慢性氣喘(chronic asthma)是一種慢性呼吸道發炎疾病，患者在接觸到環境中的過敏原後出現呼吸道收縮、黏液分泌增加、免疫細胞大量浸潤，並發生呼吸困難、胸悶、咳嗽等症狀。泡沫狀巨噬細胞(foamy macrophage, foam cell)是巨噬細胞在吞噬修飾低密度脂蛋白後在細胞內形成脂肪滴的型態，在血管中泡沫狀巨噬細胞的堆積會導致血管壁增厚，增加心血管疾病發生的風險，但泡沫狀巨噬細胞在慢性氣喘發炎所扮演的角色仍未清楚。他汀類藥物(statin)是一種HMG-CoA還原酶抑製劑主要用於心血管疾病高風險患者，用來降低患者的膽固醇以降低心血管疾病病發的風險。許多研究顯示他汀類藥物可藉由抑制細胞訊息中間物生成以達到抑制發炎之效果。我們先前的研究顯示他汀類藥物可降低氣喘患者氣喘相關緊急就診或住院的風險，但是他汀類藥物是透過何種機制影響氣喘患者尚未明朗。因此本研究想了解他汀類藥物是否可藉由抑制泡沫狀巨噬細胞發炎以達到改善慢性氣喘的效果。
首先我們建立塵螨(Dermatophagoides pteronyssinus, Der p)誘導慢性氣喘的小鼠模式，並在此動物模式下給予他汀類藥物，評估肺部發炎及纖維化情形。實驗結果顯示慢性氣喘小鼠肺部有泡沫狀巨噬細胞堆積情形。在細胞實驗中，他汀類藥物可降低氧化低密度脂蛋白(oxidized low density lipoprotein, oxLDL)誘導泡沫狀巨噬細胞生成，且他汀類藥物可隨濃度梯度有效降低氧化低密度脂蛋白受體(SR-A1)表現量，但對於氧化低密度脂蛋白受體(CD36)、膽固醇排出蛋白(ABCG1)、細胞傳訊蛋白(STAT3, p38 MAPK)磷酸化的表現量則無明顯差異。在預防性刺激細胞實驗中，預先給予他汀類藥物具有降低TNF-α分泌的現象。然而，他汀類藥物治療的慢性氣喘小鼠組別的肺功能指數、氣管發炎現象、泡沫狀巨噬細胞堆積情形與慢性氣喘小鼠組別並沒有明顯改善。綜合以上結果，他汀類藥物可能通過下調SR-A1表現量來減少泡沫狀巨噬細胞的形成，未來我們可以透過將SR-A1表現抑制的相關實驗以證實我們的推論。在未來可以透過更多的實驗來了解泡沫狀巨噬細胞在慢性氣喘中扮演著怎樣的角色以及探討他汀類藥物是否可藉由改善泡沫狀巨噬細胞以達到改善慢性氣喘的效果以及可能的作用機制。

Chronic asthma is a chronic respiratory inflammation disease. Patients with chronic asthma may have airway hyperresponsiveness, mucus secretion, immune cells invasion in the lungs. Foamy macrophage is a type of macrophage that stored lipid droplets in cell after phagocytosis of modified low density lipoproteins (mLDL). In addition, foamy macrophages had high expression of inflammatory and fibrotic cytokines compared to normal macrophages. Previous studies indicated that foamy macrophages played the key role of atherosclerosis and pulmonary fibrosis. However, the role of foamy macrophages in chronic asthma is not yet clear. Several studies have suggested that statins, HMG-CoA reductase inhibitors, has multiple functions, such as inhibition of inflammation and regulation of cholesterol production. Our previously study showed that statins decreased the risk of asthma-related ED visits and/or hospitalizations in patients with asthma. The detail mechanisms of statins in chronic asthma are not yet clear. Therefore, we will investigate the role of foamy macrophages in chronic asthma and examine whether statins improve chronic asthma by decreasing formation of foamy macrophages. First, we established chronic asthma mouse model and found a lot of foamy macrophages were accumulated in the lungs of chronic asthma mice. Next, we examined whether atorvastatin decreased the number of foamy macrophages. The in vitro results showed that atorvastatin reduced the formation of foamy macrophages and the expression of oxLDL receptor (macrophage scavenger receptor 1, SR-A1). However, the expression of oxLDL receptor (cluster of differentiation 36, CD36), cholesterol excretion protein (ATP-binding cassette sub-family G member 1, ABCG1), and cellular signaling protein phosphorylation (STAT3, p38 MAPK) did not showed significant differences between atorvastatin-treated and control group. We further investigated the effects of atorvastatin in chronic asthma mouse model. However, atorvastatin-treated chronic asthma mice did not significantly improve lung function, inflammation, and the number of foamy macrophages in the lungs compared to chronic asthma mice. Several studies had shown that statins do work on asthma. As our study shows that statins decreased the formation of foamy macrophages might through down regulated SR-A1 expression. In this study, the relationship between chronic asthma, statins and foamy macrophages is still not clear yet. In the future, we should do further experiments to evaluate the relation between chronic asthma, statins and foamy macrophages.

1. Hamida H and Lambrecht BN. Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nature reviews Immunology. 2008 Mar;8(3):193-204.
2. Parya A, Uduak G, Ramana P. A review of inflammatory mechanism in airway diseases. Inflammation Research. 2019 68:59–74.
3. Franz P, Lisa GG, Clare ML. Airway macrophages as the guardians of tissue repair in the lung. Immunology & Cell Biology. 2019; 97: 246–257.
4. K.F. Chung, I.M. Adcock. Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction. Eur Respir J 2008; 31: 1334–1356
5. Fricker M, Gibson PG. Macrophage dysfunction in the pathogenesis and treatment of asthma. Eur Respir J 2017; 50: 1700196
6. Arjun S, Danh CD, Shruthi K, et al. Macrophage Polarization and Allergic Asthma. Transl Res. 2018 Jan; 191: 1–14.
7. S.J. Jeong, M.N. Lee, G.T. Oh. The Role of Macrophage Lipophagy in Reverse Cholesterol Transport. Endocrinol Metab (Seoul). 2017 Mar; 32(1): 41–46.
8. Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis, a dynamic balance. Nat Rev Immunol. 2013 Oct;13(10):709-21.
9. Yu XH, Fu YC, Zhang DW, et al. Foam cells in atherosclerosis. Clin Chim Acta. 2013 Sep 23;424:245-52.
10. Thomas AC, Eijgelaar WJ, Daemen MJ, Newby AC. Foam Cell Formation In Vivo Converts Macrophages to a Pro-Fibrotic Phenotype. PLoS One. 2015 Jul 21;10(7):e0128163.
11. Fu Y, Luo N, Lopes-Virella MF. Oxidized LDL induces the expression of ALBP/aP2 mRNA and protein in human THP-1 macrophages. J Lipid Res. 2000 Dec;41(12):2017-23.
12. Yun SB, Jee HL, Soo HC, et al. Macrophages generate reactive oxygen species in response to minimally oxidized LDL: TLR4- and Syk-dependent activation of Nox2. Circ Res. 2009 Jan 30; 104(2): 210–218.
13. Davignon J. Beneficial Cardiovascular Pleiotropic Effects of Statins Circulation. 2004 Jun 15;109(23 Suppl 1):III39-43.
14. James KL. Effects of Statins on 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibition Beyond Low-Density Lipoprotein Cholesterol. Am J Cardiol. 2005 Sep 5; 96(5A): 24F–33F.
15. Sakoda K, Yamamoto M, Negishi Y, et al. Simvastatin Decreases IL-6 and IL-8 Production in Epithelial Cells. J Dent Res. 2006 Jun;85(6):520-3.
16. Yang J, Huang C, Yang J, et al. Statins attenuate high mobility group box-1 protein induced vascular endothelial activation: a key role for TLR4/NF-κB signaling pathway. Mol Cell Biochem. 2010 Dec;345(1-2):189-95.
17. Wang W, Le W, Ahuja R, et al. Inhibition of inflammatory mediators: role of statins in airway inflammation. Otolaryngol Head Neck Surg. 2011 Jun;144(6):982-7.
18. Iwata A, Shirai R, Ishii H, et al. Inhibitory effect of statins on inflammatory cytokine production from human bronchial epithelial cells. Clin Exp Immunol. 2012 May;168(2):234-40.
19. Yang SS, Li R, Qu X, et al. Atorvastatin decreases Toll-like receptor 4 expression and downstream signaling in human monocytic leukemia cells. Cell Immunol. 2012 Sep;279(1):96-102.
20. Kong F, Ye B, Lin L, et al. Atorvastatin suppresses NLRP3 inflammasome activation via TLR4/MyD88/NF-kB signaling in PMA-stimulated THP-1 monocytes. Biomed Pharmacother. 2016 Aug;82:167-72.
21. Lei ZB, Zhang Z, Jing Q, et al. OxLDL upregulates CXCR2 expression in monocytes via scavenger receptors and activation of p38 mitogen-activated protein kinase. Cardiovasc Res. 2002 Feb 1;53(2):524-32.
22. Senokuchi T, Matsumura T, Sakai M, et al. Statins Suppress Oxidized Low Density Lipoprotein-induced Macrophage Proliferation by Inactivation of the Small G Protein-p38 MAPK Pathway. J Biol Chem. 2005 Feb 25;280(8):6627-33.
23. Turner NA, Mughal RS, Warburton P, et al. Mechanism of TNFα-induced IL-1α, IL-1β and IL-6 expression in human cardiac fibroblasts: Effects of statins and thiazolidinediones. Cardiovasc Res. 2007 Oct 1;76(1):81-90.
24. Wang SD, Lin LJ, Chen CL, et al. Xiao-Qing-Long-Tang attenuates allergic airway inflammation and remodeling in repetitive Dermatogoides pteronyssinus challenged chronic asthmatic mice model. J Ethnopharmacol. 2012 Jul 13;142(2):531-8.
25. Huang CC, Chan WL, Chen YC, et al. Statin use in patients with asthma: a nationwide population-based study. Eur J Clin Invest. 2011 May;41(5):507-12.
26. Thomson NC, Charron CE, Chaudhuri R, et al. Atorvastatin in combination with inhaled beclometasone modulates inflammatory sputum mediators in smokers with asthma. Pulm Pharmacol Ther. 2015 Apr;31:1-8.
27. Lokhandwala T, West-Strum D, Banahan BF, et al. Do statins improve outcomes in patients with asthma on inhaled corticosteroid therapy? A retrospective cohort analysis. BMJ Open. 2012 May 22;2(3). pii: e001279.
28. Hothersall EJ, Chaudhuri R, McSharry C, et al. Effects of atorvastatin added to inhaled corticosteroids on lung function and sputum cell counts in atopic asthma. Thorax. 2008 Dec;63(12):1070-5.
29. Menzies D, Nair A, Meldrum KT, et al. Simvastatin does not exhibit therapeutic anti-inflammatory effects in asthma. J Allergy Clin Immunol. 2007 Feb;119(2):328-35.
30. Abdollatif Moini, Ghasem Azimi, and Abdolhay Farivar. Evaluation of Atorvastatin for the Treatment of Patients With Asthma: A Double-Blind Randomized Clinical Trial. Allergy Asthma Immunol Res. 2012 Sep; 4(5): 290–294.
31. Ostroukhova M, Kouides RW, Friedman E. The effect of statin therapy on allergic patients with asthma. Ann Allergy Asthma Immunol. 2009 Dec;103(6):463-8.
32. Naing C, Ni H. Statins for asthma. Cochrane Database of Systematic Reviews 2019, Issue 2. Art. No.: CD013268.
33. Kim DY, Ryu SY, Lim JE, et al. Anti-inflammatory mechanism of simvastatin in mouse allergic asthma model. Eur J Pharmacol. 2007 Feb 14;557(1):76-86.
34. Liu MW, Liu R, Wu HY, et al. Atorvastatin has a protective effect in a mouse model of bronchial asthma through regulating tissue transglutaminase and triggering receptor expressed on myeloid cells-1 expression. Exp Ther Med. 2017 Aug; 14(2): 917–930.
35. Ahmad T, Mabalirajan U, Sharma A, et al. Simvastatin improves epithelial dysfunction and airway hyperresponsiveness: from asymmetric dimethyl-arginine to asthma. Am J Respir Cell Mol Biol. 2011 Apr;44(4):531-9.
36. So JY, Dhungana S, Beros JJ, Criner GJ. Statins in the treatment of COPD and asthma — where do we stand? Curr Opin Pharmacol. 2018 Jun;40:26-33.
37. Rios FJ, Koga MM, Ferracini M, Jancar S. Co-stimulation of PAFR and CD36 is required for oxLDL-induced human macrophages activation. PLoS One. 2012;7(5):e36632.
38. Fu H, Tang YY, Ouyang XP, et al. Interleukin-27 inhibits foam cell formation by promoting macrophage ABCA1 expression through JAK2/STAT3 pathway. Biochem Biophys Res Commun. 2014 Oct 3;452(4):881-7.
39. TG Redgrave, DCK Roberts, CE West. Separation of Plasma Lipoproteins by Density-Gradient Ultracentrifugation. Analytical Biochemistry 65, 42-49 (1975)
40. Lopes-Virella MF, Koskinen S, Mironova M, et al. The preparation of copper-oxidized LDL for the measurement of oxidized LDL antibodies by EIA. Atherosclerosis. 2000 Sep;152(1):107-15.
41. Hiraiwa K, Miller S, Ngan DA, et al. Statins reduce the burden of ambient particulate matter and inflammatory cells within the lung tissues of smokers with and without COPD. Eur Respir J. 2017 Jan 3;49(1). pii: 1601689.
42. Pinho-Ribeiro V, Melo AC, Kennedy-Feitosa E, et al. Atorvastatin and Simvastatin Promoted Mouse Lung Repair After Cigarette Smoke-Induced Emphysema. Inflammation. 2017 Jun;40(3):965-979.
43. Youssef S, Stüve O, Patarroyo JC, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002 Nov 7;420(6911):78-84.
44. Yuan C, Zhou L, Cheng J, et al. Statins as potential therapeutic drug for asthma? Respir Res. 2012 Nov 24;13:108.
45. Wang JY, Yao TC, Tsai YT, et al. Increased Dose and Duration of Statin Use Is Associated with Decreased Asthma-Related Emergency Department Visits and Hospitalizations. J Allergy Clin Immunol Pract. 2018 Sep - Oct;6(5):1588-1595.e1.