Shear stress associated with cardiopulmonary bypass induces expression of inflammatory cytokines and necroptosis in monocytes
| Autor: | Ram Savan, Michael A. Portman, Lan N. Tu, Christopher Benner, Muhammad Nuri, Masaki Kajimoto, Adriana Forero, Douglas C. Bittel, Marta Scatena, Alberto Aliseda, Peter Pastuszko, Jennifer A. Marshall, Kevin Charette, Lance Hsieh, James E. O'Brien, Sarah E Hampson, Vishal Nigam, Nataliya Kibiryeva |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine THP-1 Cells medicine.medical_treatment Sus scrofa Systemic inflammation Monocytes 0302 clinical medicine Medicine RNA-Seq Cardiopulmonary Bypass General Medicine Systemic Inflammatory Response Syndrome Up-Regulation surgical procedures operative Cytokine 030220 oncology & carcinogenesis Models Animal Necroptosis Cytokines Female Tumor necrosis factor alpha Inflammation Mediators medicine.symptom Research Article circulatory and respiratory physiology Heart Defects Congenital Cardiology Inflammation Proinflammatory cytokine 03 medical and health sciences Downregulation and upregulation Animals Humans Calcium Signaling Interleukin 8 Tumor Necrosis Factor-alpha business.industry Interleukin-8 Infant Newborn Infant 030104 developmental biology Animals Newborn Immunology Surgery Stress Mechanical business |
| Zdroj: | JCI Insight JCI Insight, Vol 6, Iss 1 (2021) |
| ISSN: | 2379-3708 |
| Popis: | Cardiopulmonary bypass (CPB) is required during most cardiac surgeries. CBP drives systemic inflammation and multi-organ dysfunction that is more severe in neonatal patients. Limited understanding of molecular mechanisms underlying CPB-associated inflammation presents a significant barrier to improving clinical outcomes. To better understand these clinical issues, we performed the first mRNA-sequencing on total circulating leukocytes from neonatal patients undergoing CPB. These data identified myeloid cells, particularly monocytes, as the major cell type driving transcriptional responses to CPB. Furthermore, Interleukin-8 (IL8) and Tumor Necrosis Factor-α (TNFα) were inflammatory cytokines robustly upregulated in leukocytes from both patients and piglets exposed to CPB. To delineate a molecular mechanism, we exposed THP-1 human monocytic cells to CPB-like conditions including artificial surfaces, high shear stress, and cooling/rewarming. Here, shear stress was found to drive cytokine upregulation via calcium-dependent signaling pathways. We also observed a subpopulation of THP-1 cells died via TNFα-mediated necroptosis in our model, which we hypothesize contributes to post-CPB inflammation. Together, our study identifies a shear-stress modulated molecular mechanism that drives systemic inflammation in pediatric CPB patients. These are also the first data to demonstrate that shear-stress causes necroptosis. Finally, we observe that calcium and TNFα signaling are novel targets to ameliorate post-CPB inflammation. |
| Databáze: | OpenAIRE |
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