Ann. N.Y. Acad. Sci. ISSN 0077-8923
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Cellular and Environmental Stressors in Biology and Medicine
Exploring the link between scavenger receptor B1 expression and chronic obstructive pulmonary disease pathogenesis Giuseppe Valacchi,1 Emanuela Maioli,2 Claudia Sticozzi,1 Franco Cervellati,1 Alessandra Pecorelli,3 Carlo Cervellati,4 and Joussef Hayek5 1 Department of Life Science and Biotechnologies, University of Ferrara, Ferrara, Italy. 2 Department Life Sciences, University of Siena, Siena, Italy. 3 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy. 4 Department of Biomedical and Specialist Surgical Sciences, Section of Medical Biochemistry, Molecular Biology and Genetics, University of Ferrara, Ferrara, Italy. 5 Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy
Address for correspondence: Giuseppe Valacchi, Ph.D., Department of Life Sciences and Biotechnologies, University of Ferrara, Via Borsari, 46, 44100 Ferrara, Italy. [email protected]
Chronic obstructive pulmonary disease (COPD) has been recognized as one of the major causes of morbidity and mortality in the United States; it is the third leading cause of deaths in the United States, with approximately 15 million Americans affected with COPD. Although exposure to cigarette smoke has been shown to be the main, if not the only, risk factor for COPD, the mechanisms underlying this association remain unclear. Most smokers do not develop COPD, suggesting that a combination of exposure and susceptibility (genetic background) is required. Several mechanisms contribute to the pathogenesis of COPD, such as influx of inflammatory cells into the lung, imbalance between proteolytic and antiproteolytic molecules, disruption of the balance between apoptosis and replenishment of structural cells in the lung, and disruption of oxidant/antioxidant balance. The scavenger receptor BI (SRB1) plays an important role in mediating the uptake of high-density lipoprotein (HDL)-derived cholesterol and cholesteryl ester in tissues. In addition to its role as the HDL receptor, SRB1 is also involved in pathogen recognition, identification of apoptotic cells, tissue antioxidant uptake (tocopherol and carotenoids), and lung surfactant composition, all factors involved in COPD pathogenesis. Therefore, it is possible that lung SRB1 levels are involved in the development of COPD. Keywords: 4-hydroxynonenal; scavenger receptor B1; protein adducts; oxidative stress; lung
Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a respiratory pathology that affects more than 16 million Americans (the third highest cause of death in the United States1–3 ). This chronic disease is characterized by an altered inflammatory response of the lungs to toxic particles (mostly cigarette smoke). The most typical consequence is chronic bronchitis/bronchiolitis and/or emphysema that lead to an almost irreversible airflow limitation.1 COPD pathogenesis A number of different pathogenic mechanisms seem to be involved in COPD development.1,4,5 First,
inhalation of toxic particles, particularly through cigarette smoke (CS), leads to the migration of inflammatory cells into the airways, and consequently to the onset of a chronic inflammatory state.6,7 Second, there is an augmentation of proteolytic activity, because of the derangement of the balance between proteolytic and antiproteolytic molecules, in the lungs of COPDaffected individuals.8–10 The direct effect of this alteration in proteolytic activity is deep pulmonary parenchyma damage, which inevitably leads to emphysema. Inflammation (release of proteases by macrophages and polimorphonucleates9,10 ) and genetic factors (␣-1 antitrypsin deficiency11,12 ) have
doi: 10.1111/nyas.12714 C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
47
SRB1 involvement in COPD
Valacchi et al.
been ascribed as the most probable causes of this proteolytic burden. Third, oxidative stress appears to be involved in the pathogenic mechanisms underlying COPD development. This pathophysiological condition is characterized by an imbalance between oxidant species, primarily reactive oxygen species (ROS), and antioxidant defense systems, in favor of the former.13–15 The main sources of ROS in COPD are CS and activated cells such as leukocytes and epithelial cells. The chemical insult by these free radicals can lead to cell dysfunction or cell death, with extensive injury to the pulmonary extracellular matrix. Furthermore, oxidative stress can impair the proteinase–antiproteinase balance through the activation and inactivation of proteolytic and antiproteolytic processes.16,17 Moreover, reactive species contribute to proinflammatory reactions. Indeed, it is well recognized that ROS can enhance the activity of the transcription factor nuclear factor-B (NF-B) and, as a direct consequence, promote the transcription of proinflammatory genes.15,18,19 Recent work suggests a fourth possible mechanism that may be involved in COPD pathogenesis: derangement of the balance between apoptosis and replenishment of structural cells in pulmonary tissues may induce lung damage in response to CS, leading to emphysema.20 Proof of increased levels of apoptosis in COPD patients has been frequently shown in the literature21–23 and has been linked to diminished alveolar surface area. Furthermore, because bacterial and/or viral infections contribute remarkably to the clinical progression of COPD, these infections represent important comorbidities in this disease. Indeed, under normal conditions, the healthy human lung is capable of maintaining sterility, despite repetitive exposure to microbial inoculate from micro-aspiration and inhalation. However, in the setting of COPD, the lung’s defense system seems to be disrupted as a result of exposure to irritants such as CS. This failure of the lung defense system results in two distinct infection cycles in COPD that could contribute to the progressive decline of organ function. The lungs of COPD patients become highly sensitive to repeated acute airway mucosal viral and bacterial infections, leading to episodes of increased inflammation and worsened symptoms. Thus, microbial colonization results in
48
chronic inflammation and lung destruction, leading to a “vicious circle.” Many processes, such as chronic inflammation, oxidative stress, apoptosis, and pathogenic infection, participate in the development of COPD, and the interaction of these processes contributes to the pathogenesis of the disease. Cigarette smoke and oxidative stress Exposure to CS is by far the most important risk factor for COPD pathogenesis.6 CS is a highly complex aerosol composed of more than 4700 chemicals and consists of a gas phase and a particulate phase. Mainstream smoke (the combination of inhaled and exhaled smoke after taking a puff of a lit cigarette) includes particulates suspended in a gaseous phase. It is widely recognized that CS contains high levels of pro-oxidants,24,25 with more than 1014 lowmolecular-weight carbon- and oxygen-centered radicals per puff present in gas-phase smoke.26,27 Sidestream smoke is the smoke that goes into the air directly from a burning cigarette and is the main component of second-hand smoke. The chemical constituents of sidestream smoke are different from those of directly inhaled (mainstream) CS; it was recently shown that inhaled sidestream CS is approximately four times more toxic per gram of total particulate matter (TPM) than mainstream CS. Furthermore, sidestream condensate, compared to mainstream, is about three times more toxic per gram and two to six times more tumorigenic per gram. The gas/vapor phase of sidestream smoke is responsible for most of the sensory irritation and respiratory tract epithelium damage.28 It has been clearly demonstrated that CS is noxious for human health, mostly because of the ROS present in tobacco smoke, as well as the oxidative damage to biological molecules, in particular lipids, induced by smoke exposure.29,30 In particular, it has been shown that ␣,-unsaturated aldehydes that are present in CS (such as acrolein and crotonaldehyde) or formed during lipid peroxidation (such as 4-hydroxy-2,3-nonenal (4HNE) and malondialdehyde (MDA))31,32 are key players involved in CS toxicity. Relevant to these considerations, the ability of these aldehydes to covalently adduct to cysteine, lysine, and histidine residues can lead to significant modification of the structure and function of many proteins involved in important biochemical
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
Valacchi et al.
pathways.33,34 Recent studies have shown that the formation of adducts is a mechanism by which enzyme function can be modified; for example, it has been shown that the formation of a Michael adduct with the cytoplasmic subunits of NADPH oxidase impairs its function in neutrophils.32 Similar effects have been shown also from our group for the redox-sensitive transcription factor NF-B.35,36 COPD as a multisystemic disease COPD is no longer regarded simply as a disease of the lungs and airways. There is growing awareness of the multisystemic nature of this disease. Research has shown increased levels of systemic inflammation and neurologic, psychiatric, skeletal muscle, and endocrine system dysfunction associated with COPD. One of the most recognized manifestations includes the presence of concomitant cardiovascular disease (CVD). CVD complicating COPD is a leading cause of death in the COPD population.37,38 The mechanisms for this association remain unclear and are not fully explained by tobacco exposure. Results from a large clinical trial showed that impaired lung function (forced expiratory volume in 1 s (FEV1 )) is an independent predictor of the probability of dying from a myocardial infarction,39 and FEV1 is also a clinical aspect found in COPD patients leading to CVD complications.40 A recent study reported that patients with severe COPD have a twofold greater risk of CVD.41 Low-grade systemic inflammation could be the driving factor underlying the observed interaction between
SRB1 involvement in COPD
atherosclerotic CVD and COPD. Indeed, converging evidence showed that chronic inflammation could have a role in the pathogenesis of atherosclerotic patients with COPD.42 Although the association between atherosclerosis and COPD is not fully understood, there are epidemiological data that suggest that patients with COPD should be screened for the presence of concomitant atherosclerosis and that atherosclerotic patients should be investigated for the contemporaneous presence of impaired FEV1 . In addition, recent papers have shown that COPD patients have higher levels of high-density lipoprotein (HDL) compared with healthy subjects. Although epidemiologic studies have shown that HDL particles are strongly associated with reduced cardiovascular risks, the effects of very high HDLs suggest effects beyond cholesterol transport. Indeed, multiple pleiotropic properties of HDLs are recognized, including roles as an atherogenic particles in certain settings. Recent studies have suggested that the relationship between HDLs and risk for CVD may be U-shaped rather than a linear curve, with very high levels of HDL conferring increasing rather than decreasing cardiovascular risk.43–45 Navab et al.44 described changes observed in inflammatory states in which HDL function becomes proinflammatory and may promote the atherosclerotic process. The chronic inflammation present in COPD may promote oxidation of HDL, which could explain the high CVD incidence observed, despite what would conventionally be interpreted as favorable lipid profiles.
Figure 1. SRB1 cholesterol uptake is mediated by a hydrophobic channel that allows the uptake of cholesterol esters into the cells.
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
49
SRB1 involvement in COPD
Valacchi et al.
Figure 2. SRB1 is also involved in tissue ␣-tocopherol uptake, which follows the cellular cholesterol uptake.
Scavenger receptor B1 At the end of the 1990s, Krieger’s group was able to identify an 82-kDa cell surface protein called scavenger receptor class B1 (SRB1), which was clearly involved in the binding of HDL and in promoting the selective uptake of HDL cholesterol via a hydrophobic channel (Fig. 1). Because of its high binding affinity to HDL,46,47 SRB1 is able to affect HDL metabolism.47–49 It has been shown that SRB1 mediates selective cholesterol (i.e., cholesteryl esters) uptake from the hydrophobic HDL cores47–49 owing to its ability to bind lipoproteins. The mechanism by which SRB1 is able to facilitate lipid uptake is different from that of low-density lipoprotein receptor (LDLR). In fact, although LDLR mediates LDLparticle endocytosis,50 SRB1 mediates the transfer of cholesteryl esters from the hydrophobic core of the HDL to the cells without internalizing the lipoprotein particle. Of note, some studies have suggested an LDLR-like uptake mediated by SRB1 in hepatocytes. In addition, the role of SRB1 in selective hepatic uptake of lipids from the HDL has been shown in knock-out (KO) and knock-in animal models.51–55 Furthermore, Srb1 KO mice are also a good model to study the pathogenesis of atherosclerosis.56–58 Krieger’s group showed 50
that Srb1 KO mice have dramatically increased plasma HDL and total cholesterol levels, with abnormally large HDL particles that can then develop in atherosclerotic vessel lesions.56–58 Links between SRB1 and COPD As mentioned earlier, COPD pathogenesis is characterized by several mechanisms (infections, apoptosis, oxidative stress), and SRB1 has been shown to be involved in all of these pathways. For instance, a role for SRB1 in bacteria recognition has been proposed by several groups. Yesilaltay et al. have elegantly demonstrated a role for SRB1 in the recognition of hepatitis C virus (HCV) by binding to HCV envelope glycoprotein E2;59 a decrease in SRB1 levels increased the susceptibility of cells to infection by HCV.60 This work was also supported by a more recent study where the data showed that LPS can downregulate SRB1 levels61 and that SRB1 is able to directly recognize the pathogens.62 Besides its role in bacterial interactions, it was suggested that SRB1 could also bind to viral dsRNA,63 which could underlie its putative role in COPD pathogenesis, as many respiratory viruses present in COPD patients are able to produce dsRNA. In addition, SRB1 has been demonstrated to be involved, although indirectly, in the cellular defense against oxidative stress, because of its ability to
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
Valacchi et al.
SRB1 involvement in COPD
Figure 3. Putative role of decreased SRB1 levels in COPD pathogenesis. Several mechanisms seem to play roles in COPD: redox imbalance, chronic inflammatory response, recurrent infections, and abnormal apoptotic events. Owing to its panel of pleiotropic actions, the receptor SRB1 could be a possible common denominator among these mechanisms. In lungs, the decline in SRB1 levels induced by cigarette smoke can contribute to reduced antioxidant defenses (tocopherol and carotenoids) and failure to recognize pathogens and to detect and clear apoptotic cells.
uptake lipophilic antioxidants, including vitamin E and carotenoids (Fig. 2). Indeed, Srb1 KO animals have 50% less ␣-tocopherol in tissues (ovary, testis, lung, and brain) compared with wild-type animals.48 Specifically, lungs from Srb1 KO animals had at least 60% less vitamin E than controls,48 which indicates its role in protecting lung tissue. In fact, several reports have shown that oxidative lung damage is enhanced in vitamin E–deficient models,64 making SRB1 a potential player involved in regulating tissue vitamin E levels and a possible therapeutic target for lung pathologies. For instance, it has been suggested that SRB1 can be modulated at the posttranscriptional level in animals fed with tocopherol-depleted chow.65 Moreover, several recent reports have shown a role for SRB1 in cellular carotenoid uptake using different experimental models. Von Litig et al. have shown the importance
of SRB1 in tissue carotenoid uptake in Drosophila.66 In support of this study, van Bennekum showed that SRB1 and CD36 (another scavenger receptor) are important for intestinal carotenoid uptake.67 More recently, the role of SRB1 in the uptake of carotenoids has been demonstrated in other tissues, such as the eyes. Indeed, recent work by Sato et al. showed that SRB1 can import lutein into retinal pigmented epithelial cells. These authors, by the use of small interfering RNA (siRNA) approaches, were able to show that SRB1 is responsible for more than 75% of cellular lutein uptake.68 These reports suggest that SRB1 is able to facilitate the uptake of lipophilic antioxidants into several cells/organs, suggesting that this receptor plays a role in the maintenance of cellular redox state. However, oxidative stress can affect SRB1 expression; indeed, lung SRB1 levels are modulated by
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
51
SRB1 involvement in COPD
Valacchi et al.
aging and by exogenous oxidative stressors, such as CS and ozone. Our group was able to demonstrate that adult animals exposed to environmental oxidants presented a unique vitamin E tissue profile:69 whereas plasma tocopherol increased after CS and ozone exposure, lung tocopherol decreased significantly, and this correlated with tissue SRB1 levels.70 Increased levels of oxidative stress induced increased lipid peroxidation, with the formation of reactive aldehydes (i.e., 4HNE) that are able to covalently bind to SRB1 and induce its degradation via the proteasome system.66 As such, the controversial benefit of vitamin E supplementation could depend on the tissues’ ability to uptake this lipophilic antioxidant, which is related to SRB1 expression levels.65 In addition, increased levels of apoptotic cells may be present in COPD lung tissues. The apoptotic process is of extreme importance in the damaged airway epithelium, as it plays a crucial role in reducing inflammation. An increasing number of studies have supported the presence of an apoptotic process in COPD patients,71 and this can be linked to the ability of CS to induce apoptosis in airway epithelial cells. Furthermore, there are recent papers suggesting that SRB1 has the capacity to recognize apoptotic cells. Indeed, treatment with Srb1 antisense oligonucleotides was able to impair the ability of lung epithelial cells to bind to apoptotic thymocytes. As such, it is possible to suggest a correlation between CS exposure, decreased SRB1 levels, altered apoptotic cell clearance, and COPD (Fig. 3). Regardless, the role of SRB1 is likely independent of vitamin E uptake, since many reports have demonstrated the proapoptotic effect of vitamin E.72 Conclusions Several processes contribute to COPD pathogenesis, such as CS inflammation, increased oxidative stress, altered apoptosis, and pathogen infections. The multifunctional receptor SRB173 plays key roles in all of the above-mentioned processes: regulation of lung antioxidant intracellular levels (tocopherol and carotenoids), recognition of bacteria and virus related ligands, and identification and clearance of apoptotic cells. In addition, because genetic factors seem to play roles in COPD pathogenesis, it is possible that the different levels of SRB1 expression are involved in the genetic predisposition toward COPD development. It should be mentioned that a large part of the work summarized in this review was 52
performed using either in vitro or animal models and that, at present, the role of SRB1 in COPD has not yet been fully investigated. However, the role of SRB1 in lung immunity was recently described in a review by Dempsey,73 suggesting a possible role for SRB1 in several lung pathologies. In addition, we have preliminary data that suggested altered glycosylation of SRB1 in COPD patients, with low levels of the completely glycosylated mature form of SRB1 and high levels of the partially glycosylated immature form in these COPD samples. These results suggest that not only oxidative stress could influence SRB1 posttranslational modification, as we have demonstrated by the formation of 4HNE– SRB1 adducts,69,70 but that inefficient glycosylation machinery could also affect its functionality. Because of the aforementioned peculiar characteristics of SRB1, it is possible that SRB1 plays a role in the development of COPD, if not its etiology, although further studies, mainly in humans, are needed to confirm this hypothesis. Acknowledgment We thank the “Fondazione Umberto Veronesi” for a C.S. Fellowship. Conflicts of interest The authors declare no conflicts of interest.
References 1. Mannino, D.M. & A.S. Buist. 2007. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 370: 765– 773. 2. Mini˜no, A.M., J. Xu & K.D. Kochanek. 2010. Preliminary data for 2008. Natl. Vital Stat. Rep. 59: 1–52. 3. Hoyert, D.L. & J.Q. Xu. 2012. Deaths: preliminary data for 2011. Natl. Vital Stat. Rep. 61: 1–65. 4. Chung, K.F. & I.M. Adcock. 2008. Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction. Eur. Respir. 31: 1334–1356. 5. MacNee, W. 2007. Pathogenesis of chronic obstructive pulmonary disease. Clin. Chest Med. 28: 479–513. 6. Yao, H & I. Rahman. 2009. Current concepts on the role of inflammation in COPD and lung cancer. Curr. Opin. Pharmacol. 9: 375–383. 7. O’Donnell, R., D. Breen, S. Wilson, et al. 2006. Inflammatory cells in the airways in COPD. Thorax 61: 448–454. 8. Segura-Valdez, L., A. Pardo, M. Gaxiola, et al. 2000. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 117: 684– 694.
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
Valacchi et al.
9. Hogg, J.C., F. Chu, S. Utokaparch, et al. 2004. The nature of small airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 50: 2645–2653. 10. Kranenburg, A.R., A. Willems-Widyastuti, W.J. Moori, et al. 2006. Enhanced bronchial expression of extracellular matrix proteins in chronic obstructive pulmonary disease. Am. J. Clin. Pathol. 126: 725–735. 11. Cavarra, E., B. Bartalesi, M. Lucattelli, et al. 2001. Effects of cigarette smoke in mice with different levels of ␣-1 proteinase inhibitor and sensitivity to oxidants. Am. J. Respir. Crit. Care Med. 164: 886–890. 12. Seifart, C. & A. Plagens. 2007. Genetics of chronic obstructive pulmonary disease. Int. J. Chron. Obst. Pulmon. Dis. 2: 541– 550. 13. Rahman, I., S.K. Biswas & A. Kode. 2006. Oxidant and antioxidant balance in the airways and airway diseases. Eur. J. Pharmacol. 533: 222–239. 14. Lawless, M.W., K.J. O’Byrne & S.G. Gray. 2009. Oxidative stress induced lung cancer and COPD: opportunities for epigenetic therapy. J. Cell Mol. Med. 13: 2800–2821. 15. Rahman I. & I.M. Adcock. 2006. Oxidative stress and redox regulation of lung inflammation in COPD. Eur. Respir. J. 28: 219–242. 16. Kinnula, V.L., K. Vuorinen, H. Ilumets, et al. 2007. Thiol proteins, redox modulation and parenchymal lung disease. Curr. Med. Chem. 14: 213–222. 17. Ning, W., Y. Dong, J. Sun, et al. 2007. Cigarette smoke stimulates matrix metalloproteinase-2 activity via EGR-1 in human lung fibroblasts. Am. J. Respir. Cell Mol. Biol. 36: 480–490. 18. Moodie, F.M., J.A. Marwick, C. Anderson, et al. 2004. Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-B activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J. 18: 1897–1899. 19. Rahman, I. & W. MacNee. 2000. Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches. Free Radic. Biol. Med. 28: 1405– 1420. 20. Park, J.W., S.W. Ryter & A.M. Choi. 2007. Functional significance of apoptosis in chronic obstructive pulmonary disease. COPD 4: 347–353. 21. Morissette, M.C., J. Parent & J. Milot. 2009. Alveolar epithelial and endothelial cell apoptosis in emphysema: What we know and what we need to know. Int. J. Chron. Obstruct. Pulmon Dis. 4: 19–31. 22. Imai, K., B.A. Mercer, L.L. Schulman, et al. 2005. Correlation of lung surface area to apoptosis and proliferation in human emphysema. Eur. Respir. J. 25: 250–258. 23. Yokohori, N., K. Aoshiba & A. Nagai. 2004. Increased levels of cell death and proliferation in alveolar wall cells in patients with pulmonary emphysema. Chest 125: 626–632. 24. Valavanidis, A., T. Vlachogianni & K. Fiotakis. 2009. Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles. Int. J. Environ. Res. Public Health 6: 445–462. 25. Pryor, W.A. & K. Stone. 1993. Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann. N. Y. Acad. Sci. 686: 12–27.
SRB1 involvement in COPD
26. Dube, M.F.R. & C.R. Green. 1982. Methods of collection of smoke for analytical purpose. Rev. Adv. Top Sci. 8: 42– 102. 27. Church, D.F. & W.A. Pryor. 1985. Free-radical chemistry of cigarette smoke and its toxicological implications. Environ. Health Perspect. 64: 111–126. 28. Schick, S. & S. Glantz. 2005. Philip Morris toxicological experiments with fresh sidestream smoke: more toxic than mainstream smoke. Tob. Control. 14: 396–404. 29. Dietrich, M., G. Block, N.L. Benowitz, et al. 2003. Vitamin C supplementation decreases oxidative stress biomarker f2isoprostanes in plasma of nonsmokers exposed to environmental tobacco smoke. Nutr. Cancer 45: 176–84. 30. Uchida, K., M. Shiraishi, Y. Naito, et al. 1999. Activation of stress signaling pathways by the end product of lipid peroxidation. 4-Hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J. Biol. Chem. 274: 2234– 2242. 31. Li, L. & A. Holian. 1998. Acrolein: a respiratory toxin that suppresses pulmonary host defense. Rev. Environ. Health. 13: 99–108. 32. Finkelstein, E.I., J. Ruben, C.W. Koot, et al. 2005. Regulation of constitutive neutrophil apoptosis by the alpha,betaunsaturated aldehydes acrolein and 4-hydroxynonenal. Am. J. Physiol. Lung Cell Mol. Physiol. 289: L1019– L1028. 33. Leonarduzzi, G., M.C. Arkan, H. Bas¸a˘ga, et al. 2000. Lipid oxidation products in cell signaling. Free Radic. Biol. Med. 28: 1370–1378 34. Sticozzi, C., G. Belmonte, A. Pecorelli, et al. 2012. Cigarette smoke affects keratinocytes SRB1 expression and localization via H2 O2 production and HNE protein adducts formation. PLoS One. 7: e33592. 35. Valacchi, G., E. Pagnin, A. Phung, et al. 2005. Inhibition of NFkappaB activation and IL-8 expression in human bronchial epithelial cells by acrolein. Antioxid. Redox Signal. 7: 25–31. 36. Sticozzi, C., A. Pecorelli, G. Belmonte, et al. 2010. Cigarette smoke affects ABCAl expression via liver X receptor nuclear translocation in human keratinocytes. Int. J. Mol. Sci. 11: 3375–3386. 37. Rifai, N., P.S., Bachorik & J.J. Albers. 1999. “Lipids, lipoproteins and apolipoproteins.” In Tietz Textbook of Clinical Chemistry, 3rd Ed. Burtis, C.A. & E.R. Ashwood, Eds.: 809. Philadelphia: W.B. Saunders Company. 38. Basili, S., P. Ferroni, M. Vieri, et al. 1999. Lipoprotein (a) serum levels in patients in affected by chronic obstructive pulmonary disease. Arteriosclerosis 147: 249–252 39. Anthonisen, N.R., M.A. Skeans, R.A. Wise, et al. 2005. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann. Intern. Med. 142: 233–239. 40. Calverley, P.M., J.A. Anderson, B. Celli, et al. 2007. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N. Engl. J. Med. 356: 775– 789. 41. Mannino, D.M., D. Thorn, A. Swensen, et al. 2008. Prevalence and outcomes of diabetes, hypertension, and cardiovascular disease in chronic obstructive pulmonary disease. Eur. Respir. J. 32: 962–969.
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
53
SRB1 involvement in COPD
Valacchi et al.
42. Agusti, A. & J.B. Soriano. 2008. COPD as a systemic disease. COPD 5: 133–138. 43. Kastelein, J.J., S.I. vanLeuven, L. Burgess, et al. 2007. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N. Engl. J. Med. 356: 1620–1630. 44. Navab, M., J.A. Berliner, G. Subbanagounder, et al. 2001. HDL and the inflammatory response induced by LDLderived oxidized phospholipids. Arterioscler. Thromb. Vasc. Biol. 21: 481–488. 45. vander Steeg, W.A., I. Holme, S.M. Boekholdt, et al. 2008. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. J. Am. Coll. Cardiol. 51: 634–642. 46. Krieger, M. 1999. Charting the fate of the “good cholesterol”: identification and characterization of the highdensity lipoprotein receptor SR-BI. Annu. Rev. Biochem. 68: 523– 558. 47. Acton, S., A. Rigotti, K.T. Landschulz, et al. 1996. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271: 518–520. 48. Rigotti, A., H.E. Miettinen & M. Krieger. 2003. The role of the high-density lipoprotein receptor SR-BI in the lipid metabolism of endocrine and other tissues. Endocr. Rev. 24: 357–387. 49. Rhainds, D. & L. Brissette. 2004. The role of scavenger receptor class B type I (SR-BI) in lipid trafficking. Defining the rules for lipid traders. Int. J. Biochem. Cell Biol. 36: 39– 77. 50. Goldstein, J.L., M.S. Brown, R.G. Anderson, et al. 1985. Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. Ann. Rev. Cell Biol. 1: 1–39. 51. Brundert, M., A. Ewert, J. Heeren, et al. 2005. Scavenger receptor class B type I mediates the selective uptake of highdensity lipoprotein associated cholesteryl ester by the liver in mice. Arterioscler. Thromb. Vasc. Biol. 25: 143–148. 52. Out, R., M. Hoekstra, J.A. Spijkers, et al. 2004. Scavenger receptor class B type I is solely responsible for the selective uptake of cholesteryl esters from HDL by the liver and the adrenals in mice. J. Lipid Res. 45: 2088–2095. 53. Nieland, T.J., M. Penman, L. Dori, et al. 2002. Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI. Proc. Natl. Acad. Sci. U.S.A. 99: 15422–15427. 54. Ji, Y., N. Wang, R. Ramakrishnan, et al. 1999. Hepatic scavenger receptor BI promotes rapid clearance of high density lipoprotein free cholesterol and its transport into bile. J. Biol. Chem. 274: 33398–33402. 55. Varban, M.L., F. Rinninger, N. Wang, et al. 1998. Targeted mutation reveals a central role for SR-BI in hepatic selective uptake of high density lipoprotein cholesterol. Proc. Natl. Acad. Sci. U.S.A. 95: 4619–4624. 56. VanEck, M., J. Twisk, M. Hoekstra, et al. 2003. Differential effects of scavenger receptor BI deficiency on lipid metabolism in cells of the arterial wall and in the liver. J. Biol. Chem. 26: 23699–23705.
54
57. Rigotti, A., B.L. Trigatti, M. Penman, et al. 1997. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc. Natl. Acad. Sci. U.S.A. 23: 12610–12615. 58. Trigatti, B., H. Rayburn, M. Vi˜nals, et al. 1999. Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology. Proc. Natl. Acad. Sci. U.S.A. 16: 9322–9327. 59. Yesilaltay, A., O. Kocher, R. Pal, et al. 2006. PDZK1 is required for maintaining hepatic scavenger receptor, class B, type I (SR-BI) steady state levels but not its surface localization or function. J. Biol. Chem. 281: 28975–28980. 60. Eyre, N.S., H.E. Drummer & M.R. Beard. 2010. The SRBI partner PDZK1 facilitates hepatitis C virus entry. PLoS Pathog. 6: 1–14. 61. Baranova, I., T. Vishnyakova, A. Bocharov, et al. 2002. Lipopolysaccharide down regulates both scavenger receptor B1 and ATP binding cassette transporter A1 in RAW cells. Infect. Immun. 70: 2995–3003. 62. Sch¨afer, G., R. Guler, G. Murray, et al. 2009. The role of scavenger receptor B1 in infection with Mycobacterium tuberculosis in a murine model. PLoS One 24; 4: e8448. 63. Dieudonn´e, A., D. Torres, S. Blanchard, et al. 2012. Scavenger receptors in human airway epithelial cells: role in response to double-stranded RNA. PLoS One 7: e41952. 64. Hybertson, B.M., J.A. Leff, C.J. Beehler, et al. 1995. Effect of vitamin E deficiency and supercritical fluid aerosolized vitamin E supplementation on interleukin-1-induced oxidative lung injury in rats. Free Radic. Biol. Med. 18: 537–542. 65. Romieu, I. 2005. Nutrition and lung health Int. J. Tuberc. Lung Dis. 9: 362–374. 66. Valacchi, G., V.T. Vasu, W. Yokohama, et al. 2007. Lung vitamin E transport processes are affected by both age and environmental oxidants in mice. Toxicol. Appl. Pharmacol. 2: 227–234. 67. Witt, W., I. Kolleck, H. Fechner, et al. 2000. Regulation by vitamin E of the scavenger receptor BI in rat liver and HepG2 cells. J. Lipid Res. 41: 2009–2016. 68. Sato, Y., Kondo, Y., Sumi, M., et al. 2013. Intracellular uptake mechanism of lutein in retinal pigment epithelial cells. J. Pharm. Pharm. Sci. 16: 494–501 69. Valacchi, G., C. Sticozzi, Y. Lim, et al. 2011. Scavenger receptor class B type I: a multifunctional receptor. Ann. N. Y. Acad. Sci. 1229: E1–E7. 70. Valacchi, G., P.A. Davis, E.M. Khan, et al. 2011. Cigarette smoke exposure causes changes in Scavenger Receptor B1 level and distribution in lung cells. Int. J. Biochem. Cell Biol 1: 1–16. 71. Park, J.W., S.W. Ryter & A.M. Choi. 2007. Functional significance of apoptosis in chronic obstructive pulmonary disease. COPD 4: 347–353. 72. Sylvester, P.W. 2007. Vitamin E and apoptosis. Vitam Horm. 76: 329–356. 73. Dempsey, L.A. 2014. Scavenger receptor B1 in lung immunity. Nat. Immunol. 16: 64.
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
Copyright of Annals of the New York Academy of Sciences is the property of WileyBlackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Cellular and Environmental Stressors in Biology and Medicine
Exploring the link between scavenger receptor B1 expression and chronic obstructive pulmonary disease pathogenesis Giuseppe Valacchi,1 Emanuela Maioli,2 Claudia Sticozzi,1 Franco Cervellati,1 Alessandra Pecorelli,3 Carlo Cervellati,4 and Joussef Hayek5 1 Department of Life Science and Biotechnologies, University of Ferrara, Ferrara, Italy. 2 Department Life Sciences, University of Siena, Siena, Italy. 3 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy. 4 Department of Biomedical and Specialist Surgical Sciences, Section of Medical Biochemistry, Molecular Biology and Genetics, University of Ferrara, Ferrara, Italy. 5 Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy
Address for correspondence: Giuseppe Valacchi, Ph.D., Department of Life Sciences and Biotechnologies, University of Ferrara, Via Borsari, 46, 44100 Ferrara, Italy. [email protected]
Chronic obstructive pulmonary disease (COPD) has been recognized as one of the major causes of morbidity and mortality in the United States; it is the third leading cause of deaths in the United States, with approximately 15 million Americans affected with COPD. Although exposure to cigarette smoke has been shown to be the main, if not the only, risk factor for COPD, the mechanisms underlying this association remain unclear. Most smokers do not develop COPD, suggesting that a combination of exposure and susceptibility (genetic background) is required. Several mechanisms contribute to the pathogenesis of COPD, such as influx of inflammatory cells into the lung, imbalance between proteolytic and antiproteolytic molecules, disruption of the balance between apoptosis and replenishment of structural cells in the lung, and disruption of oxidant/antioxidant balance. The scavenger receptor BI (SRB1) plays an important role in mediating the uptake of high-density lipoprotein (HDL)-derived cholesterol and cholesteryl ester in tissues. In addition to its role as the HDL receptor, SRB1 is also involved in pathogen recognition, identification of apoptotic cells, tissue antioxidant uptake (tocopherol and carotenoids), and lung surfactant composition, all factors involved in COPD pathogenesis. Therefore, it is possible that lung SRB1 levels are involved in the development of COPD. Keywords: 4-hydroxynonenal; scavenger receptor B1; protein adducts; oxidative stress; lung
Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a respiratory pathology that affects more than 16 million Americans (the third highest cause of death in the United States1–3 ). This chronic disease is characterized by an altered inflammatory response of the lungs to toxic particles (mostly cigarette smoke). The most typical consequence is chronic bronchitis/bronchiolitis and/or emphysema that lead to an almost irreversible airflow limitation.1 COPD pathogenesis A number of different pathogenic mechanisms seem to be involved in COPD development.1,4,5 First,
inhalation of toxic particles, particularly through cigarette smoke (CS), leads to the migration of inflammatory cells into the airways, and consequently to the onset of a chronic inflammatory state.6,7 Second, there is an augmentation of proteolytic activity, because of the derangement of the balance between proteolytic and antiproteolytic molecules, in the lungs of COPDaffected individuals.8–10 The direct effect of this alteration in proteolytic activity is deep pulmonary parenchyma damage, which inevitably leads to emphysema. Inflammation (release of proteases by macrophages and polimorphonucleates9,10 ) and genetic factors (␣-1 antitrypsin deficiency11,12 ) have
doi: 10.1111/nyas.12714 C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
47
SRB1 involvement in COPD
Valacchi et al.
been ascribed as the most probable causes of this proteolytic burden. Third, oxidative stress appears to be involved in the pathogenic mechanisms underlying COPD development. This pathophysiological condition is characterized by an imbalance between oxidant species, primarily reactive oxygen species (ROS), and antioxidant defense systems, in favor of the former.13–15 The main sources of ROS in COPD are CS and activated cells such as leukocytes and epithelial cells. The chemical insult by these free radicals can lead to cell dysfunction or cell death, with extensive injury to the pulmonary extracellular matrix. Furthermore, oxidative stress can impair the proteinase–antiproteinase balance through the activation and inactivation of proteolytic and antiproteolytic processes.16,17 Moreover, reactive species contribute to proinflammatory reactions. Indeed, it is well recognized that ROS can enhance the activity of the transcription factor nuclear factor-B (NF-B) and, as a direct consequence, promote the transcription of proinflammatory genes.15,18,19 Recent work suggests a fourth possible mechanism that may be involved in COPD pathogenesis: derangement of the balance between apoptosis and replenishment of structural cells in pulmonary tissues may induce lung damage in response to CS, leading to emphysema.20 Proof of increased levels of apoptosis in COPD patients has been frequently shown in the literature21–23 and has been linked to diminished alveolar surface area. Furthermore, because bacterial and/or viral infections contribute remarkably to the clinical progression of COPD, these infections represent important comorbidities in this disease. Indeed, under normal conditions, the healthy human lung is capable of maintaining sterility, despite repetitive exposure to microbial inoculate from micro-aspiration and inhalation. However, in the setting of COPD, the lung’s defense system seems to be disrupted as a result of exposure to irritants such as CS. This failure of the lung defense system results in two distinct infection cycles in COPD that could contribute to the progressive decline of organ function. The lungs of COPD patients become highly sensitive to repeated acute airway mucosal viral and bacterial infections, leading to episodes of increased inflammation and worsened symptoms. Thus, microbial colonization results in
48
chronic inflammation and lung destruction, leading to a “vicious circle.” Many processes, such as chronic inflammation, oxidative stress, apoptosis, and pathogenic infection, participate in the development of COPD, and the interaction of these processes contributes to the pathogenesis of the disease. Cigarette smoke and oxidative stress Exposure to CS is by far the most important risk factor for COPD pathogenesis.6 CS is a highly complex aerosol composed of more than 4700 chemicals and consists of a gas phase and a particulate phase. Mainstream smoke (the combination of inhaled and exhaled smoke after taking a puff of a lit cigarette) includes particulates suspended in a gaseous phase. It is widely recognized that CS contains high levels of pro-oxidants,24,25 with more than 1014 lowmolecular-weight carbon- and oxygen-centered radicals per puff present in gas-phase smoke.26,27 Sidestream smoke is the smoke that goes into the air directly from a burning cigarette and is the main component of second-hand smoke. The chemical constituents of sidestream smoke are different from those of directly inhaled (mainstream) CS; it was recently shown that inhaled sidestream CS is approximately four times more toxic per gram of total particulate matter (TPM) than mainstream CS. Furthermore, sidestream condensate, compared to mainstream, is about three times more toxic per gram and two to six times more tumorigenic per gram. The gas/vapor phase of sidestream smoke is responsible for most of the sensory irritation and respiratory tract epithelium damage.28 It has been clearly demonstrated that CS is noxious for human health, mostly because of the ROS present in tobacco smoke, as well as the oxidative damage to biological molecules, in particular lipids, induced by smoke exposure.29,30 In particular, it has been shown that ␣,-unsaturated aldehydes that are present in CS (such as acrolein and crotonaldehyde) or formed during lipid peroxidation (such as 4-hydroxy-2,3-nonenal (4HNE) and malondialdehyde (MDA))31,32 are key players involved in CS toxicity. Relevant to these considerations, the ability of these aldehydes to covalently adduct to cysteine, lysine, and histidine residues can lead to significant modification of the structure and function of many proteins involved in important biochemical
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
Valacchi et al.
pathways.33,34 Recent studies have shown that the formation of adducts is a mechanism by which enzyme function can be modified; for example, it has been shown that the formation of a Michael adduct with the cytoplasmic subunits of NADPH oxidase impairs its function in neutrophils.32 Similar effects have been shown also from our group for the redox-sensitive transcription factor NF-B.35,36 COPD as a multisystemic disease COPD is no longer regarded simply as a disease of the lungs and airways. There is growing awareness of the multisystemic nature of this disease. Research has shown increased levels of systemic inflammation and neurologic, psychiatric, skeletal muscle, and endocrine system dysfunction associated with COPD. One of the most recognized manifestations includes the presence of concomitant cardiovascular disease (CVD). CVD complicating COPD is a leading cause of death in the COPD population.37,38 The mechanisms for this association remain unclear and are not fully explained by tobacco exposure. Results from a large clinical trial showed that impaired lung function (forced expiratory volume in 1 s (FEV1 )) is an independent predictor of the probability of dying from a myocardial infarction,39 and FEV1 is also a clinical aspect found in COPD patients leading to CVD complications.40 A recent study reported that patients with severe COPD have a twofold greater risk of CVD.41 Low-grade systemic inflammation could be the driving factor underlying the observed interaction between
SRB1 involvement in COPD
atherosclerotic CVD and COPD. Indeed, converging evidence showed that chronic inflammation could have a role in the pathogenesis of atherosclerotic patients with COPD.42 Although the association between atherosclerosis and COPD is not fully understood, there are epidemiological data that suggest that patients with COPD should be screened for the presence of concomitant atherosclerosis and that atherosclerotic patients should be investigated for the contemporaneous presence of impaired FEV1 . In addition, recent papers have shown that COPD patients have higher levels of high-density lipoprotein (HDL) compared with healthy subjects. Although epidemiologic studies have shown that HDL particles are strongly associated with reduced cardiovascular risks, the effects of very high HDLs suggest effects beyond cholesterol transport. Indeed, multiple pleiotropic properties of HDLs are recognized, including roles as an atherogenic particles in certain settings. Recent studies have suggested that the relationship between HDLs and risk for CVD may be U-shaped rather than a linear curve, with very high levels of HDL conferring increasing rather than decreasing cardiovascular risk.43–45 Navab et al.44 described changes observed in inflammatory states in which HDL function becomes proinflammatory and may promote the atherosclerotic process. The chronic inflammation present in COPD may promote oxidation of HDL, which could explain the high CVD incidence observed, despite what would conventionally be interpreted as favorable lipid profiles.
Figure 1. SRB1 cholesterol uptake is mediated by a hydrophobic channel that allows the uptake of cholesterol esters into the cells.
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
49
SRB1 involvement in COPD
Valacchi et al.
Figure 2. SRB1 is also involved in tissue ␣-tocopherol uptake, which follows the cellular cholesterol uptake.
Scavenger receptor B1 At the end of the 1990s, Krieger’s group was able to identify an 82-kDa cell surface protein called scavenger receptor class B1 (SRB1), which was clearly involved in the binding of HDL and in promoting the selective uptake of HDL cholesterol via a hydrophobic channel (Fig. 1). Because of its high binding affinity to HDL,46,47 SRB1 is able to affect HDL metabolism.47–49 It has been shown that SRB1 mediates selective cholesterol (i.e., cholesteryl esters) uptake from the hydrophobic HDL cores47–49 owing to its ability to bind lipoproteins. The mechanism by which SRB1 is able to facilitate lipid uptake is different from that of low-density lipoprotein receptor (LDLR). In fact, although LDLR mediates LDLparticle endocytosis,50 SRB1 mediates the transfer of cholesteryl esters from the hydrophobic core of the HDL to the cells without internalizing the lipoprotein particle. Of note, some studies have suggested an LDLR-like uptake mediated by SRB1 in hepatocytes. In addition, the role of SRB1 in selective hepatic uptake of lipids from the HDL has been shown in knock-out (KO) and knock-in animal models.51–55 Furthermore, Srb1 KO mice are also a good model to study the pathogenesis of atherosclerosis.56–58 Krieger’s group showed 50
that Srb1 KO mice have dramatically increased plasma HDL and total cholesterol levels, with abnormally large HDL particles that can then develop in atherosclerotic vessel lesions.56–58 Links between SRB1 and COPD As mentioned earlier, COPD pathogenesis is characterized by several mechanisms (infections, apoptosis, oxidative stress), and SRB1 has been shown to be involved in all of these pathways. For instance, a role for SRB1 in bacteria recognition has been proposed by several groups. Yesilaltay et al. have elegantly demonstrated a role for SRB1 in the recognition of hepatitis C virus (HCV) by binding to HCV envelope glycoprotein E2;59 a decrease in SRB1 levels increased the susceptibility of cells to infection by HCV.60 This work was also supported by a more recent study where the data showed that LPS can downregulate SRB1 levels61 and that SRB1 is able to directly recognize the pathogens.62 Besides its role in bacterial interactions, it was suggested that SRB1 could also bind to viral dsRNA,63 which could underlie its putative role in COPD pathogenesis, as many respiratory viruses present in COPD patients are able to produce dsRNA. In addition, SRB1 has been demonstrated to be involved, although indirectly, in the cellular defense against oxidative stress, because of its ability to
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
Valacchi et al.
SRB1 involvement in COPD
Figure 3. Putative role of decreased SRB1 levels in COPD pathogenesis. Several mechanisms seem to play roles in COPD: redox imbalance, chronic inflammatory response, recurrent infections, and abnormal apoptotic events. Owing to its panel of pleiotropic actions, the receptor SRB1 could be a possible common denominator among these mechanisms. In lungs, the decline in SRB1 levels induced by cigarette smoke can contribute to reduced antioxidant defenses (tocopherol and carotenoids) and failure to recognize pathogens and to detect and clear apoptotic cells.
uptake lipophilic antioxidants, including vitamin E and carotenoids (Fig. 2). Indeed, Srb1 KO animals have 50% less ␣-tocopherol in tissues (ovary, testis, lung, and brain) compared with wild-type animals.48 Specifically, lungs from Srb1 KO animals had at least 60% less vitamin E than controls,48 which indicates its role in protecting lung tissue. In fact, several reports have shown that oxidative lung damage is enhanced in vitamin E–deficient models,64 making SRB1 a potential player involved in regulating tissue vitamin E levels and a possible therapeutic target for lung pathologies. For instance, it has been suggested that SRB1 can be modulated at the posttranscriptional level in animals fed with tocopherol-depleted chow.65 Moreover, several recent reports have shown a role for SRB1 in cellular carotenoid uptake using different experimental models. Von Litig et al. have shown the importance
of SRB1 in tissue carotenoid uptake in Drosophila.66 In support of this study, van Bennekum showed that SRB1 and CD36 (another scavenger receptor) are important for intestinal carotenoid uptake.67 More recently, the role of SRB1 in the uptake of carotenoids has been demonstrated in other tissues, such as the eyes. Indeed, recent work by Sato et al. showed that SRB1 can import lutein into retinal pigmented epithelial cells. These authors, by the use of small interfering RNA (siRNA) approaches, were able to show that SRB1 is responsible for more than 75% of cellular lutein uptake.68 These reports suggest that SRB1 is able to facilitate the uptake of lipophilic antioxidants into several cells/organs, suggesting that this receptor plays a role in the maintenance of cellular redox state. However, oxidative stress can affect SRB1 expression; indeed, lung SRB1 levels are modulated by
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
51
SRB1 involvement in COPD
Valacchi et al.
aging and by exogenous oxidative stressors, such as CS and ozone. Our group was able to demonstrate that adult animals exposed to environmental oxidants presented a unique vitamin E tissue profile:69 whereas plasma tocopherol increased after CS and ozone exposure, lung tocopherol decreased significantly, and this correlated with tissue SRB1 levels.70 Increased levels of oxidative stress induced increased lipid peroxidation, with the formation of reactive aldehydes (i.e., 4HNE) that are able to covalently bind to SRB1 and induce its degradation via the proteasome system.66 As such, the controversial benefit of vitamin E supplementation could depend on the tissues’ ability to uptake this lipophilic antioxidant, which is related to SRB1 expression levels.65 In addition, increased levels of apoptotic cells may be present in COPD lung tissues. The apoptotic process is of extreme importance in the damaged airway epithelium, as it plays a crucial role in reducing inflammation. An increasing number of studies have supported the presence of an apoptotic process in COPD patients,71 and this can be linked to the ability of CS to induce apoptosis in airway epithelial cells. Furthermore, there are recent papers suggesting that SRB1 has the capacity to recognize apoptotic cells. Indeed, treatment with Srb1 antisense oligonucleotides was able to impair the ability of lung epithelial cells to bind to apoptotic thymocytes. As such, it is possible to suggest a correlation between CS exposure, decreased SRB1 levels, altered apoptotic cell clearance, and COPD (Fig. 3). Regardless, the role of SRB1 is likely independent of vitamin E uptake, since many reports have demonstrated the proapoptotic effect of vitamin E.72 Conclusions Several processes contribute to COPD pathogenesis, such as CS inflammation, increased oxidative stress, altered apoptosis, and pathogen infections. The multifunctional receptor SRB173 plays key roles in all of the above-mentioned processes: regulation of lung antioxidant intracellular levels (tocopherol and carotenoids), recognition of bacteria and virus related ligands, and identification and clearance of apoptotic cells. In addition, because genetic factors seem to play roles in COPD pathogenesis, it is possible that the different levels of SRB1 expression are involved in the genetic predisposition toward COPD development. It should be mentioned that a large part of the work summarized in this review was 52
performed using either in vitro or animal models and that, at present, the role of SRB1 in COPD has not yet been fully investigated. However, the role of SRB1 in lung immunity was recently described in a review by Dempsey,73 suggesting a possible role for SRB1 in several lung pathologies. In addition, we have preliminary data that suggested altered glycosylation of SRB1 in COPD patients, with low levels of the completely glycosylated mature form of SRB1 and high levels of the partially glycosylated immature form in these COPD samples. These results suggest that not only oxidative stress could influence SRB1 posttranslational modification, as we have demonstrated by the formation of 4HNE– SRB1 adducts,69,70 but that inefficient glycosylation machinery could also affect its functionality. Because of the aforementioned peculiar characteristics of SRB1, it is possible that SRB1 plays a role in the development of COPD, if not its etiology, although further studies, mainly in humans, are needed to confirm this hypothesis. Acknowledgment We thank the “Fondazione Umberto Veronesi” for a C.S. Fellowship. Conflicts of interest The authors declare no conflicts of interest.
References 1. Mannino, D.M. & A.S. Buist. 2007. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 370: 765– 773. 2. Mini˜no, A.M., J. Xu & K.D. Kochanek. 2010. Preliminary data for 2008. Natl. Vital Stat. Rep. 59: 1–52. 3. Hoyert, D.L. & J.Q. Xu. 2012. Deaths: preliminary data for 2011. Natl. Vital Stat. Rep. 61: 1–65. 4. Chung, K.F. & I.M. Adcock. 2008. Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction. Eur. Respir. 31: 1334–1356. 5. MacNee, W. 2007. Pathogenesis of chronic obstructive pulmonary disease. Clin. Chest Med. 28: 479–513. 6. Yao, H & I. Rahman. 2009. Current concepts on the role of inflammation in COPD and lung cancer. Curr. Opin. Pharmacol. 9: 375–383. 7. O’Donnell, R., D. Breen, S. Wilson, et al. 2006. Inflammatory cells in the airways in COPD. Thorax 61: 448–454. 8. Segura-Valdez, L., A. Pardo, M. Gaxiola, et al. 2000. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 117: 684– 694.
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
Valacchi et al.
9. Hogg, J.C., F. Chu, S. Utokaparch, et al. 2004. The nature of small airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 50: 2645–2653. 10. Kranenburg, A.R., A. Willems-Widyastuti, W.J. Moori, et al. 2006. Enhanced bronchial expression of extracellular matrix proteins in chronic obstructive pulmonary disease. Am. J. Clin. Pathol. 126: 725–735. 11. Cavarra, E., B. Bartalesi, M. Lucattelli, et al. 2001. Effects of cigarette smoke in mice with different levels of ␣-1 proteinase inhibitor and sensitivity to oxidants. Am. J. Respir. Crit. Care Med. 164: 886–890. 12. Seifart, C. & A. Plagens. 2007. Genetics of chronic obstructive pulmonary disease. Int. J. Chron. Obst. Pulmon. Dis. 2: 541– 550. 13. Rahman, I., S.K. Biswas & A. Kode. 2006. Oxidant and antioxidant balance in the airways and airway diseases. Eur. J. Pharmacol. 533: 222–239. 14. Lawless, M.W., K.J. O’Byrne & S.G. Gray. 2009. Oxidative stress induced lung cancer and COPD: opportunities for epigenetic therapy. J. Cell Mol. Med. 13: 2800–2821. 15. Rahman I. & I.M. Adcock. 2006. Oxidative stress and redox regulation of lung inflammation in COPD. Eur. Respir. J. 28: 219–242. 16. Kinnula, V.L., K. Vuorinen, H. Ilumets, et al. 2007. Thiol proteins, redox modulation and parenchymal lung disease. Curr. Med. Chem. 14: 213–222. 17. Ning, W., Y. Dong, J. Sun, et al. 2007. Cigarette smoke stimulates matrix metalloproteinase-2 activity via EGR-1 in human lung fibroblasts. Am. J. Respir. Cell Mol. Biol. 36: 480–490. 18. Moodie, F.M., J.A. Marwick, C. Anderson, et al. 2004. Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-B activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J. 18: 1897–1899. 19. Rahman, I. & W. MacNee. 2000. Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches. Free Radic. Biol. Med. 28: 1405– 1420. 20. Park, J.W., S.W. Ryter & A.M. Choi. 2007. Functional significance of apoptosis in chronic obstructive pulmonary disease. COPD 4: 347–353. 21. Morissette, M.C., J. Parent & J. Milot. 2009. Alveolar epithelial and endothelial cell apoptosis in emphysema: What we know and what we need to know. Int. J. Chron. Obstruct. Pulmon Dis. 4: 19–31. 22. Imai, K., B.A. Mercer, L.L. Schulman, et al. 2005. Correlation of lung surface area to apoptosis and proliferation in human emphysema. Eur. Respir. J. 25: 250–258. 23. Yokohori, N., K. Aoshiba & A. Nagai. 2004. Increased levels of cell death and proliferation in alveolar wall cells in patients with pulmonary emphysema. Chest 125: 626–632. 24. Valavanidis, A., T. Vlachogianni & K. Fiotakis. 2009. Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles. Int. J. Environ. Res. Public Health 6: 445–462. 25. Pryor, W.A. & K. Stone. 1993. Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann. N. Y. Acad. Sci. 686: 12–27.
SRB1 involvement in COPD
26. Dube, M.F.R. & C.R. Green. 1982. Methods of collection of smoke for analytical purpose. Rev. Adv. Top Sci. 8: 42– 102. 27. Church, D.F. & W.A. Pryor. 1985. Free-radical chemistry of cigarette smoke and its toxicological implications. Environ. Health Perspect. 64: 111–126. 28. Schick, S. & S. Glantz. 2005. Philip Morris toxicological experiments with fresh sidestream smoke: more toxic than mainstream smoke. Tob. Control. 14: 396–404. 29. Dietrich, M., G. Block, N.L. Benowitz, et al. 2003. Vitamin C supplementation decreases oxidative stress biomarker f2isoprostanes in plasma of nonsmokers exposed to environmental tobacco smoke. Nutr. Cancer 45: 176–84. 30. Uchida, K., M. Shiraishi, Y. Naito, et al. 1999. Activation of stress signaling pathways by the end product of lipid peroxidation. 4-Hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J. Biol. Chem. 274: 2234– 2242. 31. Li, L. & A. Holian. 1998. Acrolein: a respiratory toxin that suppresses pulmonary host defense. Rev. Environ. Health. 13: 99–108. 32. Finkelstein, E.I., J. Ruben, C.W. Koot, et al. 2005. Regulation of constitutive neutrophil apoptosis by the alpha,betaunsaturated aldehydes acrolein and 4-hydroxynonenal. Am. J. Physiol. Lung Cell Mol. Physiol. 289: L1019– L1028. 33. Leonarduzzi, G., M.C. Arkan, H. Bas¸a˘ga, et al. 2000. Lipid oxidation products in cell signaling. Free Radic. Biol. Med. 28: 1370–1378 34. Sticozzi, C., G. Belmonte, A. Pecorelli, et al. 2012. Cigarette smoke affects keratinocytes SRB1 expression and localization via H2 O2 production and HNE protein adducts formation. PLoS One. 7: e33592. 35. Valacchi, G., E. Pagnin, A. Phung, et al. 2005. Inhibition of NFkappaB activation and IL-8 expression in human bronchial epithelial cells by acrolein. Antioxid. Redox Signal. 7: 25–31. 36. Sticozzi, C., A. Pecorelli, G. Belmonte, et al. 2010. Cigarette smoke affects ABCAl expression via liver X receptor nuclear translocation in human keratinocytes. Int. J. Mol. Sci. 11: 3375–3386. 37. Rifai, N., P.S., Bachorik & J.J. Albers. 1999. “Lipids, lipoproteins and apolipoproteins.” In Tietz Textbook of Clinical Chemistry, 3rd Ed. Burtis, C.A. & E.R. Ashwood, Eds.: 809. Philadelphia: W.B. Saunders Company. 38. Basili, S., P. Ferroni, M. Vieri, et al. 1999. Lipoprotein (a) serum levels in patients in affected by chronic obstructive pulmonary disease. Arteriosclerosis 147: 249–252 39. Anthonisen, N.R., M.A. Skeans, R.A. Wise, et al. 2005. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann. Intern. Med. 142: 233–239. 40. Calverley, P.M., J.A. Anderson, B. Celli, et al. 2007. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N. Engl. J. Med. 356: 775– 789. 41. Mannino, D.M., D. Thorn, A. Swensen, et al. 2008. Prevalence and outcomes of diabetes, hypertension, and cardiovascular disease in chronic obstructive pulmonary disease. Eur. Respir. J. 32: 962–969.
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
53
SRB1 involvement in COPD
Valacchi et al.
42. Agusti, A. & J.B. Soriano. 2008. COPD as a systemic disease. COPD 5: 133–138. 43. Kastelein, J.J., S.I. vanLeuven, L. Burgess, et al. 2007. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N. Engl. J. Med. 356: 1620–1630. 44. Navab, M., J.A. Berliner, G. Subbanagounder, et al. 2001. HDL and the inflammatory response induced by LDLderived oxidized phospholipids. Arterioscler. Thromb. Vasc. Biol. 21: 481–488. 45. vander Steeg, W.A., I. Holme, S.M. Boekholdt, et al. 2008. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. J. Am. Coll. Cardiol. 51: 634–642. 46. Krieger, M. 1999. Charting the fate of the “good cholesterol”: identification and characterization of the highdensity lipoprotein receptor SR-BI. Annu. Rev. Biochem. 68: 523– 558. 47. Acton, S., A. Rigotti, K.T. Landschulz, et al. 1996. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271: 518–520. 48. Rigotti, A., H.E. Miettinen & M. Krieger. 2003. The role of the high-density lipoprotein receptor SR-BI in the lipid metabolism of endocrine and other tissues. Endocr. Rev. 24: 357–387. 49. Rhainds, D. & L. Brissette. 2004. The role of scavenger receptor class B type I (SR-BI) in lipid trafficking. Defining the rules for lipid traders. Int. J. Biochem. Cell Biol. 36: 39– 77. 50. Goldstein, J.L., M.S. Brown, R.G. Anderson, et al. 1985. Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. Ann. Rev. Cell Biol. 1: 1–39. 51. Brundert, M., A. Ewert, J. Heeren, et al. 2005. Scavenger receptor class B type I mediates the selective uptake of highdensity lipoprotein associated cholesteryl ester by the liver in mice. Arterioscler. Thromb. Vasc. Biol. 25: 143–148. 52. Out, R., M. Hoekstra, J.A. Spijkers, et al. 2004. Scavenger receptor class B type I is solely responsible for the selective uptake of cholesteryl esters from HDL by the liver and the adrenals in mice. J. Lipid Res. 45: 2088–2095. 53. Nieland, T.J., M. Penman, L. Dori, et al. 2002. Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI. Proc. Natl. Acad. Sci. U.S.A. 99: 15422–15427. 54. Ji, Y., N. Wang, R. Ramakrishnan, et al. 1999. Hepatic scavenger receptor BI promotes rapid clearance of high density lipoprotein free cholesterol and its transport into bile. J. Biol. Chem. 274: 33398–33402. 55. Varban, M.L., F. Rinninger, N. Wang, et al. 1998. Targeted mutation reveals a central role for SR-BI in hepatic selective uptake of high density lipoprotein cholesterol. Proc. Natl. Acad. Sci. U.S.A. 95: 4619–4624. 56. VanEck, M., J. Twisk, M. Hoekstra, et al. 2003. Differential effects of scavenger receptor BI deficiency on lipid metabolism in cells of the arterial wall and in the liver. J. Biol. Chem. 26: 23699–23705.
54
57. Rigotti, A., B.L. Trigatti, M. Penman, et al. 1997. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc. Natl. Acad. Sci. U.S.A. 23: 12610–12615. 58. Trigatti, B., H. Rayburn, M. Vi˜nals, et al. 1999. Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology. Proc. Natl. Acad. Sci. U.S.A. 16: 9322–9327. 59. Yesilaltay, A., O. Kocher, R. Pal, et al. 2006. PDZK1 is required for maintaining hepatic scavenger receptor, class B, type I (SR-BI) steady state levels but not its surface localization or function. J. Biol. Chem. 281: 28975–28980. 60. Eyre, N.S., H.E. Drummer & M.R. Beard. 2010. The SRBI partner PDZK1 facilitates hepatitis C virus entry. PLoS Pathog. 6: 1–14. 61. Baranova, I., T. Vishnyakova, A. Bocharov, et al. 2002. Lipopolysaccharide down regulates both scavenger receptor B1 and ATP binding cassette transporter A1 in RAW cells. Infect. Immun. 70: 2995–3003. 62. Sch¨afer, G., R. Guler, G. Murray, et al. 2009. The role of scavenger receptor B1 in infection with Mycobacterium tuberculosis in a murine model. PLoS One 24; 4: e8448. 63. Dieudonn´e, A., D. Torres, S. Blanchard, et al. 2012. Scavenger receptors in human airway epithelial cells: role in response to double-stranded RNA. PLoS One 7: e41952. 64. Hybertson, B.M., J.A. Leff, C.J. Beehler, et al. 1995. Effect of vitamin E deficiency and supercritical fluid aerosolized vitamin E supplementation on interleukin-1-induced oxidative lung injury in rats. Free Radic. Biol. Med. 18: 537–542. 65. Romieu, I. 2005. Nutrition and lung health Int. J. Tuberc. Lung Dis. 9: 362–374. 66. Valacchi, G., V.T. Vasu, W. Yokohama, et al. 2007. Lung vitamin E transport processes are affected by both age and environmental oxidants in mice. Toxicol. Appl. Pharmacol. 2: 227–234. 67. Witt, W., I. Kolleck, H. Fechner, et al. 2000. Regulation by vitamin E of the scavenger receptor BI in rat liver and HepG2 cells. J. Lipid Res. 41: 2009–2016. 68. Sato, Y., Kondo, Y., Sumi, M., et al. 2013. Intracellular uptake mechanism of lutein in retinal pigment epithelial cells. J. Pharm. Pharm. Sci. 16: 494–501 69. Valacchi, G., C. Sticozzi, Y. Lim, et al. 2011. Scavenger receptor class B type I: a multifunctional receptor. Ann. N. Y. Acad. Sci. 1229: E1–E7. 70. Valacchi, G., P.A. Davis, E.M. Khan, et al. 2011. Cigarette smoke exposure causes changes in Scavenger Receptor B1 level and distribution in lung cells. Int. J. Biochem. Cell Biol 1: 1–16. 71. Park, J.W., S.W. Ryter & A.M. Choi. 2007. Functional significance of apoptosis in chronic obstructive pulmonary disease. COPD 4: 347–353. 72. Sylvester, P.W. 2007. Vitamin E and apoptosis. Vitam Horm. 76: 329–356. 73. Dempsey, L.A. 2014. Scavenger receptor B1 in lung immunity. Nat. Immunol. 16: 64.
C 2015 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1340 (2015) 47–54
Copyright of Annals of the New York Academy of Sciences is the property of WileyBlackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
