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.

Public Health Relevance

Acute kidney injury (AKI) is a common problem in clinical medicine and a key risk factor in older adults is community-acquired pneumonia. Of more than 1 million patients in the US who are hospitalized for treatment of 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 neutrophil white blood cells, hyper-activated by the infection, release decondensed chromatin, leading to the formation of large chromatin yarns, and contributing to transient, local ischemia of the kidney tissue and subsequent AKI.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG051082-02
Application #
9114467
Study Section
Enabling Bioanalytical and Imaging Technologies Study Section (EBIT)
Program Officer
Zieman, Susan
Project Start
2015-08-01
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
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