Sepsiste Kök Hücre Tedavisi
Özet
Sepsis, konakçının enfeksiyona karşı geliştirdiği kontrolsüz immün yanıt ve buna bağlı oluşan çoklu organ hasarı ile karakterize ölümcül bir sendromdur. Gelişen patofizyolojide Toll-like reseptörler (TLR) gibi patern tanıma sistemleri, endotoksinler ve dolaşıma salınan hasar molekülleri hücresel ölümü, derin hipotansiyonu ve organ yetmezliklerini tetiklemektedir. Akciğer hasarı, akut böbrek yetmezliği ve sepsis kaynaklı karaciğer disfonksiyonu gibi klinik tablolar mortaliteyi doğrudan artırmaktadır. Antibiyotik ve sıvı resüsitasyonu gibi klasik yaklaşımlarda zamanlama kritik öneme sahip olsa da günümüzde alternatif ve tamamlayıcı bir seçenek olarak mezenkimal kök hücre (MKH) tedavileri öne çıkmaktadır. MKH’ler; kemik iliği, yağ dokusu ve göbek kordon kanı gibi çeşitli kaynaklardan kolayca elde edilebilen andiferansiye hücrelerdir. Sepsisteki etki mekanizmaları çok yönlü olup proinflamatuar sitokin yanıtını baskılarken antiinflamatuar ajanların salınımını artırırlar. Ayrıca kontrolsüz nötrofil infiltrasyonunu inhibe ederek sağlam dokuların hasar görmesini engeller ve makrofajları M1 fenotipinden iyileştirici M2 fenotipine polarize ederler. Kök hücre tedavisinin in vitro üretim sürecinde yaşanabilecek telomer kısalması veya malign transformasyon gibi riskler ve hızlı temin zorlukları bulunsa da rutin bir tedavi seçeneği hâline gelmesi adına laboratuvar ve klinik çalışmaların artması büyük önem taşımaktadır.
Sepsis is a life-threatening syndrome characterized by a host's uncontrolled immune response to an infectious agent, resulting in multiple organ damage. In its complex pathophysiology, pattern recognition receptors such as Toll-like receptors (TLRs), endotoxins, and danger molecules released into circulation trigger cell death, profound hypotension, and organ failures. Clinical manifestations such as lung injury, acute kidney injury, and sepsis-induced liver dysfunction directly increase mortality. Although timing is critical for conventional approaches like antibiotics and fluid resuscitation, mesenchymal stem cell (MSC) therapies have emerged as a prominent alternative and complementary option. MSCs are undifferentiated cells that can be easily harvested from various sources, including bone marrow, adipose tissue, and umbilical cord blood. Their mechanism of action in sepsis is multifaceted; they suppress the proinflammatory cytokine response while increasing the concentration of anti-inflammatory agents. Furthermore, MSCs prevent damage to healthy tissues by inhibiting uncontrolled neutrophil infiltration and polarize macrophages from the M1 phenotype to the healing M2 phenotype. Despite challenges in rapid procurement and potential risks during in vitro expansion—such as telomere shortening or malignant transformation—increasing laboratory and clinical studies is vital for integrating stem cell therapy into routine treatment options.
Referanslar
Singer M, Deutschman CS, Seymour CW. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10.
Evans L, Rhodes A, Alhazzani W. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11): e1063-143.
Raymond SL, Holden DC, Mira JC. Microbial recognition and danger signals in sepsis and trauma. Biochim Biophys Acta Mol Basis Dis. 2017;1863(10 Pt B):2564-73.
Hagar JA, Powell DA, Aachoui Y. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science. 2013;341(6151):1250-3.
Deng M, Tang Y, Li W. The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis. Immunity. 2018;49(4):740-753.
Pool R, Gomez H, Kellum JA. Mechanisms of Organ Dysfunction in Sepsis. Crit Care Clin. 2018;34(1):63-80.
Zhang Z-S, Chen W, Li T. Organ-specific changes in vascular reactivity and roles of inducible nitric oxide synthase and endothelin-1 in a rabbit endotoxic shock model. J Trauma Acute Care Surg. 2018;85(4):725-33.
Kim W-Y, Hong S-B. Sepsis and Acute Respiratory Distress Syndrome: Recent Update. Tuberc Respir Dis. 2016;79(2):53-7.
Bagshaw SM, Uchino S, Bellomo R. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol CJASN. 2007;2(3):431-9.
Godin M, Murray P, Mehta RL. Clinical approach to the patient with AKI and sepsis. Semin Nephrol. 2015;35(1):12-22.
Rhodes A, Evans LE, Alhazzani W. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77.
Woźnica EA, Inglot M, Woźnica RK. Liver dysfunction in sepsis. Adv Clin Exp Med Off Organ Wroclaw Med Univ. 2018;27(4):547-51.
Brierre S, Kumari R, Deboisblanc BP. The endocrine system during sepsis. Am J Med Sci. 2004;328(4):238-47.
Kumar A, Roberts D, Wood KE. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-96.
Keane C, Jerkic M, Laffey JG. Stem Cell–based Therapies for Sepsis. Anesthesiology. 2017;127(6):1017-34.
Laroye C, Gibot S, Reppel L. Concise Review: Mesenchymal Stromal/Stem Cells: A New Treatment for Sepsis and Septic Shock? Stem Cells Dayt Ohio. 2017;35(12):2331-9.
Mushahary D, Spittler A, Kasper C. Isolation, cultivation, and characterization of human mesenchymal stem cells. Cytom Part J Int Soc Anal Cytol. 2018;93(1):19-31.
Pittenger MF, Mackay AM, Beck SC. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143-7.
Fraser JK, Wulur I, Alfonso Z. Fat tissue: an underappreciated source of stem cells for biotechnology. Trends Biotechnol. 2006;24(4):150-4.
Mao Q, Nguyen PD, Shanti RM. Gingiva-Derived Mesenchymal Stem Cell-Extracellular Vesicles Activate Schwann Cell Repair Phenotype and Promote Nerve Regeneration. Tissue Eng Part A. 2019;25(11-12):887-900.
In ’t Anker PS, Scherjon SA, Kleijburg-van der Keur C. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells Dayt Ohio. 2004;22(7):1338-45.
Bieback K, Kern S, Klüter H. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells Dayt Ohio. 2004;22(4):625-34.
Cribbs SK, Matthay MA, Martin GS. Stem cells in sepsis and acute lung injury. Crit Care Med. 2010;38(12):2379-85.
Miao C-M, Jiang X-W, He K. Bone marrow stromal cells attenuate LPS-induced mouse acute liver injury via the prostaglandin E 2-dependent repression of the NLRP3 inflammasome in Kupffer cells. Immunol Lett. 2016; 179:102-13.
Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159-75.
Sônego F, Castanheira FVES, Ferreira RG. Paradoxical Roles of the Neutrophil in Sepsis: Protective and Deleterious. Front Immunol. 2016;7:155.
Chen J, Li C, Liang Z. Human mesenchymal stromal cells small extracellular vesicles attenuate sepsis-induced acute lung injury in a mouse model: the role of oxidative stress and the mitogen-activated protein kinase/nuclear factor kappa B pathway. Cytotherapy. 2021;23(10):918-30.
Sheng M, Lin Y, Xu D. CD47-Mediated Hedgehog/SMO/GLI1 Signaling Promotes Mesenchymal Stem Cell Immunomodulation in Mouse Liver Inflammation. Hepatol Baltim Md. 2021;74(3):1560-77.
Luo C, Zhang F, Zhang L. Mesenchymal stem cells ameliorate sepsis-associated acute kidney injury in mice. Shock Augusta Ga. 2014;41(2):123-9.
Lin L, Du L. The role of secreted factors in stem cells-mediated immune regulation. Cell Immunol. 2018; 326:24-32.
Wise AF, Williams TM, Rudd S. Human mesenchymal stem cells alter the gene profile of monocytes from patients with Type 2 diabetes and end-stage renal disease. Regen Med. 2016;11(2):145-58.
Sarugaser R, Hanoun L, Keating A. Human mesenchymal stem cells self-renew and differentiate according to a deterministic hierarchy. PloS One. 2009;4(8): e6498.
Rubio D, Garcia S, Paz MF. Molecular characterization of spontaneous mesenchymal stem cell transformation. PloS One. 2008;3(1): e1398.
