Fibrotic diseases such as scleroderma, severe chronic asthma, pulmonary fibrosis, and cardiac fibrosis kill tens of thousands of people each year in the US alone. Growing evidence suggests that in a fibrotic lesion a subset of blood monocytes enters the tissue and differentiates into fibroblast-like cells called fibrocytes, causing tissue dysfunction. We found that a blood protein called serum amyloid P (SAP) inhibits this differentiation in vitro. Injections of SAP prevent bleomycin-induced lung fibrosis in rats and mice, and ischemia-reperfusion induced cardiac fibrosis in mice. Some children with pulmonary fibrosis have low serum levels of SAP, and an exciting possibility is that SAP might be useful as an anti-fibrotic in humans. A critical need is to be able to identify fibrocyte precursors, early fibrocytes, and mature fibrocytes, so that in the early stages of treating a patient one could take a biopsy and determine if the treatment is affecting fibrocyte differentiation. Although there are several antigens that serve as markers for mature fibrocytes, little is known about the phenotype of early fibrocytes and the identity of the monocyte subset is unknown. We propose three specific aims to elucidate fibrocyte differentiation. First, we will determine the time course of appearance of known fibrocyte markers during human, rat, and mouse fibrocyte differentiation in vitro, to identify the earliest possible markers. We will then use this information to determine the stage at which SAP inhibits fibrocyte differentiation. Second, we will determine whether just one or several known subsets of monocytes can differentiate into fibrocytes, and thus whether known markers can serve as biomarkers of fibrocyte precursors. Third, we will induce pulmonary fibrosis in mice, and determine the timecourse of marker appearance in vivo, and use this information to test the hypothesis that SAP inhibits fibrocyte differentiation to inhibit fibrosis. Lay Language: We anticipate that identification of the markers for the circulating fibrocyte progenitor cells might lead to diagnostic assays for patients at risk for fibrosing diseases, determining what markers are expressed by fibrocytes at different times during their development will allow one to monitor clinical efficacy early in a clinical trial of an anti-fibrotic drug, and that elucidating at what stage SAP inhibits fibrocyte differentiation in a tissue will help us understand how we might use SAP to regulate fibrosis in patients. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083029-02
Application #
7272000
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Reynolds, Herbert Y
Project Start
2006-08-07
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$362,225
Indirect Cost
Name
Rice University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005
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Pilling, Darrell; Cox, Nehemiah; Vakil, Varsha et al. (2015) The long pentraxin PTX3 promotes fibrocyte differentiation. PLoS One 10:e0119709
Cox, Nehemiah; Pilling, Darrell; Gomer, Richard H (2014) Distinct Fc? receptors mediate the effect of serum amyloid p on neutrophil adhesion and fibrocyte differentiation. J Immunol 193:1701-8
Pilling, Darrell; Gomer, Richard H (2014) Persistent lung inflammation and fibrosis in serum amyloid P component (APCs-/-) knockout mice. PLoS One 9:e93730
Gomer, Richard H (2013) New approaches to modulating idiopathic pulmonary fibrosis. Curr Allergy Asthma Rep 13:607-12
White, Michael J V; Glenn, Melissa; Gomer, Richard H (2013) Trypsin potentiates human fibrocyte differentiation. PLoS One 8:e70795
Crawford, Jeffrey R; Bjorklund, Nicole L; Taglialatela, Giulio et al. (2012) Brain serum amyloid P levels are reduced in individuals that lack dementia while having Alzheimer's disease neuropathology. Neurochem Res 37:795-801
Crawford, Jeffrey R; Pilling, Darrell; Gomer, Richard H (2012) Fc?RI mediates serum amyloid P inhibition of fibrocyte differentiation. J Leukoc Biol 92:699-711
Pilling, Darrell; Gomer, Richard H (2012) Differentiation of circulating monocytes into fibroblast-like cells. Methods Mol Biol 904:191-206
Maharjan, Anu S; Pilling, Darrell; Gomer, Richard H (2011) High and low molecular weight hyaluronic acid differentially regulate human fibrocyte differentiation. PLoS One 6:e26078

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