Transient Obstruction of Capillary Networks by Chromatin Yarns from Neutrophils in Older Adults

Massachusetts General Hospital, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a common problem in clinical medicine and a key risk factor for AKI in older adults is community-acquired pneumonia. Of more than 1 million patients in the US who are hospitalized with community-acquired pneumonia every year, between 10 and 20% of develop AKI, and the associated mortality among these is as high as 10%. To better understand AKI after pneumonia, we will test the hypothesis that neutrophils, hyper-activated by the infection, die and release decondensed chromatin, leading to the formation of large chromatin yarns, and contributing to transient, local ischemia of the kidney tissue and subsequent AKI. The role of decondensed chromatin released from neutrophils in AKI has not yet been unexplored. Unlike previous studies of neutrophil-derived chromatin in the context of disease, which converged on the biochemistry of the chromatin-associated histones and enzymes, and the molecular mechanisms of neutrophil death and chromatin release, we will focus on the biomechanics of chromatin fibers and yarns formation, release, and trapping in conditions of flow. The major challenges for this project are technological. We will address this challenge by designing a unique set of microfluidic tools, which will enable us to probe the complex biomechanics of chromatin released by overly-activated neutrophils in vitro. If successful, our study will validate the formation of chromatin yarns as a critical mechanism for blood flow obstructions, which is distinct from the classical fibrin clots. The obstruction of blood flow in chromatin-yarns trapping in capillary networks could have significant implication for other diseases in which infections and inflammation result in secondary organ injury.