Вирусная инфекция и липополисахарид: патологическая ось «легкие – суставы» как потенциальная причина остеонекроза

В статье анализируется влияние вирусных инфекций, таких как SARS-CoV-2, и липополисахарида (LPS), компонента клеточной стенки грамотрицательных бактерий, на развитие остеонекроза через патологическую ось «легкие – суставы». Вирусная инфекция вызывает повреждение клеток легких и сосудистого эндотелия, что приводит к воспалительным и коагуляционным нарушениям, увеличивающим риск ишемии костной ткани. LPS, взаимодействуя с рецепторами TLR4, усиливает воспалительный ответ и нарушает кровоснабжение костей, стимулируя резорбцию и препятствуя костеобразованию. Кроме того, в статье подчеркивается роль дисбиоза легких, обусловленного вирусной инфекцией, который усиливает воспаление и повышает проницаемость барьеров для эндотоксинов. Поиск информации проводился по ключевым словам: «остеонекроз и липополисахарид», «вирус COVID-19 и липополисахарид-связывающий белок», «виремия и остеонекроз», «микрофлора легких и ЛПС» в зарубежных и отечественных наукометрических базах, таких как eLIBRARY и PubMed. Представленные данные позволяют утверждать, что сочетание дисбаланса «липополисахарид-связывающих систем», нарушенного легочного барьера, вирусной агрессии и LPS является важным отягощающим провоспалительным фактором. Это сочетание формирует предрасположенность или полноценный остеонекроз, что делает поиск механизмов влияния на эти состояния, как по отдельности, так и в комбинации, перспективным научным и клиническим направлением. В данном исследовании акцентируется внимание на многообразии механизмов, через которые вирусные инфекции и бактериальные липополисахариды могут влиять на костную ткань. Исследования показывают, что воздействие на эти механизмы может открыть новые пути для разработки терапевтических стратегий. Также рассматриваются перспективы использования целевых терапий для смягчения негативных последствий этих взаимодействий. Эти данные подчеркивают важность комплексного подхода в изучении и лечении остеонекроза, учитывающего как инфекционные, так и воспалительные компоненты процесса.

1. Белоглазов В.А., Яцков И.А., Кумельский Е.Д., Половинкина В.В. Метаболическая эндотоксинемия: возможные причины и последствия // Ожирение и метаболизм. - 2021. - Т. 18, №3. С. 320-326 DOI:10.14341/omet12750

2. Панин М.А., Петросян А.С., Хаджихараламбус К.Х., Бойко А.В. Остеонекроз головки бедренной кости после COVID-19: серия клинических наблюдений // Травматология и ортопедия России. - 2022. - Т. 28. - №1. - C. 110-117. doi: 10.17816/2311-2905-1687

3. Покусаева Д.П., Аниховская И.А., Коробкова Л.А. и др. Прогностическая значимость показателей системной эндотоксинемии в атерогенезе // Физиология человека. — 2019. — Т. 45. — №5. — С. 543-551. https://doi.org/10.1134/S0131164619050138

4. Abeles M, Urman JD, Rothfield NF. Aseptic necrosis of bone in systemic lupus erythematosus. Relationship to corticosteroid therapy. Arch Intern Med, 1978, vol. 138, no. 5: pp. 750-754. doi:10.1001/archinte.1978.03630290052018

5. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. The New England Journal of Medicine. 2020, vol. 383, no. 2, pp. 120-128. https://doi.org/10.1056/NEJMoa2015432.

6. Bar-Shavit Z. Taking a toll on the bones: regulation of bone metabolism by innate immune regulators. Autoimmunity. 2008, vol. 41 no. 3, pp. 195-203. doi: 10.1080/08916930701694469

7. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014, vol. 157 no. 1, pp. 121-41. DOI: 10.1016/j.cell.2014.03.011

8. Beutler B, Rietschel ET. Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol. 2003, vol. 3, no. 2, pp. 169-176. DOI: 10.1038/nri1004

9. Bhattacharya J, Westphalen K. Macrophage-epithelial interactions in pulmonary alveoli. Semin Immunopathol. 2016, vol. 38, no. 4, pp. 461-469 DOI: 10.1007/s00281-016-0569-x

10. Bradley BT, Maioli H, Johnston R, Chaudhry I, Fink SL, Xu H, Najafian B, Deutsch G, Lacy JM, Williams T, Yarid N, Marshall DA. Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series. Lancet. 2020, vol 396, Issue 10247, pp. 320-332. DOI: 10.1016/S0140-6736(20)31305-2

11. Beutler B. Tlr4: central component of the sole mammalian LPS sensor. Curr Opin Immunol. 2000, vol. 12, no. 1, pp. 20-26 DOI: 10.1016/s0952-7915(99)00046-1

12. Chang J, Wang Z, Tang E, Fan Z, McCauley L, Franceschi R, Guan K, Krebsbach PH, Wang CY. Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nat Med. 2009, vol. 15, no. 6, pp. 682-689. doi: 10.1038/nm.1954.

13. Charlson ES, Bittinger K, Haas AR, Fitzgerald AS, Frank I, Yadav A, Bushman FD, Collman RG. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med. 2011, vol. 184, no. 8, pp. 957-963. DOI: 10.1164/rccm.201104-0655OC

14. Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol. 2012, vol. 8, no. 3, pp. 133-43. DOI: 10.1038/nrrheum.2012.1

15. Condon TV, Sawyer RT, Fenton MJ, Riches DWH. Lung Dendritic Cells at the Innate-Adaptive Immune Interface. Journal of Leukocyte Biology. 2011 vol. 90, no. 5, pp. 883–895. doi: 10.1189/jlb.0311134

16. Denker BM, Nigam SK. Molecular structure and assembly of the tight junction. Am J Physiol. 1998, vol. 274, no.1, pp. 1-9. https://doi.org/10.1152/ajprenal.1998.274.1.F1

17. Dickson RP, Erb-Downward JR, Freeman CM, McCloskey L, Falkowski NR, Huffnagle GB, Curtis JL. Bacterial Topography of the Healthy Human Lower Respiratory Tract. mBio. 2017, vol. 8, no. 1, pp. 1-12 doi: 10.1128/mBio.02287-16.

18. Dickson RP, Erb-Downward JR, Falkowski NR, Hunter EM, Ashley SL, Huffnagle GB. The Lung Microbiota of Healthy Mice Are Highly Variable, Cluster by Environment, and Reflect Variation in Baseline Lung Innate Immunity. Am J Respir Crit Care Med. 2018, vol. 198, no. 4, pp. 497-508. doi: 10.1164/rccm.201711-2180OC

19. Disser NP, De Micheli AJ, Schonk MM, Konnaris MA, Piacentini AN, Edon DL, Toresdahl BG, Rodeo SA, Casey EK, Mendias CL. Musculoskeletal Consequences of COVID-19. J Bone Joint Surg Am. 2020, vol. 102, no. 14, pp. 1197-1204. doi: 10.2106/JBJS.20.00847.

20. Feldman GJ, Mullin JM, Ryan MP. Occludin: structure, function and regulation. Adv Drug Deliv Rev. 2005, vol. 57, no. 6, pp. 883-917. DOI: 10.1016/j.addr.2005.01.009

21. Flynn AN, Itani OA, Moninger TO, Welsh MJ. Acute regulation of tight junction ion selectivity in human airway epithelia. Proc Natl Acad Sci U S A. 2009, vol. 106, no. 9, pp. 3591-3596. doi: 10.1073/pnas.0813393106

22. Fong EL, Chan CK, Goodman SB. Stem cell homing in musculoskeletal injury. Biomaterials. 2011, vol. 32, no. 2, pp. 395-409. DOI: 10.1016/j.biomaterials.2010.08.101

23. Ghosh SS, Wang J, Yannie PJ, Ghosh S. Intestinal Barrier Dysfunction, LPS Translocation, and Disease Development. J Endocr Soc. 2020, vol. 4, no. 2, pp. 1-15 DOI: 10.1210/jendso/bvz039

24. Gollwitzer ES, Saglani S, Trompette A, Yadava K, Sherburn R, McCoy KD, Nicod LP, Lloyd CM, Marsland BJ. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat Med. 2014, vol. 20, no. 6, pp.642-647. DOI: 10.1038/nm.3568

25. Goodman SB, Pajarinen J, Yao Z, Lin T. Inflammation and Bone Repair: From Particle Disease to Tissue Regeneration. Front Bioeng Biotechnol. 2019, vol. 7, pp. 230. DOI: 10.3389/fbioe.2019.00230

26. Goodman SB, Maruyama M. Inflammation, Bone Healing and Osteonecrosis: From Bedside to Bench. J Inflamm Res. 2020, vol. 13, pp. 913-923. DOI: 10.2147/JIR.S281941

27. Guillot L, Nathan N, Tabary O, Thouvenin G, Le Rouzic P, Corvol H, Amselem S, Clement A. Alveolar epithelial cells: master regulators of lung homeostasis. Int J Biochem Cell Biol. 2013, vol. 45, no. 11, pp. 2568-2573. DOI: 10.1016/j.biocel.2013.08.009

28. Günther J, Seyfert HM. The First Line of Defence: Insights Into Mechanisms and Relevance of Phagocytosis in Epithelial Cells. Semin Immunopathol. 2018, vol. 40, no. 6, pp. 555–565. doi: 10.1007/s00281-018-0701-1

29. Han H, Yang L, Liu R, Liu F, Wu KL, Li J, Liu XH, Zhu CL. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med. 2020, vol. 58, no. 7, pp. 1116-1120. DOI: 10.1515/cclm-2020-0188

30. Herbst T, Sichelstiel A, Schär C, Yadava K, Bürki K, Cahenzli J, McCoy K, Marsland BJ, Harris NL. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am J Respir Crit Care Med. 2011, vol. 184, no. 2, pp. 198-205. DOI: 10.1164/rccm.201010-1574OC

31. Hippenstiel S, Opitz B, Schmeck B, Suttorp N. Lung epithelium as a sentinel and effector system in pneumonia--molecular mechanisms of pathogen recognition and signal transduction. Respir Res. 2006, vol. 7, no, 1, pp. 97. DOI: 10.1186/1465-9921-7-97

32. Holt PG, Strickland DH, Wikström ME, Jahnsen FL. Regulation of immunological homeostasis in the respiratory tract. Nat Rev Immunol. 2008, vol. 8, no. 2, pp. 142-152. DOI: 10.1038/nri2236

33. Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012, vol. 336 no. 6086, pp. 1268-1273. DOI: 10.1126/science.1223490

34. Horowitz MC, Coleman DL, Flood PM, Kupper TS, Jilka RL. Parathyroid hormone and lipopolysaccharide induce murine osteoblast-like cells to secrete a cytokine indistinguishable from granulocyte-macrophage colony-stimulating factor. J Clin Invest. 1989, vol. 83, no. 1,pp. 149-157. doi: 10.1172/JCI113852

35. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020, vol. 395, no. 10223, pp. 497-506. DOI: 10.1016/S0140-6736(20)30183-5

36. Inada M, Matsumoto C, Uematsu S, Akira S, Miyaura C. Membrane-bound prostaglandin E synthase-1-mediated prostaglandin E2 production by osteoblast plays a critical role in lipopolysaccharide-induced bone loss associated with inflammation. J Immunol. 2006, vol. 177, no. 3, pp. 1879-1885. DOI: 10.4049/jimmunol.177.3.1879

37. Itoh K, Udagawa N, Kobayashi K, Suda K, Li X, Takami M, Okahashi N, Nishihara T, Takahashi N. Lipopolysaccharide promotes the survival of osteoclasts via Toll-like receptor 4, but cytokine production of osteoclasts in response to lipopolysaccharide is different from that of macrophages. J Immunol. 2003, vol. 170, no. 7, pp. 3688-3695. DOI:10.4049/jimmunol.170.7.3688

38. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, Tanoue T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K, Littman DR. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009, vol. 139, no. 3, pp. 485-498. DOI: 10.1016/j.cell.2009.09.033

39. Johnson ER, Matthay MA. Acute lung injury: epidemiology, pathogenesis, and treatment. J Aerosol Med Pulm Drug Deliv. 2010, vol. 23, no. 4, pp. 243-252. DOI: 10.1089/jamp.2009.0775

40. Katagiri T, Takahashi N. Regulatory mechanisms of osteoblast and osteoclast differentiation. Oral Dis. 2002, vol. 8, no. 3, pp. 147-159. DOI: 10.1034/j.1601-0825.2002.01829.x

41. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011, vol. 34, no. 5, pp. 637-650. DOI: 10.1016/j.immuni.2011.05.006

42. Kong, Q.; Six, D.A.; Liu, Q.; Gu, L.; Wang, S.; Alamuri, P.; Raetz, C.R.H.; Curtiss, R., III. Phosphate groups of lipid A are essential for salmonella enterica serovar typhimurium virulence and affect innate and adaptive immunity. Infect. Immun. 2012, vol. 80, no. 9, pp. 3215–3224 https://doi.org/10.1128/iai.00123-12

43. Kong Q, Six DA, Roland KL, Liu Q, Gu L, Reynolds CM, Wang X, Raetz CR, Curtiss R 3rd. Salmonella synthesizing 1-dephosphorylated [corrected] lipopolysaccharide exhibits low endotoxic activity while retaining its immunogenicity. J Immunol. 2011, vol. 187, no. 1, pp. 412-423. doi: 10.4049/jimmunol.1100339

44. Laskin DL, Sunil VR, Gardner CR, Laskin JD. Macrophages and tissue injury: agents of defense or destruction? Annu Rev Pharmacol Toxicol. 2011, vol. 51, pp. 267-288 DOI:10.1146/annurev.pharmtox.010909.105812

45. Li N, Geng C, Hou S, Fan H, Gong Y. Damage-Associated Molecular Patterns and Their Signaling Pathways in Primary Blast Lung Injury: New Research Progress and Future Directions. Int J Mol Sci. 2020, vol. 21, no. 17, pp. 6303. DOI: 10.3390/ijms21176303

46. Lin T, Pajarinen J, Nabeshima A, Lu L, Nathan K, Jämsen E, Yao Z, Goodman SB. Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis. Stem Cell Res Ther. 2017, vol. 8, no. 1, pp. 277. DOI: 10.1186/s13287-017-0730-z

47. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004, vol. 25, no. 12, pp. 677-686. DOI: 10.1016/j.it.2004.09.015

48. Maruyama M, Rhee C, Utsunomiya T, Zhang N, Ueno M, Yao Z, Goodman SB. Modulation of the Inflammatory Response and Bone Healing. Front Endocrinol (Lausanne). 2020, vol. 11, pp. 386. DOI: 10.3389/fendo.2020.00386

49. Mont MA, Jones LC, Hungerford DS. Nontraumatic osteonecrosis of the femoral head: ten years later. J Bone Joint Surg Am. 2006, vol. 88 no. 5, pp. 1117-1132. DOI: 10.2106/JBJS.E.01041

50. Moreira AP, Texeira TF, Ferreira AB, Peluzio Mdo C, Alfenas Rde C. Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia. Br J Nutr. 2012, vol. 108, no. 5, pp. 801-809. DOI: 10.1017/S0007114512001213

51. Goro Motomura, Takuaki Yamamoto, Keita Miyanishi, Akihisa Yamashita, Katsuo Sueishi, Yukihide Iwamoto. Bone marrow fat-cell enlargement in early steroid-induced osteonecrosis—a histomorphometric study of autopsy cases. Pathology - Research and Practice. 2005, vol. 200, no. 11-12, pp. 807-811 https://doi.org/10.1016/j.prp.2004.10.003.

52. Nakamura H, Fukusaki Y, Yoshimura A, Shiraishi C, Kishimoto M, Kaneko T, Hara Y. Lack of Toll-like receptor 4 decreases lipopolysaccharide-induced bone resorption in C3H/HeJ mice in vivo. Oral Microbiol Immunol. 2008, vol. 23, no. 3, pp. 190-195. DOI: 10.1111/j.1399-302X.2007.00410.x

53. Nicod LP. Lung Defences: An Overview. Eur Respir Rev . 2005, vol. 14, no. 95, pp. 45–50. https://doi.org/10.1183/09059180.05.00009501

54. Pajarinen J, Lin T, Gibon E, Kohno Y, Maruyama M, Nathan K, Lu L, Yao Z, Goodman SB. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials. 2019, vol. 196, pp. 80-89 DOI: 10.1016/j.biomaterials.2017.12.025

55. Phipps MC, Huang Y, Yamaguchi R, Kamiya N, Adapala NS, Tang L, Kim HK. In vivo monitoring of activated macrophages and neutrophils in response to ischemic osteonecrosis in a mouse model. J Orthop Res. 2016, vol. 34, no. 2, pp. 307-313. DOI: 10.1002/jor.22952

56. Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002, vol. 71, pp. 635-700. DOI: 10.1146/annurev.biochem.71.110601.135414

57. Ren L, Zhang R, Rao J, Xiao Y, Zhang Z, Yang B, Cao D, Zhong H, Ning P, Shang Y, Li M, Gao Z, Wang J. Transcriptionally Active Lung Microbiome and Its Association with Bacterial Biomass and Host Inflammatory Status. 2018, vol. 3, no. 5. DOI: 10.1128/mSystems.00199-18

58. Rezaee F, Georas SN. Breaking barriers. New insights into airway epithelial barrier function in health and disease. Am J Respir Cell Mol Biol. 2014, vol. 50, no. 5, pp. 857-869. doi: 10.1165/rcmb.2013-0541RT

59. Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, Ulmer AJ, Zähringer U, Seydel U, Di Padova F, et al. Bacterial endotoxin: molecular relationships of structure to activity and function. FASEB J. 1994, vol. 8, no. 2, pp. 217-225. DOI: 10.1096/fasebj.8.2.8119492

60. Roth M. Grundlagen von Asthma und COPD [Fundamentals of chronic inflammatory lung diseases (asthma, COPD, fibrosis)]. Ther Umsch. 2014, vol. 71, no. 5, pp. 258-261. DOI: 10.1024/0040-5930/a000510

61. Rylance J, Kankwatira A, Nelson DE, Toh E, Day RB, Lin H, Gao X, Dong Q, Sodergren E, Weinstock GM, Heyderman RS, Twigg HL 3rd, Gordon SB. Household air pollution and the lung microbiome of healthy adults in Malawi: a cross-sectional study. BMC Microbiol. 2016, vol. 16, no. 1, pp. 182 DOI: 10.1186/s12866-016-0803-7

62. Whiteside SA, McGinniss JE, Collman RG. The lung microbiome: progress and promise. J Clin Invest. 2021, vol. 131, no. 15, DOI: 10.1172/JCI150473

63. Sato N, Takahashi N, Suda K, Nakamura M, Yamaki M, Ninomiya T, Kobayashi Y, Takada H, Shibata K, Yamamoto M, Takeda K, Akira S, Noguchi T, Udagawa N. MyD88 but not TRIF is essential for osteoclastogenesis induced by lipopolysaccharide, diacyl lipopeptide, and IL-1alpha. J Exp Med. 2004, vol. 200, no. 5, pp. 601-611. DOI: 10.1084/jem.20040689

64. Schippers M, Post E, Eichhorn I, Langeland J, Beljaars L, Malo MS, Hodin RA, Millán JL, Popov Y, Schuppan D, Poelstra K. Phosphate Groups in the Lipid A Moiety Determine the Effects of LPS on Hepatic Stellate Cells: A Role for LPS-Dephosphorylating Activity in Liver Fibrosis. Cells. 2020, vol. 9, no. 12, pp. 2708. DOI: 10.3390/cells9122708

65. Seamon, Jesse, Keller, Thomas, Saleh, Jamal, Cui, Quanjun, The Pathogenesis of Nontraumatic Osteonecrosis, Arthritis, 2012, pp. 11. https://doi.org/10.1155/2012/601763

66. Segal LN, Clemente JC, Tsay JC, Koralov SB, Keller BC, Wu BG, Li Y, Shen N, Ghedin E, Morris A, Diaz P, Huang L, Wikoff WR, Ubeda C, Artacho A, Rom WN, Sterman DH, Collman RG, Blaser MJ, Weiden MD. Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype. Nat Microbiol. 2016, vol 1. DOI: 10.1038/nmicrobiol.2016.31

67. Simon-Soro A, Sohn MB, McGinniss JE, Imai I, Brown MC, Knecht VR, Bailey A, Clarke EL, Cantu E, Li H, Bittinger K, Diamond JM, Christie JD, Bushman FD, Collman RG. Upper Respiratory Dysbiosis with a Facultative-dominated Ecotype in Advanced Lung Disease and Dynamic Change after Lung Transplant. Ann Am Thorac Soc. 2019, vol. 16, no. 11, pp.1383-1391. DOI: 10.1513/AnnalsATS.201904-299OC

68. Suda K, Woo JT, Takami M, Sexton PM, and Nagai K. Lipopolysaccharide supports survival and fusion of preosteoclasts independent of TNF-alpha, IL-1, and RANKL.. J Cell Physiol. 2002 vol. 190, no. 1, pp. 101-108. https://doi.org/10.1002/jcp.10041

69. Sulaiman I, Wu BG, Li Y, Tsay JC, Sauthoff M, Scott AS, Ji K, Koralov SB, Weiden M, Clemente JC, Jones D, Huang YJ, Stringer KA, Zhang L, Geber A, Banakis S, Tipton L, Ghedin E, Segal LN. Functional lower airways genomic profiling of the microbiome to capture active microbial metabolism. Eur Respir J. 2021, vol. 58, no. 1. DOI: 10.1183/13993003.03434-2020

70. Tian L, Wen Q, Dang X, You W, Fan L, Wang K. Immune response associated with Toll-like receptor 4 signaling pathway leads to steroid-induced femoral head osteonecrosis. BMC Musculoskelet Disord. 2014, vol. 15, no. 18. https://doi.org/10.1186/1471-2474-15-18

71. Tobioka, H., Y. Tokunaga, H. Isomura, Y. Kokai, J. Yamaguchi, and N. Sawada.. Expression of occludin, a tight-junction-associated protein, in human lung carcinomas. Virchows Archiv . 2004, vol. 445, no. 5, pp. 472–476. https://doi.org/10.1007/s00428-004-1054-9

72. van der Vaart H, Postma DS, Timens W, Hylkema MN, Willemse BW, Boezen HM, Vonk JM, de Reus DM, Kauffman HF, ten Hacken NH. Acute effects of cigarette smoking on inflammation in healthy intermittent smokers. Respir Res. 2005, vol. 6, no. 1, pp. 22. DOI: 10.1186/1465-9921-6-22

73. Verdecchia P, Cavallini C, Spanevello A, Angeli F. COVID-19: ACE2centric Infective Disease? Hypertension. 2020, vol. 76, no. 2, pp. 294-299. DOI: 10.1161/HYPERTENSIONAHA.120.15353

74. Weir EC, Insogna KL, Horowitz MC. Osteoblast-like cells secrete granulocyte-macrophage colony-stimulating factor in response to parathyroid hormone and lipopolysaccharide. Endocrinology. 1989, vol. 124, no. 2, pp. 899-904. DOI: 10.1210/endo-124-2-899

75. Yu K, Ma Y, Li X, Wu X, Liu W, Li X, Shen J, Wang H. Lipopolysaccharide increases IL-6 secretion via activation of the ERK1/2 signaling pathway to up-regulate RANKL gene expression in MLO-Y4 cells. Cell Biol Int. 2017, vol. 41, no. 1, pp. 84-92. DOI: 10.1002/cbin.10696

76. Zhang R, Chen L, Cao L, Li KJ, Huang Y, Luan XQ, Li G. Effects of smoking on the lower respiratory tract microbiome in mice. Respir Res. 2018, vol. 19, no. 1, pp. 253. DOI: 10.1186/s12931-018-0959-9

77. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020, vol. 382, no. 8, pp. 727-733. DOI: 10.1056/NEJMoa2001017