into the alveolar space [68]. Data have indicated that expression of MMP-8 and MMP-9 significantly increased in BALF in VAP patients [61,68]. Furthermore, the imbalance between MMP-9 and TIMP-1 might indicate severe alveolar capillary damage and poor outcomes [61]. Several recent studies evaluating the MMP plasma levels in CAP patients have been performed. Our laboratory first reported that in CAP patients, the activity and level of MMP-9 in serum were significantly
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higher compared with healthy controls. We suggested that MMP-9 may play an essential role in the pathogenesis of CAP [69,70]. In addition, MMP-9 expression may be inhibited by TIMP-1 [71]. The plasma TIMP-1 concentration was positively correlated with CAP severity, and the MMP-9/TIMP-1 molar ratio was significantly increased in patients with CAP; thus, we suggested that incorporating plasma MMP-9 levels and the MMP-9/TIMP-1 molar ratio into a clinical evaluation will aid in CAP diagnosis [72]. Lipocalin 2 (LCN2), also known as neutrophil gelatinase-associated lipocalin [73], forms a complex with MMP-9, thereby preventing the autodegradation of MMP-9 and increasing its activity [74]. We determined that the plasma level of LCN2 was correlated with the severity of CAP and significantly correlated with LCN2/ MMP-9 levels. We suggested that serum LCN2 and the LCN2/MMP-9 complex can act as adjuvant diagnostic biomarkers for CAP [75]. M. pneumoniae is a prominent etiology of CAP cases that are sufficiently severe to require hospitalization [76]. Puljiz et al. discovered that in M. pneumonia-infected CAP patients, MMP-2 plasma levels decreased in the acute phase but increased in the convalescent phase; in contrast, the MMP-9 mRNA expression in peripheral blood mononuclear cells (PBMCs) increased in the acute phase of the illness and then decreased in the convalescent phase, and the same results were observed in the MMP-9 plasma levels. They speculated that MMP-2 in the acute phase of the disease was attracted to the pulmonary compartment containing other inflammatory mediators and that PBMCs are vital sources of MMP-9 during CAP caused by M. pneumoniae [77]. MMP concentration and activation are markers for the severity of inflammation [44] and are reported to be positively correlated with pneumonia. Thus, incorporating MMPs into clinical information is beneficial to assist with the diagnosis and prognosis of CAP. Elevated levels of MMP activity and quantity were detected among three types of pneumonia subjects: MMP-2, 8, 9 in HAP; MMP-8, 9 in VAP; and MMP-2, 9 in CAP. However, the precise mechanism and prognosis to which they contribute to pneumonia requires further studies. Previous studies have shown that MMPs are essential for pulmonary epithelial immune responses (MMP-7, 10, 28); maintaining immunity by activating specific proteins (MMP-2, 3, 7, 9, 12, 28); various leukocyte migration (MMP-2, 8, 9); and killing and phagocytosis of bacteria (MMP-9), although many roles MMPs in pneumonia pathology remain unclear. In the pathology of pneumonia, MMPs are necessary in the defense against a pathogen, but it is also responsible for lung tissue damage. This might be one reason why there is no directly significant correlated result between the severity of pneumonia and MMP levels. Thus, additional studies for the development of MMPs into biomarkers for the diagnosis or prognosis of pneumonia are required. However, it is possible to determine the potential range of MMP levels, which are adequate for the immune system to work but are not excessive enough to result in severe complications. The long-term goal is to use MMP levels to evaluate the severity of pneumonia. Moreover, we may be able to suppress specific MMP expression or use inhibitors of MMPs to prevent complications in pneumonia patients who overexpress in MMPs. References [1] WHO. The top 10 causes of death; 2013. [2] Metlay JP, Fine MJ. Testing strategies in the initial management of patients with community-acquired pneumonia. Ann Intern Med 2003;138:109–18. [3] Baron EJ, Miller JM, Weinstein MP, Richter SS, Gilligan PH, Thomson Jr RB, et al. A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM)(a). Clin Infect Dis 2013;57:e22-121. [4] Cheng CW, Chien MH, Su SC, Yang SF. New markers in pneumonia. Clin Chim Acta 2013;419:19–25. [5] Longo ASF, Dan L, Kasper Dennis L, Hauser Stephen L, Jameson J Larry, Loscalzo Joseph, editors. Harrison's™ Principles of internal medicine eighteenth edition; 2011. [6] Anand N, Kollef MH. The alphabet soup of pneumonia: CAP, HAP, HCAP, NHAP, and VAP. Semin Respir Crit Care Med 2009;30:3–9.
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Invited critical review
Matrix metalloproteinases in pneumonia☆ Ting-Yen Chiang a, Shih-Ming Tsao a,b, Chao-Bin Yeh a,c, Shun-Fa Yang d,e,⁎ a
School of Medicine, Chung Shan Medical University, Taichung, Taiwan Division of Infectious Diseases, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan c Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan d Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan e Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan b
a r t i c l e
i n f o
Article history: Received 19 January 2014 Received in revised form 25 March 2014 Accepted 26 March 2014 Available online 8 April 2014 Keywords: Pneumonia Matrix metalloproteinase
a b s t r a c t Pneumonia is a worldwide infectious disease that is associated with significant morbidity and mortality and is the most common fatal infection acquired in hospitals. Despite advances in preventive strategies, such as antibiotic therapies and intensive care, the mortality rate still requires substantial improvement. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases, which are known as the major enzymes responsible for the proteolytic degradation of proteinaceous components of the extracellular matrix (ECM). Although the main function of MMPs is the removal of the ECM during tissue resorption and progression of various diseases, MMPs also interact with multiple cytokines, participating in the pathology of infection and inflammation. This review presents a schematic overview of the different MMPs expressed in pneumonia. MMPs are key factors in the pathogenesis of various types of pneumonia, such as community-acquired pneumonia, hospital-acquired pneumonia, and ventilator-associated pneumonia. Here, we review the pathological roles of various MMPs in pneumonia. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction to pneumonia . . . . . . . . . . . . . Three types of pneumonia . . . . . . . . . . . . . . Matrix metalloproteinases participating in the pathology of inflammation . . . . . . . . . . . . . . . . . . 4. Role of matrix metalloproteinases in pneumonia . . . . References . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction to pneumonia Pneumonia is associated with significant morbidity and mortality, causing the deaths of 3.2 million people in 2011 and ranking third among the 10 most common causes of death worldwide [1]. The primary method for diagnosing pneumonia is the identification of a microbiological pathogen isolated directly from lung tissue; however, this invasive procedure is not routinely performed. Performing clinical evaluations followed by chest radiography can help physicians to preliminarily ☆ The authors have declared no conflicts of interest. ⁎ Corresponding author at: Institute of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo N. Road, Taichung, Taiwan. Tel.: +886 4 24739595x34253; fax: +886 4 24723229. E-mail address: [email protected] (S.-F. Yang).
http://dx.doi.org/10.1016/j.cca.2014.03.031 0009-8981/© 2014 Elsevier B.V. All rights reserved.
determine pneumonia impressions [2], and laboratory techniques, such as Gram's stain, sputum cultures, blood cultures, antigen tests, polymerase chain reaction, and serology, can be used to determine the potential etiology [3]. Biological markers are occasionally used to evaluate pneumonia [4]. Thus, developing a biomarker for performing rapid and reliable diagnoses would be beneficial.
2. Three types of pneumonia Pneumonia is defined as an infection of the pulmonary parenchyma that develops from the proliferation of microbial pathogens at the alveolar level of the respiratory track and the response of the host itself [5]. Because the epidemiology, pathogenesis, and risk factors for infection of pneumonia patients are different, the American Thoracic Society
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and Infectious Diseases Society of America have developed guidelines for distinguishing among three types of pneumonia. Communityacquired pneumonia (CAP) is defined as pneumonia acquired from the community. Hospital-acquired (or nosocomial) pneumonia (HAP) is defined as pneumonia that occurs 48 h or more after hospital admission and does not appear to be incubating at the time of admission. Among HAP patients, those who develop pneumonia after more than 48 to 72 h of endotracheal intubation are classified as having ventilatorassociated pneumonia (VAP) [6,7]. The etiology of pneumonia includes bacteria, viruses, fungi, and protozoa [8]. Generally, two groups of pathogens that potentially cause pneumonia exist: “typical” bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and gram-negative bacilli, such as Klebsiella pneumoniae and Pseudomonas aeruginosa; and “atypical” organisms, including Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella species, and respiratory viruses, such as influenza viruses, adenoviruses, and respiratory syncytial viruses. Determining whether a case is typical or atypical pneumonia is imperative because this diagnosis provides considerable implications for therapy. However, 11–20% of pneumonia cases are polymicrobial, and the etiology often includes a combination of typical and atypical pathogens [9]. 3. Matrix metalloproteinases participating in the pathology of inflammation Matrix metalloproteinases (MMPs), which are also called matrixins, are a large family of zinc-dependent endopeptidases that are known Table 1 Classification of MMPs.
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as the major enzymes responsible for the proteolytic degradation of proteinaceous components of the extracellular matrix (ECM) [10], which are essential for embryonic development, morphogenesis, reproduction, tissue homeostasis, tumorigenesis, and organ fibrogenesis [11, 12]. Excreted MMPs contain 23 proteases in humans and are categorized into four classes based on their substrate specificity (Table 1): collagenases (MMP-1, -8, and -13); gelatinases (MMP-2 and -9); stromelysins (MMP-3, -10, and -11); and a heterogeneous group that includes matrilysin (MMP-7), metalloelastase (MMP-12), enamelysin (MMP-20), endometase (MMP-26), and epilysin (MMP-28). The membrane MMPs (MMP-14, -15, -16, -17, -24, and -25) are anchored to the cell surface. An alternate classification system that categorizes the MMPs based on domain structure is also used [13]. MMPs typically consist of four domains: the propeptide domain, which contains a cysteine-switch motif for ligating catalytic zinc to maintain the latency of the inactive form of MMPs [14]; the catalytic domain, which contains two zinc ions that coordinate with the zincbinding motif HEXXHXXGXXH and a conserved methionine, which forms a unique Met-turn structure for stabilization [15]; and the cysteine residue in the propeptide domain interacts with the catalytic zinc ion, which prevents its association with water molecules until the propeptide domain is removed [16]. Except for MMP-7, MMP-23, and MMP-26, MMPs have C-terminal hemopexin-like domains that are recognized by substrates. The hemopexin domain consists of a four-bladed propeller structure and confers substrate specificity to the MMPs; thus, degradation of the triple-helical collagens is absolutely necessary [17].
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Each type of MMP contains a linker region that varies in length, and several MMPs possess slight structural differences. The gelatinases (MMP-2 and -9) contain three repeats of a fibronectin type II inserted into the catalytic domain for binding to gelatin and collagen [18]. MMP-23 contains a cysteine-rich region and an immunoglobulin domain instead of the hemopexin domain [19]. Finally, membrane-type MMPs contain a transmembrane domain or a glycosylphosphatidylinositol anchor [16, 20]. MMP function is regulated at several levels. The first level of control of MMP production is transcriptional regulation. The induction of gene expression is controlled by effectors, including growth factors, cytokines, chemical agents, physiological stress, and oncogenic cellular transformation. In addition, enhanced MMP gene expression may be downregulated by suppressive factors, such as transforming growth factor b, retinoic acids, or glucocorticoids. Moreover, specific signaling pathways result in the expression of particular MMP genes [11]. For example, activation of the Rho family guanosine triphosphatase (GTPase) pathway increased the expression of MMP-1 [21]; ultraviolet B (UVB) irradiation mediated signaling pathway up-regulates MMP-1 and MMP-3 expression [22]. Moreover, activation of the ceramide signaling pathway inhibits MMP-1 gene expression [23]. Most MMPs are translated into an inactive zymogen form. Secreted zymogens are activated either intracellularly by zymogen convertases, such as furin, in the normal secretory pathway, at the cell surface, or extracellularly by other proteases [16]. In all cases, activation requires the disruption of the Cys–Zn2+ (cysteine switch) interaction [24]. For example, in neutrophils, specific MMPs (MMP-8 or MMP-9) can be stored as proenzymes in intracellular granules, and their exocytosis is stimulated by external signals (including cytokine signaling or CD40 signaling) [16]. Finally, active MMP proteins are naturally inhibited by tissue inhibitors of metalloproteinases (TIMPs) in extracellular environments [16]. Although the main function of MMPs is the removal of the ECM during tissue resorption and the progression of various diseases, MMPs also interact with numerous cytokines, participating in the pathology of infection and inflammation [11,25]. In the pathology of pneumonia, an infectious disease, MMPs are understandable and have been shown to play a role.
4. Role of matrix metalloproteinases in pneumonia The first line of defense against invasive respiratory pathogens is the airway epithelium, and the mechanisms include the prevention of bacterial colonization and infection in the airways. Epithelial cells maintain a barrier to the environment, and provide enzymes (such as lysozyme, β-defensins, cathelicidin, and other enzymes [26]) and an airway mucus layer for physical protection [27]. In addition, they regulate inflammation as a secondary line of defense in response to infection by secreting factors that recruit inflammatory cells to attack invasive pathogens; MMPs are components of these factors [28], and several reports have described the presence of an increased epithelial MMP
expression in response to bacterial infection, such as those of MMP-7 [29], MMP-10 [28], and MMP-28 [30] (Table 2). MMP-7 and MMP-28 are constitutively expressed in low concentrations by bronchial epithelial cells and are induced by bacterial infections [30–32]. Previous studies have reported that MMP-7 has several functions involved in immune responses, which include re-epithelializing airways by cleaving E-cadherin [33,34], processing antibacterial peptides [35], regulating acute alveolar neutrophil transepithelial migration by shedding syndecan-1/KC complexes [31], clearing pathogens [36] by promoting apoptosis through the generation of soluble Fas (CD95) ligands [36,37], and regulating growth factor signaling through epidermal growth factors and insulin-like growth factors [38]. MMP-28 has been shown to control neutrophil recruitment into the lung in a P. aeruginosa pneumonia model [30]. Most MMPs play roles in maintaining immunity by cleaving specific proteins, which increases the activity of the target substrates [39]. For example, MMP-2, MMP-3, and MMP-9 can activate IL-1β [40], and MMP-7 and MMP-12 can activate latent TNFα [41–43]. In addition, MMP-28 restrains macrophage recruitment by retarding the chemotaxis of these cells [30]. Moreover, Kassim et al. demonstrated that MMP-10 restrains the inflammatory response and controls apoptosis [28]. In the lung, neutrophils are located in the vascular bed. Neutrophils are recruited to pulmonary capillaries by inflammatory cytokines, such as interleukin-8 (IL-8) and leukrotrien B4 in patients with pneumonia [44]. Subsequently, the activated MMPs contribute to neutrophil migration into the alveolar compartment [45]. The release of MMP-8 and MMP-9 [44,46] is speculated to result in a disruption of basement membrane components, which facilitates the neutrophil invasion of extravascular tissue [47]. However, Rosendahl et al. proposed that bacteria can exploit MMP-9 to open tissue barriers and cause its own dissemination from the local site of infection using an S. pneumonia-infected model [48]. In the role of degrading the tissue barriers, MMPs have two aspects in the pathology of pneumonia, it benefits the inflammatory cells to infiltrate to the infected site; simultaneously, it results in the dissemination of the pathogen. The alveolar compartment is the location where neutrophils degranulate with the exocytosis of MMPs, such as MMP-8, MMP-9 [49], as well as other types of neutrophil granules and reactive oxygen species, which can execute antimicrobial functions [50]. In pneumonia patients, compared with peripheral neutrophils, pulmonary neutrophils are highly stimulated during infections to release MMPs [51]. Released MMPs are activated by bacterial MMPs [52], plasmin [53], or other neutrophil products such as myeloperoxidase and neutrophil elastase [44,54]. Oggioni et al. discovered that a pneumococcal zinc metalloproteinase can cleave and activate MMP-9 in a murine model of pneumonia [44]. MMP-9 and MMP-2 play key roles in the migration of various leukocytes, such as T cells and neutrophils [47]. MMP-2 and, to a lesser degree, MMP-9 were observed to efficiently cleave and inactivate IL-17A, which is a pathogen-associated proinflammatory molecule that induces the recruitment of activated neutrophils to infection sites [55].
Table 2 Role of MMPs in pneumonia. MMPs
Pneumonia
MMP-2, MMP-9 MMP-2, MMP-9 MMP-7 MMP-7, MMP-10 MMP-8, MMP-9 MMP-8, MMP-9 MMP-8, MMP-9 MMP-8, MMP-9, TIMP-1 MMP-9 MMP-9, TIMP-1 MMP-9, LCN2 MMP-28
S. pneumoniae pneumonia in murine model M. pneumoniae CAP Airway epithelial cells infected with P. aeruginosa in vivo P. aeruginosa pneumonia in murine model HAP HAP with high-risk bacteria VAP P. aeruginosa VAP CAP CAP CAP P. aeruginosa pneumonia in murine model
References MMPs serves in the early host immune response MMP-9 activity elevated in M. pneumoniae CAP patients Infection induced MMP-7 expression Infection induced MMP expression MMP levels are increased in HAP patients MMP activities are elevated in HAP patients MMPs elevated in VAP patients Higher MMP-9/TIMP-1 ratio determine poor outcome MMP-9 elevated in CAP patients MMP-9/TIMP-1 ratio elevated in CAP patients LCN2/MMP-9 correlated with the CAP severity MMP-28 negative regulates macrophage recruitment
Hong et al. [57] Puljiz et al. [77] Lopez-Boado et al. [29] Kassim et al. [28] Hartog et al. [51] Schaaf et al. [44] Wilkinson et al. [68] El-Solh et al. [61] Yang et al. [69] Chiang et al. [72] Yeh et al. [75] Manicone et al. [30]
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High levels of MMP-9 in the lungs were reported to promote the infiltration of inflammatory cells [56]. Furthermore, MMP-9 is critical for effective bacterial phagocytosis and the generation of reactive oxygen species in neutrophils [57]. In addition, MMP-2 and MMP-9 have been reported to play roles in regulating adaptive immune processes by degrading ECM proteins and modifying chemokines [57]. Hong et al. elaborated that MMP-2 and MMP-9 serve as anti-inflammatory mediators by avoiding excess neutrophil recruitment to the lung, and MMP-9 is essential to neutrophil-mediated bacterial killing as well as phagocytosis. Thus, the mortality rate increased in S. pneumoniae-infected MMP-2, 9−/− mice [57]. MMPs were reported to contribute to the innate immune and adaptive immune systems. Furthermore, they were shown to be crucial factors in eliminating pathogen and protecting the host itself from its own immune system. A positive feedback loop exists between cytokines and MMPs. For example, MMP-9 cleaves IL-8 into an active form, which increases MMP-9 levels, resulting in a potent IL-8 [49]. This type of positive feedback may maintain excessive MMP activity, such as the degradation of ECM, which eventually leads to severe ECM destruction and alveolocapillary leakage accompanied by an increased risk of developing acute respiratory distress syndrome (ARDS), which is the most severe complication of pneumonia [49]. The local production of MMPs can directly alter the local tissue architecture by degrading proteins of the ECM [58]. The evidence suggests that MMPs in the lung control the pathogenesis of ARDS by disrupting structures of the basement membrane. Torii et al. reported that in ARDS patients, MMP-9 levels were correlated with 7S collagen, a marker of basement membrane disruption [59]. In such cases, inhibition of MMP activity may attenuate several crucial pathogenetic steps in the inflammatory cascade, such as preventing an acute lung injury from severe infection [60]. In the pathology of pneumonia, MMPs might have a dual effect involving the ultimate outcome, duration of exposure, site of release, and characteristics of the defending pathogen [61]. HAP is the leading cause of death among hospital-acquired infections [62]. Various bacterial species differentially affect MMP secretion and activation. Clinically, infections with P. aeruginosa, S. aureus, and Stenotrophomonas maltophilia are associated with the most severe form of HAP [63]. In HAP patients, high-risk pathogens appear to induce the release of strong neutrophil MMPs. In addition, Schaaf et al. observed higher MMP-8 and MMP-9 levels in the lungs, and an increased MMP-9/TIMP-1 molar ratio and MMP-9-activity compared with HAP patients with low-risk bacteria and control patients [44]. HAP patients exhibited a close correlation between pulmonary MMP levels and the laboratory parameters of systemic inflammation, such as high-serum C-reactive protein, high white blood cell counts, and high body temperature [44]. Hartog et al. observed increased levels and activity of MMP-8 and MMP-9 in plasma and in the minibronchoalveolar lavage fluid (mini-BALF) of patients with HAP, which correlated with systemic signs of inflammation [51]. MMP activation in HAP patients might be necessary for bacterial clearance, but unresolved infections might trigger ongoing MMP activation and tissue destruction [64,65]. In intensive care units, 15% to 30% of patients who are intubated and mechanically ventilated develop VAP as a complication [66]. VAP patients are known to possess dysfunctional neutrophils, which are less capable of phagocytosis and cytotoxicity, and once recruited, they can easily damage pulmonary epithelial membranes [67]. Wilkinson et al. suggested that excessive dysfunctional neutrophils are recruited to the lungs of VAP patients and active proteolytic enzymes are secreted into the alveolar space [68]. Data have indicated that expression of MMP-8 and MMP-9 significantly increased in BALF in VAP patients [61,68]. Furthermore, the imbalance between MMP-9 and TIMP-1 might indicate severe alveolar capillary damage and poor outcomes [61]. Several recent studies evaluating the MMP plasma levels in CAP patients have been performed. Our laboratory first reported that in CAP patients, the activity and level of MMP-9 in serum were significantly
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higher compared with healthy controls. We suggested that MMP-9 may play an essential role in the pathogenesis of CAP [69,70]. In addition, MMP-9 expression may be inhibited by TIMP-1 [71]. The plasma TIMP-1 concentration was positively correlated with CAP severity, and the MMP-9/TIMP-1 molar ratio was significantly increased in patients with CAP; thus, we suggested that incorporating plasma MMP-9 levels and the MMP-9/TIMP-1 molar ratio into a clinical evaluation will aid in CAP diagnosis [72]. Lipocalin 2 (LCN2), also known as neutrophil gelatinase-associated lipocalin [73], forms a complex with MMP-9, thereby preventing the autodegradation of MMP-9 and increasing its activity [74]. We determined that the plasma level of LCN2 was correlated with the severity of CAP and significantly correlated with LCN2/ MMP-9 levels. We suggested that serum LCN2 and the LCN2/MMP-9 complex can act as adjuvant diagnostic biomarkers for CAP [75]. M. pneumoniae is a prominent etiology of CAP cases that are sufficiently severe to require hospitalization [76]. Puljiz et al. discovered that in M. pneumonia-infected CAP patients, MMP-2 plasma levels decreased in the acute phase but increased in the convalescent phase; in contrast, the MMP-9 mRNA expression in peripheral blood mononuclear cells (PBMCs) increased in the acute phase of the illness and then decreased in the convalescent phase, and the same results were observed in the MMP-9 plasma levels. They speculated that MMP-2 in the acute phase of the disease was attracted to the pulmonary compartment containing other inflammatory mediators and that PBMCs are vital sources of MMP-9 during CAP caused by M. pneumoniae [77]. MMP concentration and activation are markers for the severity of inflammation [44] and are reported to be positively correlated with pneumonia. Thus, incorporating MMPs into clinical information is beneficial to assist with the diagnosis and prognosis of CAP. Elevated levels of MMP activity and quantity were detected among three types of pneumonia subjects: MMP-2, 8, 9 in HAP; MMP-8, 9 in VAP; and MMP-2, 9 in CAP. However, the precise mechanism and prognosis to which they contribute to pneumonia requires further studies. Previous studies have shown that MMPs are essential for pulmonary epithelial immune responses (MMP-7, 10, 28); maintaining immunity by activating specific proteins (MMP-2, 3, 7, 9, 12, 28); various leukocyte migration (MMP-2, 8, 9); and killing and phagocytosis of bacteria (MMP-9), although many roles MMPs in pneumonia pathology remain unclear. In the pathology of pneumonia, MMPs are necessary in the defense against a pathogen, but it is also responsible for lung tissue damage. This might be one reason why there is no directly significant correlated result between the severity of pneumonia and MMP levels. Thus, additional studies for the development of MMPs into biomarkers for the diagnosis or prognosis of pneumonia are required. However, it is possible to determine the potential range of MMP levels, which are adequate for the immune system to work but are not excessive enough to result in severe complications. The long-term goal is to use MMP levels to evaluate the severity of pneumonia. Moreover, we may be able to suppress specific MMP expression or use inhibitors of MMPs to prevent complications in pneumonia patients who overexpress in MMPs. References [1] WHO. The top 10 causes of death; 2013. [2] Metlay JP, Fine MJ. Testing strategies in the initial management of patients with community-acquired pneumonia. Ann Intern Med 2003;138:109–18. [3] Baron EJ, Miller JM, Weinstein MP, Richter SS, Gilligan PH, Thomson Jr RB, et al. A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM)(a). Clin Infect Dis 2013;57:e22-121. [4] Cheng CW, Chien MH, Su SC, Yang SF. New markers in pneumonia. Clin Chim Acta 2013;419:19–25. [5] Longo ASF, Dan L, Kasper Dennis L, Hauser Stephen L, Jameson J Larry, Loscalzo Joseph, editors. Harrison's™ Principles of internal medicine eighteenth edition; 2011. [6] Anand N, Kollef MH. The alphabet soup of pneumonia: CAP, HAP, HCAP, NHAP, and VAP. Semin Respir Crit Care Med 2009;30:3–9.
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