Inhibition of Necroptosis to Prevent Long-term Cardiac Damage During Pneumococcal Pneumonia and Invasive Disease
| Autor: | Katherine L Kruckow, Ashleigh N. Riegler, Sarah M. Beno, Yong Wang, Marcos I. Restrepo, Ryan P. Gilley, Anukul T. Shenoy, Griffin M. Wright, Norberto Gonzalez-Juarbe, Sara N Stoner, Jeevan Kumar Jadapalli, Ganesh V. Halade, Jessy S. Deshane, Carlos J. Orihuela, Terry Brissac |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Programmed cell death Pathology medicine.medical_specialty Necroptosis Bacteremia medicine.disease_cause Pneumococcal Infections Proinflammatory cytokine 03 medical and health sciences chemistry.chemical_compound Major Articles and Brief Reports Mice 0302 clinical medicine Streptococcus pneumoniae medicine Immunology and Allergy Animals 030212 general & internal medicine Sirius Red Mice Inbred BALB C Pneumolysin Leukemia Cell Death business.industry Ponatinib Imidazoles Heart Pneumonia Pneumococcal medicine.disease Mice Inbred C57BL Pyridazines Disease Models Animal 030104 developmental biology Infectious Diseases chemistry Receptor-Interacting Protein Serine-Threonine Kinases Pneumococcal pneumonia Female business Protein Kinases |
| Zdroj: | J Infect Dis |
| Popis: | Background Streptococcus pneumoniae infection can result in bacteremia with devastating consequences including heart damage. Necroptosis is a proinflammatory form of cell death instigated by pore-forming toxins such as S. pneumoniae pneumolysin. Necroptosis-inhibiting drugs may lessen organ damage during invasive pneumococcal disease (IPD). Methods In vitro experiments were carried out with human and mouse cardiomyocytes. Long-term cardiac damage was assessed using high-resolution echocardiography in ampicillin-rescued mice 3 months after challenge with S. pneumoniae. Ponatinib, a necroptosis-inhibiting and Food and Drug Administration–approved drug for lymphocytic leukemia treatment, was administered intraperitoneally alongside ampicillin to test its therapeutic efficacy. Histology of heart sections included hematoxylin-eosin staining for overt damage, immunofluorescence for necroptosis, and Sirius red/fast green staining for collagen deposition. Results Cardiomyocyte death and heart damage was due to pneumolysin-mediated necroptosis. IPD leads to long-term cardiac damage, as evidenced by de novo collagen deposition in mouse hearts and a decrease in fractional shortening. Adjunct necroptosis inhibition reduced the number of S. pneumoniae foci observed in hearts of acutely infected mice and serum levels of troponin I. Ponatinib reduced collagen deposition and protected heart function in convalescence. Conclusions Acute and long-term cardiac damage incurred during IPD is due in part to cardiomyocyte necroptosis. Necroptosis inhibitors may be a viable adjunct therapy. |
| Databáze: | OpenAIRE |
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