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The blood–saliva barrier (BSB) is a biological barrier that consists of the epithelial cell layers of the oral mucosa and salivary glands, and provides physiological separation between blood vessels and the saliva in the oral cavity.^[1]^[2] In Russian academic literature the barrier is usually called the hematosalivary or hematosalivarian barrier.^[3]^[2]

Structure

The blood–saliva barrier is primarily formed by the endothelial cells lining the blood vessels and the epithelial cells lining the oral mucosa,^[4]^[1] and also has a connective tissue layer. The epithelial cells of the blood–saliva barrier present in gingival epithelium (lining the gums) and junctional epithelium (that surrounds teeth at their base where they emerge from gums).

Function

The blood–saliva barrier is a protective mechanism that helps maintain the integrity and stability of the blood and prevents the exchange of certain substances between the bloodstream and saliva, such as electrolytes,^[5] small-molecular-weight proteins, metabolic products, and specific/non-specific defense factors.^[4]^[1]^[2]

The blood–saliva barrier also plays a role in immune defense mechanisms within the oral cavity. Immune cells, such as macrophages and lymphocytes, are contained within the connective tissue layer beneath the barrier.

Salivary glands are well-perfused organs due to the presence of numerous arterio-venous anastomoses^[6] with sphincters. When these sphincters close, they increase the pressure in the capillaries of salivary glands, facilitating the movement of various metabolites from the capillary lumen into secretory epithelial cells for saliva formation. Salivary glands exhibit high selectivity in their activity, confirming the functioning of the barrier which regulates its permeability in response to physiological or pathological changes within the body. Substance entry through the barrier mainly occurs via simple passive diffusion (paracellular),^[5]^[2] active transport, or endocytosis, primarily determined by lipophilicity, charge, and size of substances being transported. Proteinaceous substances are thought to be primarily transported across the mucosa via a paracellular mechanism facilitated by passive diffusion.^[2]

The blood–saliva barrier changes permeability under the influence of the autonomic nervous system and humoral factors.^[2]

Clinical significance

In vitro models of the blood–saliva barrier are used to investigate and understand the transport of salivary biomarkers from blood to saliva.^[7]^[1]

The ability of blood–saliva barrier of preventing the transport of certain molecules from blood to saliva while allowing the transport of the other has a practical application in measuring levels of steroids which are unbound ("free") and have biological activity. An example of such molecule is cortisol, which is lipophilic, and is transported bound to transcortin (also known as corticosteroid-binding globulin) and albumin, while only a small part of the total serum cortisol is unbound and has biological activity.^[8] This binding of cortisol to transcortin is accomplished through hydrophobic interactions in which cortisol binds in a 1:1 ratio.^[9] Serum cortisol assays measure total cortisol, and such results may be misleading for patients with altered serum protein concentrations. The salivary cortisol test avoids this problem because only free cortisol can pass through blood–saliva barrier^[10]^[11]^[12]^[13] due to the fact that transcortin particles are too large to pass through the barrier.^[14]^[1]

History

A key milestone in the study of the blood–saliva barrier in medicine was reached when Soviet physiologist Lina Stern introduced the concept of "histohematological barriers" in 1929, highlighting their plasticity and their ability to regulate internal environment homeostasis through interactions with exogenous and endogenous physiological compounds.^[2] While working at the University of Geneva, Stern published a series of studies demonstrating the existence of the blood–brain barrier with colleague Raymond Gautier.^[15]^[16]^[17] In a 1934 paper, Stern also introduced the notions of barrier selectivity and barrier resistance, realizing that the blood–brain barrier both selectively allows certain substances to enter the brain and protects the internal milieu of the brain from that of the blood.^[18] The study of the blood–brain barrier contributed to the subsequent studies of the other anatomical barriers. A significant place in understanding of the barrier mechanisms is occupied by the placental barrier, which exists between maternal blood and fetal tissues. Following extended research, the blood–saliva barrier was described for the first time in 1977^[19] by a Soviet physician Yurii Alexandrovich Petrovich^[20] as "hematosalivary barrer".^[2]

Research directions

In recent years, significant progress has been made in studying different aspects blood–saliva barrier function using advanced tools such as molecular biology techniques, confocal microscopy, immunofluorescence staining methods, and transcellular migration assays. These studies elucidate cellular interactions involved in creating tight junctions^[5]^[2] between endothelial cells lining capillaries within salivary glands.^[2]

Furthermore, experimental models utilizing cell cultures have demonstrated potential applications for tissue engineering approaches aimed at developing artificial salivary glands or improving treatments for conditions associated with reduced salivation.^[2]

References

^ ^a ^b ^c ^d ^e Lin GC, Smajlhodzic M, Bandian AM, Friedl HP, Leitgeb T, Oerter S, Stadler K, Giese U, Peham JR, Bingle L, Neuhaus W (August 2020). "An In Vitro Barrier Model of the Human Submandibular Salivary Gland Epithelium Based on a Single Cell Clone of Cell Line HTB-41: Establishment and Application for Biomarker Transport Studies". Biomedicines. 8 (9): 302. doi:10.3390/biomedicines8090302. PMC 7555419. PMID 32842479.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Selezneva IA, Gilmiyarova FN, Tlustenko VS, Domenjuk DA, Gusyakova OA, Kolotyeva NA, Gilmiyarova IE, Nazarkina IA (June 2022). "Hematosalivarian barrier: structure, functions, study methods (review of literature)". Klin Lab Diagn. 67 (6): 334–338. doi:10.51620/0869-2084-2022-67-6-334-338. PMID 35749597. S2CID 250022158.
^ Ulanova EA, Grigor'ev IV, Novikova IA (2001). "[Hematosalivary mechanisms of regulation in rheumatoid arthritis]". Ter Arkh (in Russian). 73 (11): 92–4. PMID 11806220.
^ ^a ^b Lin GC, Leitgeb T, Vladetic A, Friedl HP, Rhodes N, Rossi A, Roblegg E, Neuhaus W (April 2020). "Optimization of oral mucosa in vitro model based on cell line TR146". Tissue Barriers. 8 (2): 1748459. doi:10.1080/21688370.2020.1748459. PMC 7549749. PMID 32314665.
^ ^a ^b ^c Zhang GH, Castro R (September 2015). "Role of Oral Mucosal Fluid and Electrolyte Absorption and Secretion in Dry Mouth". Chin J Dent Res. 18 (3): 135–54. PMID 26485506.
^ Walløe L (2016). "Arterio-venous anastomoses in the human skin and their role in temperature control". Temperature (Austin). 3 (1): 92–103. doi:10.1080/23328940.2015.1088502. PMC 4861183. PMID 27227081.
^ Lin GC, Küng E, Smajlhodzic M, Domazet S, Friedl HP, Angerer J, Wisgrill L, Berger A, Bingle L, Peham JR, Neuhaus W (February 2021). "Directed Transport of CRP Across In Vitro Models of the Blood-Saliva Barrier Strengthens the Feasibility of Salivary CRP as Biomarker for Neonatal Sepsis". Pharmaceutics. 13 (2): 256. doi:10.3390/pharmaceutics13020256. PMC 7917918. PMID 33673378.
^ Verbeeten KC, Ahmet AH (January 2018). "The role of corticosteroid-binding globulin in the evaluation of adrenal insufficiency". Journal of Pediatric Endocrinology & Metabolism. 31 (2): 107–115. doi:10.1515/jpem-2017-0270. PMID 29194043. S2CID 28588420.
^ Henley D, Lightman S, Carrell R (October 2016). "Cortisol and CBG - Getting cortisol to the right place at the right time" (PDF). Pharmacology & Therapeutics. 166: 128–135. doi:10.1016/j.pharmthera.2016.06.020. hdl:1983/d7ed507d-52d5-496b-ae1f-de220ae1b190. PMID 27411675. Archived (PDF) from the original on 20 August 2023. Retrieved 1 November 2023.
^ de Medeiros GF, Lafenêtre P, Janthakhin Y, Cerpa JC, Zhang CL, Mehta MM, Mortessagne P, Helbling JC, Ferreira G, Moisan MP (2019). "Corticosteroid-Binding Globulin Deficiency Specifically Impairs Contextual and Recognition Memory Consolidation in Male Mice". Neuroendocrinology. 109 (4): 322–332. doi:10.1159/000499827. PMID 30904918. S2CID 85498121.
^ Henley DE, Lightman SL (April 2011). "New insights into corticosteroid-binding globulin and glucocorticoid delivery". Neuroscience. 180: 1–8. doi:10.1016/j.neuroscience.2011.02.053. PMID 21371536. S2CID 26843500.
^ Salzano C, Saracino G, Cardillo G (October 2021). "Possible Adrenal Involvement in Long COVID Syndrome". Medicina (Kaunas). 57 (10): 1087. doi:10.3390/medicina57101087. PMC 8537520. PMID 34684123.
^ Granger DA, Hibel LC, Fortunato CK, Kapelewski CH (November 2009). "Medication effects on salivary cortisol: tactics and strategy to minimize impact in behavioral and developmental science". Psychoneuroendocrinology. 34 (10): 1437–48. doi:10.1016/j.psyneuen.2009.06.017. PMID 19632788. S2CID 3100315.
^ Lane J (2006). "Can non-invasive glucocorticoid measures be used as reliable indicators of stress in animals?". Animal Welfare. 15 (4): 331–342. doi:10.1017/S0962728600030657. S2CID 80026053.
^ Davson H (1989), "History of the Blood-Brain Barrier Concept", Implications of the Blood-Brain Barrier and Its Manipulation, Springer US, pp. 27–52, doi:10.1007/978-1-4613-0701-3_2, ISBN 978-1-4612-8039-2
^ Davson H (1 February 1976). "Review lecture. The blood-brain barrier". The Journal of Physiology. 255 (1): 1–28. doi:10.1113/jphysiol.1976.sp011267. ISSN 0022-3751. PMC 1309232. PMID 1255511.
^ Ribatti D, Nico B, Crivellato E, Artico M (25 January 2006). "Development of the blood-brain barrier: A historical point of view". The Anatomical Record Part B: The New Anatomist. 289B (1): 3–8. doi:10.1002/ar.b.20087. ISSN 1552-4906. PMID 16437552.
^ Saunders NR, Dreifuss JJ, Dziegielewska KM, Johansson PA, Habgood MD, Møllgård K, Bauer HC (2014). "The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history". Frontiers in Neuroscience. 8: 404. doi:10.3389/fnins.2014.00404. ISSN 1662-453X. PMC 4267212. PMID 25565938.
^ Konovalova TA, Kozlova MV (2023). Коморбидность Патологии Слюнных Желез И Кислотозависимых Заболеваний Желудочно-Кишечного Тракта [The Comorbidity of Salivary Gland Pathology and Acid-Dependent Diseases of the Gastrointestinal Tract]. Кремлевская Медицина. Клинический Вестник КРЕМЛЕВСКАЯ МЕДИЦИНА клинический вестник (in Russian) (1): 51–56. doi:10.48612/cgma/h9nz-etr7-ff5v.
^ "Петрович Юрий Александрович – штрихи к портрету". Archived from the original on 8 November 2023. Retrieved 8 November 2023.

[pmid32842479-1] Lin GC, Smajlhodzic M, Bandian AM, Friedl HP, Leitgeb T, Oerter S, Stadler K, Giese U, Peham JR, Bingle L, Neuhaus W (August 2020). "An In Vitro Barrier Model of the Human Submandibular Salivary Gland Epithelium Based on a Single Cell Clone of Cell Line HTB-41: Establishment and Application for Biomarker Transport Studies". Biomedicines. 8 (9): 302. doi:10.3390/biomedicines8090302. PMC 7555419. PMID 32842479.

[pmid35749597-2] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Selezneva IA, Gilmiyarova FN, Tlustenko VS, Domenjuk DA, Gusyakova OA, Kolotyeva NA, Gilmiyarova IE, Nazarkina IA (June 2022). "Hematosalivarian barrier: structure, functions, study methods (review of literature)". Klin Lab Diagn. 67 (6): 334–338. doi:10.51620/0869-2084-2022-67-6-334-338. PMID 35749597. S2CID 250022158.

[pmid11806220-3] Ulanova EA, Grigor'ev IV, Novikova IA (2001). "[Hematosalivary mechanisms of regulation in rheumatoid arthritis]". Ter Arkh (in Russian). 73 (11): 92–4. PMID 11806220.

[pmid32314665-4] Lin GC, Leitgeb T, Vladetic A, Friedl HP, Rhodes N, Rossi A, Roblegg E, Neuhaus W (April 2020). "Optimization of oral mucosa in vitro model based on cell line TR146". Tissue Barriers. 8 (2): 1748459. doi:10.1080/21688370.2020.1748459. PMC 7549749. PMID 32314665.

[pmid26485506-5] Zhang GH, Castro R (September 2015). "Role of Oral Mucosal Fluid and Electrolyte Absorption and Secretion in Dry Mouth". Chin J Dent Res. 18 (3): 135–54. PMID 26485506.

[pmid27227081-6] Walløe L (2016). "Arterio-venous anastomoses in the human skin and their role in temperature control". Temperature (Austin). 3 (1): 92–103. doi:10.1080/23328940.2015.1088502. PMC 4861183. PMID 27227081.

[pmid33673378-7] Lin GC, Küng E, Smajlhodzic M, Domazet S, Friedl HP, Angerer J, Wisgrill L, Berger A, Bingle L, Peham JR, Neuhaus W (February 2021). "Directed Transport of CRP Across In Vitro Models of the Blood-Saliva Barrier Strengthens the Feasibility of Salivary CRP as Biomarker for Neonatal Sepsis". Pharmaceutics. 13 (2): 256. doi:10.3390/pharmaceutics13020256. PMC 7917918. PMID 33673378.

[pmid29194043-8] Verbeeten KC, Ahmet AH (January 2018). "The role of corticosteroid-binding globulin in the evaluation of adrenal insufficiency". Journal of Pediatric Endocrinology & Metabolism. 31 (2): 107–115. doi:10.1515/jpem-2017-0270. PMID 29194043. S2CID 28588420.

[9] Henley D, Lightman S, Carrell R (October 2016). "Cortisol and CBG - Getting cortisol to the right place at the right time" (PDF). Pharmacology & Therapeutics. 166: 128–135. doi:10.1016/j.pharmthera.2016.06.020. hdl:1983/d7ed507d-52d5-496b-ae1f-de220ae1b190. PMID 27411675. Archived (PDF) from the original on 20 August 2023. Retrieved 1 November 2023.

[pmid30904918-10] Medeiros GF, Lafenêtre P, Janthakhin Y, Cerpa JC, Zhang CL, Mehta MM, Mortessagne P, Helbling JC, Ferreira G, Moisan MP (2019). "Corticosteroid-Binding Globulin Deficiency Specifically Impairs Contextual and Recognition Memory Consolidation in Male Mice". Neuroendocrinology. 109 (4): 322–332. doi:10.1159/000499827. PMID 30904918. S2CID 85498121.

[pmid21371536-11] Henley DE, Lightman SL (April 2011). "New insights into corticosteroid-binding globulin and glucocorticoid delivery". Neuroscience. 180: 1–8. doi:10.1016/j.neuroscience.2011.02.053. PMID 21371536. S2CID 26843500.

[pmid34684123-12] Salzano C, Saracino G, Cardillo G (October 2021). "Possible Adrenal Involvement in Long COVID Syndrome". Medicina (Kaunas). 57 (10): 1087. doi:10.3390/medicina57101087. PMC 8537520. PMID 34684123.

[pmid19632788-13] Granger DA, Hibel LC, Fortunato CK, Kapelewski CH (November 2009). "Medication effects on salivary cortisol: tactics and strategy to minimize impact in behavioral and developmental science". Psychoneuroendocrinology. 34 (10): 1437–48. doi:10.1016/j.psyneuen.2009.06.017. PMID 19632788. S2CID 3100315.

[14] Lane J (2006). "Can non-invasive glucocorticoid measures be used as reliable indicators of stress in animals?". Animal Welfare. 15 (4): 331–342. doi:10.1017/S0962728600030657. S2CID 80026053.

[15] Davson H (1989), "History of the Blood-Brain Barrier Concept", Implications of the Blood-Brain Barrier and Its Manipulation, Springer US, pp. 27–52, doi:10.1007/978-1-4613-0701-3_2, ISBN 978-1-4612-8039-2

[16] Davson H (1 February 1976). "Review lecture. The blood-brain barrier". The Journal of Physiology. 255 (1): 1–28. doi:10.1113/jphysiol.1976.sp011267. ISSN 0022-3751. PMC 1309232. PMID 1255511.

[17] Ribatti D, Nico B, Crivellato E, Artico M (25 January 2006). "Development of the blood-brain barrier: A historical point of view". The Anatomical Record Part B: The New Anatomist. 289B (1): 3–8. doi:10.1002/ar.b.20087. ISSN 1552-4906. PMID 16437552.

[18] Saunders NR, Dreifuss JJ, Dziegielewska KM, Johansson PA, Habgood MD, Møllgård K, Bauer HC (2014). "The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history". Frontiers in Neuroscience. 8: 404. doi:10.3389/fnins.2014.00404. ISSN 1662-453X. PMC 4267212. PMID 25565938.

[19] Konovalova TA, Kozlova MV (2023). Коморбидность Патологии Слюнных Желез И Кислотозависимых Заболеваний Желудочно-Кишечного Тракта [The Comorbidity of Salivary Gland Pathology and Acid-Dependent Diseases of the Gastrointestinal Tract]. Кремлевская Медицина. Клинический Вестник КРЕМЛЕВСКАЯ МЕДИЦИНА клинический вестник (in Russian) (1): 51–56. doi:10.48612/cgma/h9nz-etr7-ff5v.

[20] "Петрович Юрий Александрович – штрихи к портрету". Archived from the original on 8 November 2023. Retrieved 8 November 2023.

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PROFILPELAJAR.COM

Blood–saliva barrier

Structure

Function

Clinical significance

History

Research directions

See also

References

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