mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-VIA-3139mimmun-3139Research ArticleОБЗОРЫREVIEWSВирусная инфекция и липополисахарид: патологическая ось «легкие – суставы» как потенциальная причина остеонекрозаViral infection and lipopolysaccharide: Pathological axis “lung–joints” as a potential cause of osteonecrosishttps://orcid.org/0000-0002-5486-7262ЯцковИ. А.YatskovI. A.

к.м.н., доцент кафедры внутренней медицины № 2

PhD (Medicine), Associate Professor, Department of Internal Medicine No. 2

egermd@yandex.ruhttps://orcid.org/0000-0001-9640-754XБелоглазовВ. А.BeloglazovV. A.

д.м.н., профессор, заведующий кафедрой внутренней медицины № 2

PhD, MD (Medicine), Professor, Head, Department of Internal Medicine No. 2

biloglazov@mail.ruhttps://orcid.org/0000-0001-9147-8461ЗаяеваА. А.ZayaevaA. A.

к.м.н., доцент кафедры внутренней медицины № 2

PhD (Medicine), Associate Professor, Department of Internal Medicine No. 2

a.zayayeva@yandex.comhttps://orcid.org/0000-0002-8960-602XБублейК. В.BubleyK. V.

ассистент/ординатор кафедры внутренней медицины № 2

Assistant Professor, Department of Internal Medicine No. 2

bubley.99@mail.ruОрдена Трудового Красного Знамени Медицинский институт имени С.И. Георгиевского ФГАОУ ВО «Крымский федеральный университет имени В.И. Вернадского»РоссияS. Georgievsky Medical Institute, V. Vernadsky Crimean Federal UniversityRussian Federation20252012202527611951204Copyright © Яцков И.А., Белоглазов В.А., Заяева А.А., Бублей К.В., 20252025Яцков И.А., Белоглазов В.А., Заяева А.А., Бублей К.В.Yatskov I.A., Beloglazov V.A., Zayaeva A.A., Bubley K.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/3139

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.

The article concerns the effects of viral infections, e.g., SARS-CoV-2, and bacterial lipopolysaccharide (LPS), a component of the cell wall of Gram-negative microbes, on the development of osteonecrosis via the pathological lung–joint axis. Viral infection causes damage to lung cells and vascular endothelium, and leads to inflammatory and blood clotting disorders, increasing the risk of bone ischemia. LPS, by interacting with TLR4 receptors, enhances the inflammatory response and disrupts the blood supply to bones, thus stimulating resorption and preventing bone formation. In addition, the article highlights the role of lung dysbiosis caused by viral infection, which enhances inflammation and increases permeability of tissue barriers for endotoxins. Appropriate information was searched for the keywords “osteonecrosis and lipopolysaccharide”, “COVID-19 virus and lipopolysaccharide-binding protein”, “viremia and osteonecrosis”, “lung microflora and LPS” in foreign and domestic scientometric databases such as PubMed and eLIBRARY. The presented data suggest that the combined effect of imbalanced LPS-binding systems, impaired pulmonary barrier, viral infection and LPS exposure is an important aggravating pro-inflammatory factor. This combination may propote a predisposal for the full-scale osteonecrosis. This concept seems to be promising for clinical research of potential tools influencing these conditions, either single factors or their combined effects. This study focuses on the variety of effects exerted by viral infections and bacterial LPS upon the bone tissue. Current research shows that influencing these mechanisms may open up new ways for the development of therapeutic strategies. The prospects of using targeted therapies to mitigate the negative effects of these interactions are also being considered. These data emphasize a need for integrated approach in the study and treatment of osteonecrosis, with respect to both infectious and inflammatory components of this disorder.

LPSостеонекрозBPILBPэндотоксинIL-17пулы LPSCOVID-19TLR4lipopolysaccharideosteonecrosisBPILPS-binding proteinendotoxinIL-17LPS poolsCOVID-19TLR4ReferencesБелоглазов 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/omet12750Beloglazov V.A., Yatskov I.A., Kumelsky E.D., Polovinkina V.V. Metabolic endotoxinemia: possible causes and consequences // Obesity and metabolism. - 2021. - vol. 18, No. 3. Pp. 320-326 DOI:10.14341/omet12750Панин 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: 10.17816/2311-2905-1687Panin M.A., Petrosyan A.S., Hadjicharalambous K.K., Boiko A.V. Avascular Necrosis of the Femoral Head After COVID-19: A Case Series // Traumatology and Orthopedics of Russia. - 2022. - Vol. 28. - No. 1. - Pp. 110-117 doi: 10.17816/2311-2905-1687Покусаева 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/S0131164619050138Pokusaeva D.P., Anikhovskaya I.A., Korobkova L.A., etc. Prognostic significance of indicators of systemic endotoxinemia in atherogenesis // Human Physiology. — 2019. — vol. 45. — No.5. — pp. 543-551. https://doi.org/10.1134/S0131164619050138Abeles 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.1978.03630290052018Abeles 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.1978.03630290052018Ackermann 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.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.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: 10.1080/08916930701694469Bar-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: 10.1080/08916930701694469Belkaid 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.2014.03.011Belkaid 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.2014.03.011Beutler 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/nri1004Beutler 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/nri1004Bhattacharya 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-xBhattacharya 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-xBradley 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)31305-2Bradley 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)31305-2Beutler 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)00046-1Beutler 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)00046-1Chang 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.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.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.201104-0655OCCharlson 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.201104-0655OCClaes 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.2012.1Claes 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.2012.1Condon 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.0311134Condon 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.0311134Denker 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.F1Denker 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.F1Dickson 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.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.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.201711-2180OCDickson 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.201711-2180OCDisser 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.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.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.2005.01.009Feldman 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.2005.01.009Flynn 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.0813393106Flynn 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.0813393106Fong 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.2010.08.101Fong 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.2010.08.101Ghosh 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/bvz039Ghosh 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/bvz039Gollwitzer 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.3568Gollwitzer 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.3568Goodman 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.2019.00230Goodman 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.2019.00230Goodman 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.S281941Goodman 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.S281941Guillot 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.2013.08.009Guillot 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.2013.08.009Günther 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/s00281-018-0701-1Günther 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/s00281-018-0701-1Han 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-2020-0188Han 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-2020-0188Herbst 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.201010-1574OCHerbst 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.201010-1574OCHippenstiel 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: 10.1186/1465-9921-7-97Hippenstiel 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: 10.1186/1465-9921-7-97Holt 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/nri2236Holt 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/nri2236Hooper 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.1223490Hooper 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.1223490Horowitz 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/JCI113852Horowitz 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/JCI113852Huang 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)30183-5Huang 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)30183-5Inada 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.177.3.1879Inada 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.177.3.1879Itoh 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.170.7.3688Itoh 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.170.7.3688Ivanov 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.2009.09.033Ivanov 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.2009.09.033Johnson 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.2009.0775Johnson 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.2009.0775Katagiri 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.xKatagiri 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.xKawai 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.2011.05.006Kawai 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.2011.05.006Kong, 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.00123-12Kong, 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.00123-12Kong 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.1100339Kong 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.1100339Laskin 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.010909.105812Laskin 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.010909.105812Li 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/ijms21176303Li 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/ijms21176303Lin 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-zLin 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-zMantovani 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.2004.09.015Mantovani 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.2004.09.015Maruyama 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.2020.00386Maruyama 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.2020.00386Mont 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.01041Mont 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.01041Moreira 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/S0007114512001213Moreira 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/S0007114512001213Goro 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.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.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.xNakamura 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.xNicod LP. Lung Defences: An Overview. Eur Respir Rev . 2005, vol. 14, no. 95, pp. 45–50. https://doi.org/10.1183/09059180.05.00009501Nicod LP. Lung Defences: An Overview. Eur Respir Rev . 2005, vol. 14, no. 95, pp. 45–50. https://doi.org/10.1183/09059180.05.00009501Pajarinen 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.2017.12.025Pajarinen 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.2017.12.025Phipps 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.22952Phipps 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.22952Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002, vol. 71, pp. 635-700. DOI: 10.1146/annurev.biochem.71.110601.135414Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002, vol. 71, pp. 635-700. DOI: 10.1146/annurev.biochem.71.110601.135414Ren 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.00199-18Ren 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.00199-18Rezaee 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.2013-0541RTRezaee 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.2013-0541RTRietschel 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.8.2.8119492Rietschel 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.8.2.8119492Roth 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/a000510Roth 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/a000510Rylance 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/s12866-016-0803-7Rylance 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/s12866-016-0803-7Whiteside SA, McGinniss JE, Collman RG. The lung microbiome: progress and promise. J Clin Invest. 2021, vol. 131, no. 15, DOI: 10.1172/JCI150473Whiteside SA, McGinniss JE, Collman RG. The lung microbiome: progress and promise. J Clin Invest. 2021, vol. 131, no. 15, DOI: 10.1172/JCI150473Sato 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.20040689Sato 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.20040689Schippers 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/cells9122708Schippers 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/cells9122708Seamon, Jesse, Keller, Thomas, Saleh, Jamal, Cui, Quanjun, The Pathogenesis of Nontraumatic Osteonecrosis, Arthritis, 2012, pp. 11. https://doi.org/10.1155/2012/601763Seamon, Jesse, Keller, Thomas, Saleh, Jamal, Cui, Quanjun, The Pathogenesis of Nontraumatic Osteonecrosis, Arthritis, 2012, pp. 11. https://doi.org/10.1155/2012/601763Segal 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.2016.31Segal 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.2016.31Simon-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.201904-299OCSimon-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.201904-299OCSuda 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.10041Suda 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.10041Sulaiman 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: 10.1183/13993003.03434-2020Sulaiman 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: 10.1183/13993003.03434-2020Tian 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/10.1186/1471-2474-15-18Tian 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/10.1186/1471-2474-15-18Tobioka, 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/s00428-004-1054-9Tobioka, 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/s00428-004-1054-9van 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: 10.1186/1465-9921-6-22van 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: 10.1186/1465-9921-6-22Verdecchia 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.120.15353Verdecchia 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.120.15353Weir 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-124-2-899Weir 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-124-2-899Yu 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.10696Yu 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.10696Zhang 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/s12931-018-0959-9Zhang 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/s12931-018-0959-9Zhu 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/NEJMoa2001017Zhu 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

The authors declare that there are no conflicts of interest present.