Protective mechanisms of lungs

Abstract

Respiratory system maintains a close contact with the environment and is constantly exposed to numerous pathogenic factors. In response to action of pathogen, different strategies of specific and non-specific defense have been formed: barrier functions of the epithelium, defense reflexes (coughing, sneezing), muco-ciliary clearance, resident and recruited cells, secretion of a number of proteins and peptides with protective functions.

Aim. To systematize modern concepts of the protective mechanisms of lungs on the basis of the data of the relevant literature.

In the work, the mechanisms and clinical significance of muco-ciliary clearance, resident alveolar and recruited macrophages, epithelial cells, neutrophils, lymphocytes and platelets are analyzed.

Conclusion. The presented mechanisms can counteract the action of various pathogenic agents with sufficient effectiveness. However, in some cases an organism develops insufficient, excessive or perverted response to permeation of pathogens. This results in damage to the lung tissue by exogenous agents and/or by self immune system. Knowledge of protective mechanisms realized in the respiratory system, is necessary for understanding pathogenesis of respiratory diseases and for choice of the optimal treatment tactics.

Keywords

protective functions of lungs / mucociliary clearance / barrier function / resident alveolar macrophages / recruited macrophages / humoral antimicrobial factors

References

[1] Moroz VV, Tuchina LM, Poroshenko GG. Mechanisms of Protection of the Lung. Obshchaya Reanimatologiya. 2005;1(5):69-77. (In Russ).

[2] Мороз В.В., Тучин Л.М., Порошенко Г.Г. О механизмах защиты легких // Общая реаниматология. 2005. Т. 1, №5. С. 69-77.

[3] Asgharian B, Price OT, Oldham M, et al. Computational modeling of nanoscale and microscale particle deposition, retention and dosimetry in the mouse respiratory tract. Inhalation Toxicology. 2014;26 (14):829-42. doi:10.3109/08958378.2014.935535

[4] Asgharian B., Price O.T., Oldham M., et al. Computational modeling of nanoscale and microscale particle deposition, retention and dosimetry in the mouse respiratory tract // Inhalation Toxicology. 2014. Vol. 26, №14. Р. 829-842. doi:10.3109/08958378.2014.935535

[5] Widdicombe JH, Wine JJ. Airway Gland Structure and Function. Physiological Reviews. 2015;95(4):1241-319. doi:10.1152/physrev.00039.2014

[6] Widdicombe J.H., Wine J.J. Airway Gland Structure and Function // Physiological Reviews. 2015. Vol. 95, №4. Р. 1241-1319. doi:10.1152/physrev.00039.2014

[7] Whitsett JA, Alenghat T. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nature Immunology. 2015;16(1):27-35. doi:10.1038/ni.3045

[8] Whitsett J.A., Alenghat T. Respiratory epithelial cells orchestrate pulmonary innate immunity // Nature Immunology. 2015. Vol. 16, №1. Р. 27-35. doi:10.1038/ni.3045

[9] Whitsett JA. Airway Epithelial Differentiation and Mucociliary Clearance. Annals of the American Thoracic Society. 2018;15(Suppl 3):S143-8. doi:10.1513/AnnalsATS.201802-128AW

[10] Whitsett J.A. Airway Epithelial Differentiation and Mucociliary Clearance // Annals of the American Thoracic Society. 2018. Vol. 15, Suppl 3. Р. S143-S148. doi:10.1513/AnnalsATS.201802-128AW

[11] Ma J, Rubin BK, Voynow JA. Mucins, Mucus, and Goblet Cells. Chest. 2018;154(1):169-76. doi:10. 1016/j.chest.2017.11.008

[12] Ma J., Rubin B.K., Voynow J.A. Mucins, Mucus, and Goblet Cells // Chest. 2018. Vol. 154, №1. Р. 169-176. doi:10.1016/j.chest.2017.11.008

[13] Bonser LR, Erle DJ. Airway Mucus and Asthma: The Role of MUC5AC and MUC5B. Journal of Clinical Medicine. 2017;6(12):112. doi:10.3390/jcm6120112

[14] Bonser L.R., Erle D.J. Airway Mucus and Asthma: The Role of MUC5AC and MUC5B // Journal of Clinical Medicine. 2017. Vol. 6, №12. Р. 112. doi:10.3390/jcm6120112

[15] Roy MG, Livraghi-Butrico A, Fletcher AA, et al. Muc5b is required for airway defence. Nature. 2014;505(7483):412-6. doi:10.1038/nature12807

[16] Roy M.G., Livraghi-Butrico A., Fletcher A.A., et al. Muc5b is required for airway defence // Nature. 2014. Vol. 505, №7483. Р. 412-416. doi:10.1038/ nature12807

[17] Evans CM, Raclawska DS, Ttofali F, et al. The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. Nature Communications. 2015;6:(6281). doi:10.1038/ncomms7281

[18] Evans C.M., Raclawska D.S., Ttofali F., et al. The polymeric mucin Muc5ac is required for allergic airway hyperreactivity // Nature Communications. 2015. Vol. 6. P. 6281. doi:10.1038/ncomms7281

[19] Iida H, Matsuura S, Shirakami G, et al. Differential effects of intravenous anesthetics on ciliary motility in cultured rat tracheal epithelial cells. Canadian Journal of Anesthesia. 2006;53(3):242-9. doi:10.1007/bf03022209

[20] Iida H., Matsuura S., Shirakami G., et al. Differential effects of intravenous anesthetics on ciliary motility in cultured rat tracheal epithelial cells // Canadian Journal of Anesthesia. 2006. Vol. 53, №3. Р. 242-249. doi:10.1007/BF03022209

[21] Shapiro AJ, Zariwala MA, Ferkol T, et al. Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review. Pediatric Pulmonology. 2016;51(2):115-32. doi:10.1002/ppul.23304

[22] Shapiro A.J., Zariwala M.A., Ferkol T., et al. Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review // Pediatric Pulmonology. 2016. Vol. 51, №2. Р. 115-132. doi:10.1002/ppul.23304

[23] Zhou-Suckow Z, Duerr J, Hagner M, et al. Airway mucus, inflammation and remodeling: emerging links in the pathogenesis of chronic lung diseases. Cell and Tissue Research. 2017;367(3):537-50. doi:10.1007/s00441-016-2562-z

[24] Zhou-Suckow Z., Duerr J., Hagner M., et al. Airway mucus, inflammation and remodeling: emerging links in the pathogenesis of chronic lung diseases // Cell and Tissue Research. 2017. Vol. 367, №3. Р. 537-550. doi:10.1007/s00441-016-2562-z

[25] Guschin MY, Barkhina TG, Golovanova VE, et al. Modern views on the relationship of the upper and lower respiratory tract in allergic rhinitis and asthma. I.P. Pavlov Russian Medical Biological Herald. 2011;(4):154-60. (In Russ).

[26] Гущин М.Ю., Бархина Т.Г., Голованова В.Е., и др. Современные представления о взаимосвязи верхних и нижних дыхательных путей при аллергическом рините и бронхиальной астме // Российский медикобиологический вестник имени академика И.П. Павлова. 2011. №4. С. 154-160.

[27] Murphy J, Summer R, Wilson AA, et al. The Prolonged Life-Span of Alveolar Macrophages. American Journal of Respiratory Cell and Molecular Biology. 2008;38(4):380-5. doi:10.1165/rcmb.2007-0224RC

[28] Murphy J., Summer R., Wilson A.A., et al. The Prolonged Life-Span of Alveolar Macrophages // American Journal of Respiratory Cell and Molecular Biology. 2008. Vol. 38, №4. Р. 380-385. doi:10.1165/rcmb.2007-0224RC

[29] Taylor PR, Martinez-Pomares L, Stacey M, et al. Macrophage receptors and immune recognition. Annual Review of Immunology. 2005;23:901-44. doi:10.1146/annurev.immunol.23.021704.115816

[30] Taylor P.R., Martinez-Pomares L., Stacey M., et al. Macrophage receptors and immune recognition // Annual Review of Immunology. 2005. Vol. 23. Р. 901-944. doi:10.1146/annurev.immunol.23.021704. 115816

[31] Gregory AD, Hogue LA, Ferkol TW, et al. Regulation of systemic and local neutrophil responses by G-CSF during pulmonary Pseudomonas aeruginosa infection. Blood. 2006;109(8):3235-43. doi:10.1182/blood-2005-01-015081

[32] Gregory A.D., Hogue L.A., Ferkol T.W., et al. Regulation of systemic and local neutrophil responses by G-CSF during pulmonary Pseudomonas aeruginosa infection // Blood. 2006. Vol. 109, №8. Р. 3235-3243. doi:10.1182/blood-2005-01-015081

[33] Pittet LA, Quinton LJ, Yamamoto K, et al. Earliest Innate Immune Responses Require Macrophage RelA during Pneumococcal Pneumonia. American Journal of Respiratory Cell and Molecular Biology. 2011;45(3):573-81. doi:10.1165/rcmb.2010-0210OC

[34] Pittet L.A., Quinton L.J., Yamamoto K., et al. Earliest Innate Immune Responses Require Macrophage RelA during Pneumococcal Pneumonia // American Journal of Respiratory Cell and Molecular Biology. 2011. Vol. 45, №3. Р. 573-581. doi:10.1165/rcmb.2010-0210OC

[35] Han S, Mallampalli RK. The Role of Surfactant in Lung Disease and Host Defense against Pulmonary Infections. Annals of the American Thoracic Society. 2015;12(5):765-74. doi:10.1513/AnnalsATS.201411-507FR

[36] Han S.H., Mallampalli R.K. The Role of Surfactant in Lung Disease and Host Defense against Pulmonary Infections // Annals of the American Thoracic Society. 2015. Vol. 12, №5. Р. 765-774. doi:10. 1513/AnnalsATS.201411-507FR

[37] Kamata H, Yamamoto K, Wasserman GA, et al. Epithelial Cell – Derived Secreted and Transmembrane 1a Signals to Activated Neutrophils during Pneumococcal Pneumonia. American Journal of Respiratory Cell and Molecular Biology. 2016; 55(3):407-18. doi:10.1165/rcmb.2015-0261OC

[38] Kamata H., Yamamoto K., Wasserman G.A., et al. Epithelial Cell – Derived Secreted and Transmembrane 1a Signals to Activated Neutrophils during Pneumococcal Pneumonia // American Journal of Respiratory Cell and Molecular Biology. 2016. Vol. 55, №3. Р. 407-418. doi:10.1165/rcmb.2015-0261OC

[39] Jones MR, Simms BT, Lupa MM, et al. Lung NF-κB Activation and Neutrophil Recruitment Require IL-1 and TNF Receptor Signaling during Pneumococcal Pneumonia. Journal of Immunology. 2005; 175(11):7530-5. doi:10.4049/jimmunol.175.11.7530

[40] Jones M.R., Simms B.T., Lupa M.M., et al. Lung NF-κB Activation and Neutrophil Recruitment Require IL-1 and TNF Receptor Signaling during Pneumococcal Pneumonia // Journal of Immunology. 2005. Vol. 175, №11. Р. 7530-7535. doi:10. 4049/jimmunol.175.11.7530

[41] Paats MS, Bergen IM, Hanselaar WEJJ, et al. T helper 17 cells are involved in the local and systemic inflammatory response in community-acquired pneumonia. Thorax. 2013;68(5):468-74. doi:10.1136/thoraxjnl-2012-202168

[42] Paats M.S., Bergen I.M., Hanselaar W.E.J.J., et al. T helper 17 cells are involved in the local and systemic inflammatory response in community-acquired pneumonia // Thorax. 2013. Vol. 68, №5. Р. 468-474. doi:10.1136/thoraxjnl-2012-202168

[43] Chan YR, Liu JS, Pociask DA, et al. Lipocalin 2 is required for pulmonary host defense against Klebsiella infection. Journal of Immunology. 2009; 182(8):4947-56. doi:10.4049/jimmunol.0803282

[44] Chan Y.R., Liu J.S., Pociask D.A., et al. Lipocalin 2 is required for pulmonary host defense against Klebsiella infection // Journal of Immunology. 2009. Vol. 182, №8. Р. 4947-4956. doi:10.4049/ jimmunol.0803282

[45] Choi S-M, Mc Aleer JP, Zheng M, et al. Innate Stat3-mediated induction of the antimicrobial protein Reg3γ is required for host defense against MRSA pneumonia. The Journal of Experimental Medicine. 2013;210(3):551-61. doi:10.1084/jem.20120260

[46] Choi S.-M., Mc Aleer J.P., Zheng M., et al. Innate Stat3-mediated induction of the antimicrobial protein Reg3γ is required for host defense against MRSA pneumonia // The Journal of Experimental Medicine. 2013. Vol. 210, №3. Р. 551-561. doi:10. 1084/jem.20120260

[47] Traber KE, Hilliard KL, Allen E, et al. Induction of STAT3-Dependent CXCL5 Expression and Neutrophil Recruitment by Oncostatin-M during Pneumonia. American Journal of Respiratory Cell and Molecular Biology. 2015;53(4):479-88. doi:10.1165/ rcmb.2014-0342OC

[48] Traber K.E., Hilliard K.L., Allen E., et al. Induction of STAT3-Dependent CXCL5 Expression and Neutrophil Recruitment by Oncostatin-M during Pneumonia // American Journal of Respiratory Cell and Molecular Biology. 2015. Vol. 53, №4. Р. 479-488. doi:10.1165/rcmb.2014-0342OC

[49] Yamamoto K, Ahyi A-NN, Pepper-Cunningham ZA, et al. Roles of Lung Epithelium in Neutrophil Recruitment During Pneumococcal Pneumonia. American Journal of Respiratory Cell and Molecular Biology. 2014;50(2):253-62. doi:10.1165/rcmb.2013-0114OC

[50] Yamamoto K., Ahyi A-N.N., Pepper-Cunningham Z.A., et al. Roles of Lung Epithelium in Neutrophil Recruitment During Pneumococcal Pneumonia // American Journal of Respiratory Cell and Molecular Biology. 2014. Vol. 50, №2. Р. 253-262. doi:10.1165/rcmb.2013-0114OC

[51] Evans SE, Scott BL, Clement CG, et al. Stimulated innate resistance of lung epithelium protects mice broadly against bacteria and fungi. American Journal of Respiratory Cell and Molecular Biology. 2010;42(1):40-50. doi:10.1165/rcmb.2008-0260OC

[52] Evans S.E., Scott B.L., Clement C.G., et al. Stimulated innate resistance of lung epithelium protects mice broadly against bacteria and fungi // American Journal of Respiratory Cell and Molecular Biology. 2010. Vol. 42, №1. Р. 40-50. doi:10.1165/rcmb. 2008-0260OC

[53] Craig A, Mai J, Cai S, et al. Neutrophil recruitment to the lungs during bacterial pneumonia. Infection and Immunity. 2009;77(2):568-75. doi:10.1128/iai.00832-08

[54] Craig A., Mai J., Cai S., et al. Neutrophil recruitment to the lungs during bacterial pneumonia // Infection and Immunity. 2009. Vol. 77, №2. Р. 568-575. doi:10.1128/IAI.00832-08

[55] Brinkmann V. Neutrophil Extracellular Traps in the Second Decade. Journal of Innate Immunity. 2018; 10(5-6):414-21. doi:10.1159/000489829

[56] Brinkmann V. Neutrophil Extracellular Traps in the Second Decade // Journal of Innate Immunity. 2018. Vol. 10, №5-6. Р. 414-421. doi:10.1159/000489829

[57] Maus U, von Grote K, Kuziel WA, et al. The role of CC chemokine receptor 2 in alveolar monocyte and neutrophil immigration in intact mice. American Journal of Respiratory and Critical Care Medicine. 2002;166(3):268-73. doi:10.1164/rccm.2112012

[58] Maus U., von Grote K., Kuziel W.A., et al. The role of CC chemokine receptor 2 in alveolar monocyte and neutrophil immigration in intact mice // American Journal of Respiratory and Critical Care Medicine. 2002. Vol. 166, №3. Р. 268-273. doi:10.1164/rccm.2112012

[59] Aggarwal NR, King LS, D’Alessio FR. Diverse macrophage populations mediate acute lung inflammation and resolution. American Journal of Physiology, Lung Cellular and Molecular Physiology. 2014; 306(8):L709-25. doi:10.1152/ajplung.00341.2013

[60] Aggarwal N.R., King L.S., D’Alessio F.R. Diverse macrophage populations mediate acute lung inflammation and resolution // American Journal of Physiology, Lung Cellular and Molecular Physiology. 2014. Vol. 306, №8. Р. L709-L725. doi:10.1152/ajplung.00341.2013

[61] Belskikh E.S., Uryas'ev O.M., Zvyagina V.I., et al. Investigation of oxidative stress and function of mitochondria in mononuclear leukocytes of blood in patients with chronic bronchitis and with chronic obstructive pulmonary disease. Nauka Molodykh (Eruditio Juvenium). 2018;6(2):203-10. (In Russ).

[62] Бельских Э.С., Урясьев О.М., Звягина В.И., и др. Исследование окислительного стресса и функции митохондрий в мононуклеарных лейкоцитах крови у больных с хроническим бронхитом и с хронической обструктивной болезнью легких // Наука молодых (Eruditio Juvenium). 2018. Т. 6, №2. С. 203-210.

[63] Sonnenberg GF, Artis D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nature Medicine. 2015;21(7):698-708. doi:10.1038/nm.3892

[64] Sonnenberg G.F., Artis D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation // Nature Medicine. 2015. Vol. 21, №7. Р. 698-708. doi:10.1038/nm.3892

[65] Orange JS. Human natural killer cell deficiencies and susceptibility to infection. Microbes and Infection. 2002;4(15):1545-58. doi:10.1016/s1286-4579(02)00038-2

[66] Orange J.S. Human natural killer cell deficiencies and susceptibility to infection // Microbes and Infection. 2002. Vol. 4, №15. Р. 1545-1558. doi:10.1016/s1286-4579(02)00038-2

[67] Abboud G, Tahiliani V, Desai P, et al. Natural Killer Cells and Innate Interferon Gamma Participate in the Host Defense against Respiratory Vaccinia Virus Infection. Journal of Virology. 2015;90(1): 129-41. doi:10.1128/jvi.01894-15

[68] Abboud G., Tahiliani V., Desai P., et al. Natural Killer Cells and Innate Interferon Gamma Participate in the Host Defense against Respiratory Vaccinia Virus Infection // Journal of Virology. 2015. Vol. 90, №1. Р. 129-141. doi:10.1128/JVI.01894-15

[69] Elhaik-Goldman S, Kafka D, Yossef R, et al. The natural cytotoxicity receptor 1 contribution to early clearance of streptococcus pneumoniae and to natural killer-macrophage cross talk. PLoS One. 2011; 6(8):e23472. doi:10.1371/journal.pone.0023472

[70] Elhaik-Goldman S., Kafka D., Yossef R., et al. The natural cytotoxicity receptor 1 contribution to early clearance of streptococcus pneumoniae and to natural killer-macrophage cross talk // PLoS One. 2011. Vol. 6, №8. P. e23472. doi:10.1371/journal.pone.0023472

[71] Minutti CM, Jackson-Jones LH, García-Fojeda B, et al. Local amplifiers of IL-4Rα–mediated macrophage activation promote repair in lung and liver. Science. 2017;356(6342):1076-80. doi:10.1126/science.aaj2067

[72] Minutti C.M., Jackson-Jones L.H., García-Fojeda B., et al. Local amplifiers of IL-4Rα–mediated macrophage activation promote repair in lung and liver // Science. 2017. Vol. 356, №6342. Р. 1076-1080. doi:10.1126/science.aaj2067

[73] Muir R, Osbourn M, Dubois AV, et al. Innate Lymphoid Cells Are the Predominant Source of IL-17A during the Early Pathogenesis of Acute Respiratory Distress Syndrome. American Journal of Respiratory and Critical Care Medicine. 2016;193 (4):407-16. doi:10.1164/rccm.201410-1782OC

[74] Muir R., Osbourn M., Dubois A.V., et al. Innate Lymphoid Cells Are the Predominant Source of IL-17A during the Early Pathogenesis of Acute Res-piratory Distress Syndrome // American Journal of Respiratory and Critical Care Medicine. 2016. Vol. 193, №4. Р. 407-416. doi:10.1164/rccm.201410-1782OC

[75] Nakasone C, Yamamoto N, Nakamatsu M, et al. Accumulation of gamma/delta T cells in the lungs and their roles in neutrophil-mediated host defense against pneumococcal infection. Microbes and

[76] Nakasone C., Yamamoto N., Nakamatsu M., et al. Accumulation of gamma/delta T cells in the lungs and their roles in neutrophilmediated host defense against pneumococcal infection // Microbes and Infection. 2007. Vol. 9, №3. Р. 251-258. doi:10.1016/j.micinf.2006.11.015

[77] Infection. 2007;9(3):251-8. doi:10.1016/j.micinf.2006.11.015

[78] Baumgarth N. The double life of a B-1 cell: selfreactivity selects for protective effector functions // Nature Reviews. Immunology. 2011. Vol. 11, №1. Р. 34-46. doi:10.1038/nri2901

[79] Baumgarth N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nature Reviews. Immunology. 2011;11(1):34-46. doi:10.1038/nri2901

[80] Yadav H., Kor D.J. Platelets in the pathogenesis of acute respiratory distress syndrome // American Journal of Physiology, Lung Cellular and Molecular Physiology. 2015. Vol. 309, №9. Р. L915-L923. doi:10.1152/ajplung.00266.2015

[81] Yadav H, Kor DJ. Platelets in the pathogenesis of acute respiratory distress syndrome. American Journal of Physiology, Lung Cellular and Molecular Physiology. 2015;309(9):L915-23. doi:10.1152/ajplung.00266.2015

[82] De Stoppelaar S.F., van’t Veer C., Roelofs J.J.T.H., et al. Platelet and endothelial cell Pselectin are required for host defense against Klebsiella pneumoniae-induced pneumosepsis // Journal of Thrombosis and Haemostasis. 2015. Vol. 13, №6. Р. 1128-1138. doi:10.1111/jth.12893

[83] De Stoppelaar SF, van’t Veer C, Roelofs JJTH, et al. Platelet and endothelial cell P-selectin are required for host defense against Klebsiella pneumoniae-induced pneumosepsis. Journal of Thrombosis and Haemostasis. 2015;13(6):1128-38. doi:10.1111/jth.12893

[84] Krijgsveld J., Zaat S.A.J., Meeldijk J., et al. Thrombocidins, Microbicidal Proteins from Human Blood Platelets, Are C-terminal Deletion Products of CXC Chemokines // The Journal of Biological Chemistry. 2000. Vol. 275, №27. Р. 20374-20381. doi:10.1074/jbc.275.27.20374

[85] Krijgsveld J, Zaat SAJ, Meeldijk J, et al. Thrombocidins, Microbicidal Proteins from Human Blood Platelets, Are C-terminal Deletion Products of CXC Chemokines. The Journal of Biological Chemistry. 2000; 275(27):20374-81. doi:10.1074/jbc.275.27.20374

[86] Lê V.B., Schneider J.G., Boergeling Y., et al. Platelet Activation and Aggregation Promote Lung In-flammation and Influenza Virus Pathogenesis // American Journal of Respiratory and Critical Care Medicine. 2015. Vol. 191, №7. Р. 804-819. doi:10.1164/rccm.201406-1031OC

[87] Lê VB, Schneider JG, Boergeling Y, et al. Platelet Activation and Aggregation Promote Lung Inflammation and Influenza Virus Pathogenesis. American Journal of Respiratory and Critical Care Medicine. 2015;191(7):804-19. doi:10.1164/rccm.201406-1031OC

RIGHTS & PERMISSIONS

Eco-Vector