OBJECTIVE: To investigate the effect of ulinastatin on the inflammatory mediators and their signaling pathways miR-146a/TLR4/NF-κB in rats with hemorrhagic shock. METHODS: Seventy-two SD rats were randomly assigned into shock without resuscitation group (SR group, n=24), acetated Ringer's solution resuscitation group (AR group, n=24) and ulinastatin treatment group (n=24). In all the 3 groups hemorrhagic shock models were established by femoral artery bleeding (with the mean arterial pressure maintained at 30-40 mmHg) without resuscitation (in SR group) or with resuscitation (in AR and ulinastatin groups) using acetated Ringer's solution for 30 min at 60 min after the onset of shock. At 1, 4, and 6 h after the shock onset or immediately after shock if the rats died, the lung tissues were taken for measurement of mRNA expressions of miR-146a, tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-4, IL-6 and IL-10 using real-time quantitative PCR and the protein expressions of TLR4, MyD88, IκB-α, p-IκB-α, NF-κB p65, IRAK4, p-IRAK4 (Thr345, Ser346), p-IRAK4 (Thr342) and TRAF6 using Western blotting. The lung histopathology of the rats was examined under optical microscope with HE staining. RESULTS: Compared with the SR group, the rats in the AR group showed slightly alleviated inflammatory infiltration in the lung tissues with significantly increased mRNA levels of miR-146a, IL-4 and IL-10 (P < 0.05) and protein expressions of IκB-α, p-IRAK4 (Thr342) and p-IRAK4 (Thr345, ser346) (P < 0.05), and decreased mRNA levels of TNF-α, IL-1 and IL-6 (P < 0.05) and protein expressions of TLR4, MyD88, NF-κB p65, p-IκB-α, IRAK-4 and TRAF6 (P < 0.05). Compared with those in AR group, the rats in ulinastatin group showed further alleviation of inflammatory lung tissue injury, with increased mRNA levels of miR-146a, IL-4 and IL-10 (P < 0.01) and protein expressions of IκB-α, p-IRAK4 and p-IRAK4 (P < 0.01) and decreased mRNA levels of TNF-α, IL-1 and IL-6 (P < 0.01) and protein expressions of TLR4, MyD88, NF-κB p65, p-IκB-α, IRAK-4 and TRAF6 (P < 0.01). CONCLUSIONS: Ulinastatin combined with acetated Ringer's solution resuscitation alleviates lung inflammations in rats with hemorrhagic shock possibly by enhancing miR-146a expression to regulate TLR4/NF-κB signaling pathway through a negative feedback mechanism and thus modulate the balance of pro-inflammatory and anti-inflammatory factors.
OBJECTIVE: To investigate the effect of ulinastatin on the inflammatory mediators and their signaling pathways miR-146a/TLR4/NF-κB in rats with hemorrhagic shock. METHODS: Seventy-two SD rats were randomly assigned into shock without resuscitation group (SR group, n=24), acetated Ringer's solution resuscitation group (AR group, n=24) and ulinastatin treatment group (n=24). In all the 3 groups hemorrhagic shock models were established by femoral artery bleeding (with the mean arterial pressure maintained at 30-40 mmHg) without resuscitation (in SR group) or with resuscitation (in AR and ulinastatin groups) using acetated Ringer's solution for 30 min at 60 min after the onset of shock. At 1, 4, and 6 h after the shock onset or immediately after shock if the rats died, the lung tissues were taken for measurement of mRNA expressions of miR-146a, tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-4, IL-6 and IL-10 using real-time quantitative PCR and the protein expressions of TLR4, MyD88, IκB-α, p-IκB-α, NF-κB p65, IRAK4, p-IRAK4 (Thr345, Ser346), p-IRAK4 (Thr342) and TRAF6 using Western blotting. The lung histopathology of the rats was examined under optical microscope with HE staining. RESULTS: Compared with the SR group, the rats in the AR group showed slightly alleviated inflammatory infiltration in the lung tissues with significantly increased mRNA levels of miR-146a, IL-4 and IL-10 (P < 0.05) and protein expressions of IκB-α, p-IRAK4 (Thr342) and p-IRAK4 (Thr345, ser346) (P < 0.05), and decreased mRNA levels of TNF-α, IL-1 and IL-6 (P < 0.05) and protein expressions of TLR4, MyD88, NF-κB p65, p-IκB-α, IRAK-4 and TRAF6 (P < 0.05). Compared with those in AR group, the rats in ulinastatin group showed further alleviation of inflammatory lung tissue injury, with increased mRNA levels of miR-146a, IL-4 and IL-10 (P < 0.01) and protein expressions of IκB-α, p-IRAK4 and p-IRAK4 (P < 0.01) and decreased mRNA levels of TNF-α, IL-1 and IL-6 (P < 0.01) and protein expressions of TLR4, MyD88, NF-κB p65, p-IκB-α, IRAK-4 and TRAF6 (P < 0.01). CONCLUSIONS:Ulinastatin combined with acetated Ringer's solution resuscitation alleviates lung inflammations in rats with hemorrhagic shock possibly by enhancing miR-146a expression to regulate TLR4/NF-κB signaling pathway through a negative feedback mechanism and thus modulate the balance of pro-inflammatory and anti-inflammatory factors.
Authors: Khalid Almahmoud; Rami A Namas; Othman Abdul-Malak; Akram M Zaaqoq; Ruben Zamora; Brian S Zuckerbraun; Jason Sperry; Andrew B Peitzman; Timothy R Billiar; Yoram Vodovotz Journal: Shock Date: 2015-08 Impact factor: 3.454
Authors: Rafael Lozano; Mohsen Naghavi; Kyle Foreman; Stephen Lim; Kenji Shibuya; Victor Aboyans; Jerry Abraham; Timothy Adair; Rakesh Aggarwal; Stephanie Y Ahn; Miriam Alvarado; H Ross Anderson; Laurie M Anderson; Kathryn G Andrews; Charles Atkinson; Larry M Baddour; Suzanne Barker-Collo; David H Bartels; Michelle L Bell; Emelia J Benjamin; Derrick Bennett; Kavi Bhalla; Boris Bikbov; Aref Bin Abdulhak; Gretchen Birbeck; Fiona Blyth; Ian Bolliger; Soufiane Boufous; Chiara Bucello; Michael Burch; Peter Burney; Jonathan Carapetis; Honglei Chen; David Chou; Sumeet S Chugh; Luc E Coffeng; Steven D Colan; Samantha Colquhoun; K Ellicott Colson; John Condon; Myles D Connor; Leslie T Cooper; Matthew Corriere; Monica Cortinovis; Karen Courville de Vaccaro; William Couser; Benjamin C Cowie; Michael H Criqui; Marita Cross; Kaustubh C Dabhadkar; Nabila Dahodwala; Diego De Leo; Louisa Degenhardt; Allyne Delossantos; Julie Denenberg; Don C Des Jarlais; Samath D Dharmaratne; E Ray Dorsey; Tim Driscoll; Herbert Duber; Beth Ebel; Patricia J Erwin; Patricia Espindola; Majid Ezzati; Valery Feigin; Abraham D Flaxman; Mohammad H Forouzanfar; Francis Gerry R Fowkes; Richard Franklin; Marlene Fransen; Michael K Freeman; Sherine E Gabriel; Emmanuela Gakidou; Flavio Gaspari; Richard F Gillum; Diego Gonzalez-Medina; Yara A Halasa; Diana Haring; James E Harrison; Rasmus Havmoeller; Roderick J Hay; Bruno Hoen; Peter J Hotez; Damian Hoy; Kathryn H Jacobsen; Spencer L James; Rashmi Jasrasaria; Sudha Jayaraman; Nicole Johns; Ganesan Karthikeyan; Nicholas Kassebaum; Andre Keren; Jon-Paul Khoo; Lisa Marie Knowlton; Olive Kobusingye; Adofo Koranteng; Rita Krishnamurthi; Michael Lipnick; Steven E Lipshultz; Summer Lockett Ohno; Jacqueline Mabweijano; Michael F MacIntyre; Leslie Mallinger; Lyn March; Guy B Marks; Robin Marks; Akira Matsumori; Richard Matzopoulos; Bongani M Mayosi; John H McAnulty; Mary M McDermott; John McGrath; George A Mensah; Tony R Merriman; Catherine Michaud; Matthew Miller; Ted R Miller; Charles Mock; Ana Olga Mocumbi; Ali A Mokdad; Andrew Moran; Kim Mulholland; M Nathan Nair; Luigi Naldi; K M Venkat Narayan; Kiumarss Nasseri; Paul Norman; Martin O'Donnell; Saad B Omer; Katrina Ortblad; Richard Osborne; Doruk Ozgediz; Bishnu Pahari; Jeyaraj Durai Pandian; Andrea Panozo Rivero; Rogelio Perez Padilla; Fernando Perez-Ruiz; Norberto Perico; David Phillips; Kelsey Pierce; C Arden Pope; Esteban Porrini; Farshad Pourmalek; Murugesan Raju; Dharani Ranganathan; Jürgen T Rehm; David B Rein; Guiseppe Remuzzi; Frederick P Rivara; Thomas Roberts; Felipe Rodriguez De León; Lisa C Rosenfeld; Lesley Rushton; Ralph L Sacco; Joshua A Salomon; Uchechukwu Sampson; Ella Sanman; David C Schwebel; Maria Segui-Gomez; Donald S Shepard; David Singh; Jessica Singleton; Karen Sliwa; Emma Smith; Andrew Steer; Jennifer A Taylor; Bernadette Thomas; Imad M Tleyjeh; Jeffrey A Towbin; Thomas Truelsen; Eduardo A Undurraga; N Venketasubramanian; Lakshmi Vijayakumar; Theo Vos; Gregory R Wagner; Mengru Wang; Wenzhi Wang; Kerrianne Watt; Martin A Weinstock; Robert Weintraub; James D Wilkinson; Anthony D Woolf; Sarah Wulf; Pon-Hsiu Yeh; Paul Yip; Azadeh Zabetian; Zhi-Jie Zheng; Alan D Lopez; Christopher J L Murray; Mohammad A AlMazroa; Ziad A Memish Journal: Lancet Date: 2012-12-15 Impact factor: 79.321