Year 2021 Vol. 29 No 2




Pirogov Russian National Research Medical University, Moscow,
The Russian Federation

Obstruction of the lumen of the appendix is still considered to be the main cause of acute appendicitis (including feces), followed by the increased intraluminal pressure, the development of ischemia and mucosal hypoxia of the appendix, ulceration, violation of the mucous barrier and the development of necrosis. A sufficient number of scientific facts have been accumulated completely refuting this postulate. Current fundamental achievements in molecular biology, biochemistry, etc. did not become the basis for a clinical revision of the ancient well-established theories and concepts of the etiopathogenesis of many diseases in almost all medical specialties. Surgery isnt an exception in this context. The review considers the etiopathogenesis of acute inflammation of the appendix from the current point of view of the hypothesis of epithelial-endothelial dysfunction and epithelial-endothelial distress syndrome, since it most fully characterizes the integration of the etiopathogenesis of almost all common diseases of organs with mucous membranes and the recent fundamental research their structures and functions. It is based on general and local factors of violation of the lymphoid apparatus and the integumentary epithelium barrier functions. Thus, this work presents a new concept of the etiopathogenesis of acute appendicitis, which in turn will allow the surgery of acute appendicitis to reach new levels of understanding.

Keywords: acute appendicitis, etiopathogenesis of appendicitis, a new concept, epithelial-endothelial distress syndrome, microbiota
p. 221-233 of the original issue
  1. Williams GR. Presidential Address: a history of appendicitis. With anecdotes illustrating its importance. Ann Surg. 1983 May;197(5):495-506. doi: 10.1097/00000658-198305000-00001
  2. Khan MS, Chaudhry MBH, Shahzad N, Tariq M, Memon WA, Alvi AR. Risk of appendicitis in patients with incidentally discovered appendicoliths. J Surg Res. 2018 Jan;221:84-87. doi: 10.1016/j.jss.2017.08.021
  3. Kolesov VI, red. Ostryi appenditsit. Leningrad: MEDGIZ; 1959. 290 p. (In Russ.)
  4. Chandrasegaram MD, Rothwell LA, An EI, Miller RJ. Pathologies of the appendix: a 10-year review of 4670 appendicectomy specimens. ANZ J Surg. 2012 Nov;82(11):844-47. doi: 10.1111/j.1445-2197.2012.06185.x
  5. Swidsinski A, Dörffel Y, Loening-Baucke V, Theissig F, Rückert JC, Ismail M, Rau WA, Gaschler D, Weizenegger M, Kühn S, Schilling J, Dörffel WV. Acute appendicitis is characterised by local invasion with Fusobacterium nucleatum/necrophorum. Gut. 2011 Jan;60(1):34-40. doi: 10.1136/gut.2009.191320
  6. Arnbjörnsson E, Bengmark S. Role of obstruction in the pathogenesis of acute appendicitis. Am J Surg. 1984 Mar;147(3):390-92. doi: 10.1016/0002-9610(84)90174-0
  7. Petukhov VA, Kriukov AI, Petukhova NA. Lipidnyi distress-sindrom. Moscow, RF: Borges; 2018; 600 p. (In Russ.)
  8. Sarkisov DS. Ocherki istorii obshchei patologii. Moscow, RF: Meditsina; 1994. 336 p.
  9. Hajishengallis G, Lamont RJ. Dancing with the stars: how choreographed bacterial interactions dictate nososymbiocity and give rise to keystone pathogens, accessory pathogens, and pathobionts. Trends Microbiol. 2016 Jun;24(6):477-89. doi: 10.1016/j.tim.2016.02.010
  10. Vitetta L, Chen J, Clarke S. The vermiform appendix: an immunological organ sustaining a microbiome inoculum. Clin Sci (Lond). 2019 Jan 3;133(1):1-8. doi: 10.1042/CS20180956
  11. Lu M, Munford RS. The transport and inactivation kinetics of bacterial lipopolysaccharide influence its immunological potency in vivo. J Immunol. 2011 Sep 15;187(6):3314-20. doi: 10.4049/jimmunol.1004087
  12. Hajishengallis G, Darveau RP, Curtis MA. The keystone-pathogen hypothesis. Nat Rev Microbiol. 2012 Oct;10(10):717-25. doi: 10.1038/nrmicro2873
  13. Kane M, Case LK, Kopaskie K, Kozlova A, MacDearmid C, Chervonsky AV, Golovkina TV. Successful transmission of a retrovirus depends on the commensal microbiota. Science. 2011 Oct 14;334(6053):245-49. doi: 10.1126/science.1210718
  14. Sears CL. Enterotoxigenic Bacteroides fragilis: a rogue among symbiotes. Clin Microbiol Rev. 2009 Apr;22(2):349-69, Table of Contents. doi: 10.1128/CMR.00053-08
  15. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Doré J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J; MetaHIT Consortium, Bork P, Ehrlich SD, Wang J. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010 Mar 4;464(7285):59-65. doi: 10.1038/nature08821
  16. dHennezel E, Abubucker S, Murphy LO, Cullen TW. Total lipopolysaccharide from the human gut microbiome silences toll-like receptor signaling. mSystems. 2017 Nov 14;2(6). pii: e00046-17. doi: 10.1128/mSystems.00046-17. eCollection 2017 Nov-Dec.
  17. Rossi O, Khan MT, Schwarzer M, Hudcovic T, Srutkova D, Duncan SH, Stolte EH, Kozakova H, Flint HJ, Samsom JN, Harmsen HJ, Wells JM. Faecalibacterium prausnitzii strain HTF-F and its extracellular polymeric matrix attenuate clinical parameters in DSS-Induced Colitis. PLoS One. 2015 Apr 24;10(4):e0123013. doi: 10.1371/journal.pone.0123013. eCollection 2015.
  18. Siracusa F, Schaltenberg N, Villablanca EJ, Huber S, Gagliani N. Dietary habits and intestinal immunity: from food intake to CD4+ T H Cells. Front Immunol. 2019 Jan 15;9:3177. doi: 10.3389/fimmu.2018.03177. eCollection 2018.
  19. Worthington JJ. The intestinal immunoendocrine axis: novel cross-talk between enteroendocrine cells and the immune system during infection and inflammatory disease. Biochem Soc Trans. 2015 Aug;43(4):727-33. doi: 10.1042/BST20150090
  20. Kroemer A, Elsabbagh AM, Matsumoto CS, Zasloff M, Fishbein TM. The microbiome and its implications in intestinal transplantation. Curr Opin Organ Transplant. 2016 Apr;21(2):135-39. doi: 10.1097/MOT.0000000000000278
  21. McElroy SJ, Underwood MA, Sherman MP. Paneth cells and necrotizing enterocolitis: a novel hypothesis for disease pathogenesis. Neonatology. 2013;103(1):10-20. doi: 10.1159/000342340
  22. Nowicki PT. Ischemia and necrotizing enterocolitis: where, when, and how. Semin Pediatr Surg. 2005 Aug;14(3):152-18. doi: 10.1053/j.sempedsurg.2005.05.003
  23. Bockman DE. Functional histology of appendix. Arch Histol Jpn. 1983 Jun;46(3):271-92. doi: 10.1679/aohc.46.271
  24. Watson Ng W, Hampartzoumian T, Lloyd A, Grimm M. A murine model of appendicitis and the impact of inflammation on appendiceal lymphocyte constituents. Clin Exp Immunol. 2007 Oct;150(1):169-78. doi: 10.1111/j.1365-2249.2007.03463.x
  25. Al-Soudi A, Kaaij MH, Tas SW. Endothelial cells: From innocent bystanders to active participants in immune responses. Autoimmun Rev. 2017 Sep;16(9):951-62. doi: 10.1016/j.autrev.2017.07.008
  26. Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. 2007 Oct;7(10):803-15. doi: 10.1038/nri2171
  27. Voisin MB, Nourshargh S. Neutrophil transmigration: emergence of an adhesive cascade within venular walls. J Innate Immun. 2013;5(4):336-47. doi: 10.1159/000346659
  28. Weninger W, Biro M, Jain R. Leukocyte migration in the interstitial space of non-lymphoid organs. Nat Rev Immunol. 2014 Apr;14(4):232-46. doi: 10.1038/nri3641
  29. Ager A. High Endothelial Venules and Other Blood Vessels: Critical Regulators of Lymphoid Organ Development and Function. Front Immunol. 2017 Feb 3;8:45. doi: 10.3389/fimmu.2017.00045. eCollection 2017.
  30. Geng YJ, Hansson GK. High endothelial cells of postcapillary venules express the scavenger receptor in human peripheral lymph nodes. Scand J Immunol. 1995 Sep;42(3):289-96. doi: 10.1111/j.1365-3083.1995.tb03658.x
  31. Hirosue S, Vokali E, Raghavan VR, Rincon-Restrepo M, Lund AW, Corthésy-Henrioud P, Capotosti F, Halin Winter C, Hugues S, Swartz MA. Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells. J Immunol. 2014 Jun 1;192(11):5002-11. doi: 10.4049/jimmunol.1302492
  32. Anichkov NM, Ashoff L. 12 ocherkov po istorii patologii i meditsiny. S-Petersburg, RF: Sintez buk; 2013. 238 p. (In Russ.)
  33. Randolph GJ, Ivanov S, Zinselmeyer BH, Scallan JP. The Lymphatic System: Integral Roles in Immunity. Annu Rev Immunol. 2017 Apr 26;35:31-52. doi: 10.1146/annurev-immunol-041015-055354
  34. Levick JR, Michel CC. Microvascular fluid exchange and the revised Starling principle. Cardiovasc Res. 2010 Jul 15;87(2):198-10. doi: 10.1093/cvr/cvq062
  35. Mehta D, Malik AB. Signaling mechanisms regulating endothelial permeability. Physiol Rev. 2006 Jan;86(1):279-367. doi: 10.1152/physrev.00012.2005
  36. Förster R, Schubel A, Breitfeld D, Kremmer E, Renner-Müller I, Wolf E, Lipp M. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 1999 Oct 1;99(1):23-33. doi: 10.1016/s0092-8674(00)80059-8
  37. Lee KM, McKimmie CS, Gilchrist DS, Pallas KJ, Nibbs RJ, Garside P, McDonald V, Jenkins C, Ransohoff R, Liu L, Milling S, Cerovic V, Graham GJ. D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion. Blood. 2011 Dec 1;118(23):6220-29. doi: 10.1182/blood-2011-03-344044
  38. Bouta EM, Wood RW, Brown EB, Rahimi H, Ritchlin CT, Schwarz EM. In vivo quantification of lymph viscosity and pressure in lymphatic vessels and draining lymph nodes of arthritic joints in mice. J Physiol. 2014 Mar 15;592(6):1213-23. doi: 10.1113/jphysiol.2013.266700
  39. Angeli V, Ginhoux F, Llodrà J, Quemeneur L, Frenette PS, Skobe M, Jessberger R, Merad M, Randolph GJ. B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity. 2006 Feb;24(2):203-15. doi: 10.1016/j.immuni.2006.01.003
  40. Sarma DR, Thomas D, Watson M. Retained mesoappendix fat nodule mimicking appendicitis. Journal of Gastroenterology and Its Complications (JGIC). 2016;1(1). doi: 10.15744/2575-5501.1.101
  41. de Souza HS, Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol. 2016 Jan;13(1):13-27. doi: 10.1038/nrgastro.2015.186
  42. Pipi E, Nayar S, Gardner DH, Colafrancesco S, Smith C, Barone F. Tertiary lymphoid structures: autoimmunity goes local. Front Immunol. 2018 Sep 12;9:1952. doi: 10.3389/fimmu.2018.01952. eCollection 2018.
  43. Kuan EL, Ivanov S, Bridenbaugh EA, Victora G, Wang W, Childs EW, Platt AM, Jakubzick CV, Mason RJ, Gashev AA, Nussenzweig M, Swartz MA, Dustin ML, Zawieja DC, Randolph GJ. Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells. J Immunol. 2015 Jun 1;194(11):5200-10. doi: 10.4049/jimmunol.1500221
  44. Gunn MD, Kyuwa S, Tam C, Kakiuchi T, Matsuzawa A, Williams LT, Nakano H. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med. 1999 Feb 1;189(3):451-60. doi: 10.1084/jem.189.3.451
  45. Knight SC. Specialized perinodal fat fuels and fashions immunity. Immunity. 2008 Feb;28(2):135-38. doi: 10.1016/j.immuni.2008.01.003
  46. Kokkonen TS, Augustin MT, Mäkinen JM, Kokkonen J, Karttunen TJ. High endothelial venules of the lymph nodes express Fas ligand. J Histochem Cytochem. 2004 May;52(5):693-99. doi: 10.1177/002215540405200513
  47. Kokkonen TS, Karttunen TJ. Fas/Fas ligand-mediated apoptosis in different cell lineages and functional compartments of human lymph nodes. J Histochem Cytochem. 2010 Feb;58(2):131-40. doi: 10.1369/jhc.2009.954669
  48. Kokkonen T, Karttunen T. Endothelial fas-ligand in inflammatory bowel diseases and in acute appendicitis. J Histochem Cytochem. 2015 Dec; 63(12):931-42. Published online 2015 Sep 15. doi: 10.1369/0022155415608917
  49. Hauser AE, Junt T, Mempel TR, Sneddon MW, Kleinstein SH, Henrickson SE, von Andrian UH, Shlomchik MJ, Haberman AM. Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns. Immunity. 2007 May;26(5):655-67. doi: 10.1016/j.immuni.2007.04.008
  50. Peter ME, Budd RC, Desbarats J, Hedrick SM, Hueber AO, Newell MK, Owen LB, Pope RM, Tschopp J, Wajant H, Wallach D, Wiltrout RH, Zörnig M, Lynch DH. The CD95 receptor: apoptosis revisited. Cell. 2007 May 4;129(3):447-50. doi: 10.1016/j.cell.2007.04.031
Address for correspondence:
117997, Russian Federation,
Moscow, Ostrovityanov Str.,
Pirogov Russian National Research Medical University, the Faculty Surgery Department No1,
tel.: +7 (916) 223-46-60,
Stradymov Egor A.
Information about the authors:
Sazhin Aleksandr V., MD, Professor, Corresponding member of RAS, Head of the Faculty Surgery Department No1 Pirogov Russian National Research Medical University, Moscow, Russian Federation.
Petukhov Vitalii A., MD, Professor of the Faculty Surgery Department No1 PirogovRussian National Research Medical University, Moscow, Russian Federation.
Nechay Taras V., PhD, Associate Professor of the Faculty Surgery Department No1 Pirogov Russian National Research Medical University, Moscow, Russian Federation.
Ivakhov Georgii B., PhD, Associate Professor of the Faculty Surgery Department No 1 Pirogov Russian National Research Medical University, Moscow, Russian Federation.
Stradymov Egor A., Assistant of the Faculty Surgery Department No 1 Pirogov Russian National Research Medical University, Moscow, Russian Federation.
Akperov Aliverdi I., Clinical Intern of the Faculty Surgery Department No 1 Pirogov Russian National Research Medical University, Moscow, Russian Federation.
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