Öz
Giriş: Sepsiste düzensiz sistemik enflamatuvar yanıt, sekonder akut akciğer hasarına (ALI) neden olabilir. Bu akciğer dokusunun abartılı enflamasyonu ile karakterizedir. Kolşisin bazı enflamatuvar yolları inhibe ederek sepsis kaynaklı akciğer hasarını önleyebilir. Bu çalışma, lipopolisakarit (LPS) ile oluşturulan deneysel sıçan sepsis modelinde kolşisinin akciğer dokusu üzerindeki histopatolojik etkilerini incelemek için tasarlanmıştır.
Gereç ve Yöntem: Yirmi sekiz sıçan rastgele dört gruba ayrıldı; altışar sıçan ‘sham’ (grup 1) ve ‘sadece kolşisin’ (grup 2) gruplarına, sekizer sıçan ‘sadece sepsis’ (grup 3) ve ‘sepsis+kolşisin’ (grup 4) gruplarına ayrıldı. Grup 1’e (sham) hem intraperitoneal (IP) hem de intragastrik (IG) olarak %0,9 NaCl verildi. Grup 2’ye (sadece kolşisin grubu) IP NaCl ve IG kolşisin verildi. Grup 3 ve 4’te sepsis, 0 zaman noktasında 1 mg/kg LPS IP uygulanmasıyla indüklendi. Grup 4’e deneyin 90. dakikasında, ek olarak IG olarak kolşisin verildi. Sepsis belirtilerini gözlemlemek için gözlemsel sepsis skorlama sistemi kullanıldı ve sıçanlar 24. saatte sakrifiye edildi. Akciğer dokuları Amerikan Toraks Derneği’nin hayvanlarda ALI’ye ilişkin değerlendirme raporuna göre incelendi.
Bulgular: Histopatolojik akciğer hasarı skorlama sistemi değerlendirmesine göre; ‘sepsis+kolşisin’ grubunda skor ‘sham’ grubuna göre anlamlı olarak yüksek (0,23±0,18’e karşı 0±0, p<0,05), ancak ‘sadece sepsis’ grubuna göre anlamlı olarak düşük bulundu (0,23±0,18’e karşı 0,57±0,14, p<0,001). Akciğer hasar skorunun analizinde: kolşisin, ‘sepsis+kolşisin’ grubunda ‘sadece sepsis’ grubuna göre alveolar ve interstisyel nötrofil sayısındaki artışı baskılamış, hiyalin membran sayısındaki ve alveolar duvar kalınlığındaki artışı da sınırlamış olarak gözlendi.
Sonuç: Çalışmamızda oluşturduğumuz deneysel sepsis sıçan modelinde sepsis oluştuktan sonra verilen kolşisinin sepsise bağlı sekonder akciğer hasarını sınırladığı görülmüştür.
Anahtar Kelimeler: Sepsis, akut akciğer hasarı, kolşisin, sıçan deney modeli
Kaynakça
Stapleton RD, Wang BM, Hudson LD, Rubenfeld GD, Caldwell ES, Steinberg KP. Causes and timing of death in patients with ARDS. Chest. 2005;128:525-32.
Kim WY, Hong SB. Sepsis and Acute Respiratory Distress Syndrome: Recent Update. Tuberc Respir Dis (Seoul). 2016;79:53-7.
Han S, Mallampalli RK. The acute respiratory distress syndrome: from mechanism to translation. J Immunol. 2015;194:855-60.
Thommasen HV, Russell JA, Boyko WJ, Hogg JC. Transient leucopenia associated with adult respiratory distress syndrome. Lancet. 1984;1:809-12.
Hogg JC. Neutrophil kinetics and lung injury. Physiological Reviews. 1987;67:1249-95.
Williams AE, Chambers RC. The mercurial nature of neutrophils: still an enigma in ARDS? Am J Physiol Lung Cell Mol Physiol. 2014;306:217-30.
Leung YY, Yao Hui LL, Kraus VB. Colchicine--Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015;45:341-50.
Martínez GJ, Celermajer DS, Patel S. The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation. Atherosclerosis. 2018;269:262-71.
Fu Y, Cheng Y, Wu Y. Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools. Virol Sin. 2020;35:266-71.
Lien CH, Lee MD, Weng SL, Lin CH, Liu LY, Tai YL, Lei WT, Liu JM, Huang YN, Chi H, Chiu NC, Lin CY. Repurposing Colchicine in Treating Patients with COVID-19: A Systematic Review and Meta-Analysis. Life (Basel). 2021;11:864.
Shrum B, Anantha RV, Xu SX, Donnelly M, Haeryfar SM, McCormick JK, Mele T. A robust scoring system to evaluate sepsis severity in an animal model. BMC Res Notes. 2014;7:233.
Chappey ON, Niel E, Wautier JL, Hung PP, Dervichian M, Cattan D, Scherrmann JM. Colchicine disposition in human leukocytes after single and multiple oral administration. Clin Pharmacol Ther. 1993;54:360-7.
Matute-Bello G, Downey G, Moore BB, Groshong SD, Matthay MA, Slutsky AS, Kuebler WM. An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol. 2011;44:725-38.
Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2008;295:379-99.
Fodor RŞ, Georgescu AM, Cioc AD, Grigorescu BL, Cotoi OS, Fodor P, Copotoiu SM, Azamfirei L. Time- and dose-dependent severity of lung injury in a rat model of sepsis. Rom J Morphol Embryol. 2015;56:1329-37.
Domscheit H, Hegeman MA, Carvalho N, Spieth PM. Molecular Dynamics of Lipopolysaccharide-Induced Lung Injury in Rodents. Front Physiol. 2020;11:36.
Festing MF. Genetic variation in outbred rats and mice and its implications for toxicological screening. J Exp Anim Sci. 1993;35:210-20.
Üstündağ DGB. Are we doing wrong by providing nutritional support in sepsis treatment? Is physiological starving the key solution? Dokuz Eylül Üniversitesi, Tıp Fakültesi, Turkey. 2020;108.
Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7:27-31.
Kenig A, Keidar-Haran T, Azmanov H, Kessler A, Kolben Y, Tayri-Wilk T, Kalisman N, Weksler-Zangen S, Ilan Y. Low-Dose Colchicine Attenuates Sepsis-Induced Liver Injury: A Novel Method for Alleviating Systemic Inflammation. Inflammation. 2023;46:963-74.
Dupuis J, Sirois MG, Rhéaume E, Nguyen QT, Clavet-Lanthier MÉ, Brand G, Mihalache-Avram T, Théberge-Julien G, Charpentier D, Rhainds D, Neagoe PE, Tardif JC. Colchicine reduces lung injury in experimental acute respiratory distress syndrome. PLoS One. 2020;15:e0242318.
Yue Q, Liu T, Cheng Z. Protective Effect of Colchicine on LPS-Induced Lung Injury in Rats via Inhibition of P-38, ERK1/2, and JNK Activation. Pharmacology. 2020;105:639-44.
Ozdemir R, Yurttutan S, Talim B, Uysal B, Erdeve O, Oguz SS, Dilmen U. Colchicine protects against hyperoxic lung injury in neonatal rats. Neonatology. 2012;102:265-9.
Ghio AJ, Kennedy TP, Hatch GE, Tepper JS. Reduction of neutrophil influx diminishes lung injury and mortality following phosgene inhalation. J Appl Physiol (1985). 1991;71:657-65.
Deftereos S, Giannopoulos G, Vrachatis DA, Siasos G, Giotaki SG, Cleman M, Dangas G, Stefanadis C. Colchicine as a potent anti-inflammatory treatment in COVID-19: can we teach an old dog new tricks? Eur Heart J Cardiovasc Pharmacother. 2020;6:255.
Tardif JC, Bouabdallaoui N, L’Allier PL, Gaudet D, Shah B, Pillinger MH, Lopez-Sendon J, da Luz P, Verret L, Audet S, Dupuis J, Denault A, Pelletier M, Tessier PA, Samson S, Fortin D, Tardif JD, Busseuil D, Goulet E, Lacoste C, Dubois A, Joshi AY, Waters DD, Hsue P, Lepor NE, Lesage F, Sainturet N, Roy-Clavel E, Bassevitch Z, Orfanos A, Stamatescu G, Grégoire JC, Busque L, Lavallée C, Hétu PO, Paquette JS, Deftereos SG, Levesque S, Cossette M, Nozza A, Chabot-Blanchet M, Dubé MP, Guertin MC, Boivin G; COLCORONA Investigators. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med. 2021;9:924-32.
RECOVERY Collaborative Group. Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet Respir Med. 2021;9:1419-26.
Dorward J, Yu LM, Hayward G, Saville BR, Gbinigie O, Van Hecke O, Ogburn E, Evans PH, Thomas NP, Patel MG, Richards D, Berry N, Detry MA, Saunders C, Fitzgerald M, Harris V, Shanyinde M, de Lusignan S, Andersson MI, Butler CC, Hobbs FR; PRINCIPLE Trial Collaborative Group. Colchicine for COVID-19 in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial. Br J Gen Pract. 2022;72:e446-e55.
Lu N, Yang Y, Liu H, Ding X, Ou Y, Xia J, Du Y. Inhibition of respiratory syncytial virus replication and suppression of RSV-induced airway inflammation in neonatal rats by colchicine. 3 Biotech. 2019;9:392.
Ognibene FP, Martin SE, Parker MM, Schlesinger T, Roach P, Burch C, Shelhamer JH, Parrillo JE. Adult respiratory distress syndrome in patients with severe neutropenia. N Engl J Med. 1986;315:547-51.
Wiesenfeld PL, Garthoff LH, Sobotka TJ, Suagee JK, Barton CN. Acute oral toxicity of colchicine in rats: effects of gender, vehicle matrix and pre-exposure to lipopolysaccharide. J Appl Toxicol. 2007;27:421-33.
Igarashi S, Nozu T, Ishioh M, Kumei S, Saito T, Toki Y, Hatayama M, Yamamoto M, Shindo M, Tanabe H, Okumura T. Centrally administered orexin prevents lipopolysaccharide and colchicine induced lethality via the vagal cholinergic pathway in a sepsis model in rats. Biochem Pharmacol. 2020;182:114262.
Jiang Z, Hong Z, Guo W, Xiaoyun G, Gengfa L, Yongning L, Guangxia X. A synthetic peptide derived from bactericidal/permeability-increasing protein neutralizes endotoxin in vitro and in vivo. Int Immunopharmacol. 2004;4:527-37.
Lechner AJ, Velasquez A, Knudsen KR, Johanns CA, Tracy TF Jr, Matuschak GM. Cholestatic liver injury increases circulating TNF-alpha and IL-6 and mortality after Escherichia coli endotoxemia. Am J Respir Crit Care Med. 1998;157:1550-8.
