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Dr Jianmin Chen

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Dr Jianmin Chen Sepsis-induced cardiac dysfunction: Pathophysiology and experimental treatments A thesis presented by Dr Jianmin Chen registered at Barts and The London School of Medicine and Dentistry Queen Mary University of London for the degree of Doctor of Philosophy Centre for Translational Medicine & Therapeutics, The William Harvey Research Institute John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom | ABSTRACT The severity of cardiac dysfunction predicts mortality in septic patients. In this thesis, I have investigated the pathophysiology and the novel therapeutic strategy to attenuate cardiac dysfunction in experimental sepsis. I have developed a model of cardiac dysfunction caused by lipopolysaccharide (LPS)/peptidoglycan (PepG) co-administration or polymicrobial sepsis in young and old, male and female mice. There is good evidence that females tolerate sepsis better than males. Here, I have demonstrated for the first time that the cardiac dysfunction caused by sepsis was less pronounced in female than in male mice; this protection was associated with cardiac activation of a pro-survival pathway [Akt and endothelial nitric oxide synthase], and the decreased activation of a pro-inflammatory signalling pathway [nuclear factor (NF)-κB]. Patients with chronic kidney disease (CKD) requiring dialysis have a higher risk of sepsis and a 100-fold higher mortality. Activation of NF-κB is associated with sepsis- induced cardiac dysfunction and NF-κB is activated by IκB kinase (IKK). Here, I have shown that 5/6th nephrectomy for 8 weeks caused a small, but significant, cardiomyopathy, cardiac activation of NF-κB and expression of inducible nitric oxide synthase (iNOS). When subjected to LPS or polymicrobial sepsis, CKD mice exhibited exacerbation of cardiac dysfunction and cardiac activation of NF-κB and iNOS expression, which were attenuated by a specific IKK inhibitor (IKK 16). Thus, selective inhibition of IKK may represent a novel therapeutic approach for the sepsis- induced cardiac dysfunction in CKD patients. Activation of transient receptor potential vanilloid receptor type 1 (TRPV1) improves outcome in sepsis/endotoxaemia. The identity of the endogenous activators of TRPV1 and the role of the channel in the cardiac dysfunction caused by sepsis/endotoxaemia is unknown. Here, I have shown that activation of TRPV1 by 12-(S)-HpETE and 20- HETE (potent ligands of TRPV1) leads to the release of calcitonin gene-related peptide (downstream mediator of TRPV1 activation), which protects the heart against the cardiac dysfunction caused by LPS. ABSTRACT 2 | ACKNOWLEDGEMENTS I would first like to express my enormous gratitude to my brilliant PhD supervisor, Prof Christoph Thiemermann, for his great support, encouragement, mentoring and guidance in my study as well as my personal life throughout the last four years, and I could not thank him more, and he continues to be my great mentor. I would also like to acknowledge China Scholarship Council for granting me a PhD scholarship, and many colleagues who made this thesis possible. In particular, I would like to thank Dr Nimesh Patel, as my secondary supervisor, for the enlightening discussions and his help. I would also like to thank Dr Sina Coldewey and Dr Areeg Khan for teaching me the echocardiography, CLP and myocardial infarction models during my early PhD, Mr Julius Kieswich for his help with CKD model, Dr Thomas Gobbetti for his support with macrophage study and bacterial counting, Mr Alexander Hamers and Dr Michaela Finsterbusch for working together with me on TRPV1 project, Prof Amrita Ahluwalia for sharing her knowledge and always lending a helping hand, Prof Magdi Yaqoob for his enthusiastic support, and at last, but not least, Prof Massimo Collino and Mr Fausto Chiazza for their support with signalling analysis, and for accommodating me in the Department of Drug Science and Technology, University of Turin to learn western blot and MPO assays. During my PhD in William Harvey Research Institute, I have had the great pleasure developing a number of friendships; in particular, I would like to thank Flow and Regina for sharing life stories and being great supporters. Finally, I would like to express a heartfelt thank you to my family - my Mum, Dad, Brother, Sister-in-law, Nephew and Niece - and friends - Cindy, Irina and Beeny for their love, encouragement and unending support. ACKNOWLEDGEMENT 3 | DECLARATION I declare that this thesis is a presentation of my original research. I acknowledge that Dr Thomas Gobbetti has carried out the macrophage study and the bacterial counting of the peritoneal lavage samples I have generated (chapter III). I also acknowledge that Mr Alexander Hamers and Dr Michaela Finsterbusch have carried out the western blot analysis on TRPV1 phosphorylation and the neuropeptides measurements of the samples I have generated (chapter IV). Name: Dr Jianmin Chen Signature: Supervisor: Prof Christoph Thiemermann Signature: Date: London, 28/07/2016 DECLARATION 4 | LIST OF PUBLISHED PAPERS Jianmin Chen*, Alexander J.P. Hamers*, Michaela Finsterbusch, Maleeha Zafar, Roger Corder, Romain A. Colas, Jesmond Dalli, Christoph Thiemermann*, Amrita Ahluwalia* (2016). Endogenously generated arachidonate-derived ligands for TRPV1 underlie cardiac protection in sepsis. Nature Communication, under review. (*These authors contributed equally to this work) Jianmin Chen, Julius Kieswich, Fausto Chiazza, Amie J. Moyes, Thomas Gobbetti, Nimesh S.A. Patel, Mauro Perretti, Adrian J. Hobbs, Massimo Collino, Muhammad M. Yaqoob, Christoph Thiemermann (2016). IκB kinase inhibitor attenuates sepsis- induced cardiac dysfunction in CKD. Journal of the American Society of Nephrology, DOI: 10.1681/ASN.2015060670. Jianmin Chen, Christoph Thiemermann. (2016). Selenium and niacin for sepsis therapy: The sum is greater than its parts. Critical Care Medicine, 44(6):1256-7. doi: 10.1097/CCM.0000000000001493. Jianmin Chen, Fausto Chiazza, Massimo Collino, Nimesh S.A. Patel, Sina M. Coldewey, Christoph Thiemermann. (2014). Gender dimorphism of the cardiac dysfunction in murine sepsis: Signalling mechanisms and age-dependency. PLoS ONE, 9(6): e100631. Thomas Gobbetti, Sina M Coldewey, Jianmin Chen, Simon McArthur, Pauline le Fauder, Nicolas Cenac, Roderick J Flower, Christoph Thiemermann, Mauro Perretti. (2014). Non-redundant protective properties of FPR2/ALX in polymicrobial murine sepsis. Proceedings of the National Academy of Sciences, 111(52):18685-90. LIST OF PUBLISHED PAPERS 5 | LIST OF PUBLISHED ABSTRACTS Jianmin Chen, Alexander J.P. Hamers, Michaela Finsterbusch, Christoph Thiemermann, Amrita Ahluwalia. Activation of TRPV1 by 12(s)-HpETE and 20- HETE releases CGRP and protects the heart against the cardiac dysfunction caused by LPS. Experimental Biology 2016 Congress, 2nd-6th April 2016, San Diego, USA (Oral presentation). ASIP Trainee Travel Award winner Jianmin Chen, Julius Kieswich, Fausto Chiazza, Thomas Gobbetti, Nimesh S.A. Patel, Mauro Perretti, Massimo Collino, Muhammad M. Yaqoob, Christoph Thiemermann. The cardiac dysfunction caused by sepsis in animals with chronic kidney disease is attenuated by inhibiting IκB kinase. Shock, 2015, 44(Supplement 2): 16. 16th Congress of the European Shock Society, 24th-26th September 2015, Cologne, Germany (Oral presentation). European New Investigator Award, Travel Award winner Jianmin Chen, Julius Kieswich, Fausto Chiazza, Thomas Gobbetti, Nimesh S.A. Patel, Mauro Perretti, Massimo Collino, Muhammad M. Yaqoob, Christoph Thiemermann. The cardiac dysfunction caused by sepsis in animals with chronic kidney disease is attenuated by inhibiting IκB kinase. Shock, 2015, 43(Supplement 1): 92. Thirty-Eighth Annual Conference on Shock, 6th-9th June 2015, Denver, USA (Poster presentation). Travel Award winner Jianmin Chen, Julius Kieswich, Fausto Chiazza, Nimesh S.A. Patel, Massimo Collino, Muhammad M. Yaqoob, Christoph Thiemermann. Pre-existing chronic kidney disease worsens the myocardial dysfunction caused by sepsis in mice. pA2 online, E-journal of the British Journal of Pharmacology, 2015, http://www.pa2online.org/abstract/abstract.jsp?abid=32407&author=J%20Chen&cat= -1&period=-1. Pharmocology 2014, 16th-18th Dec 2014, London (Oral presentation). Jianmin Chen, Julius Kieswich, Muhammad M. Yaqoob, Christoph Thiemermann. Effects of pre-existing chronic kidney disease on pathophysiology of sepsis. Shock, 2014, 41(Supplement 2): 40. Thirty-Seventh Annual Conference on Shock, 7th-10th June 2014, Westin Charlotte, USA (Poster presentation). Travel Award winner LIST OF PUBLISHED ABSTRACTS 6 Jianmin Chen, Fausto Chiazza, Massimo Collino, Sina M. Coldewey, Nimesh S.A. Patel, Christoph Thiemermann. Gender dimorphism of the cardiac dysfunction in sepsis. Shock, 2014, 41(Supplement 2): 35. Thirty-Seventh Annual Conference on Shock, 7th-10th June 2014, Westin Charlotte, USA (Poster presentation). Jianmin Chen, Julius Kieswich, Fausto Chiazza, Thomas Gobbetti, Nimesh S.A. Patel, Mauro Perretti, Massimo Collino, Muhammad M. Yaqoob, Christoph Thiemermann. The cardiac dysfunction caused by sepsis in animals with chronic kidney disease is attenuated by inhibiting IκB kinase. Czech Medical Mission to the UK, 4th September 2015, London (Invited lecture). Jianmin Chen, Julius Kieswich, Fausto Chiazza, Nimesh S.A. Patel, Massimo Collino, Muhammad M. Yaqoob, Christoph Thiemermann. Pre-existing chronic kidney disease worsens the myocardial dysfunction caused by sepsis in mice. William Harvey Research Institute New Year Celebration, 13th Feb 2015, London
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