The chemokine, CCL3, and its receptor, CCR1, mediate thoracic radiation-induced pulmonary fibrosis.
Patients receiving thoracic radiation often develop pulmonary injury and fibrosis. Currently, there are no effective measures to prevent or treat these conditions. We tested whether blockade of the chemokine, CC chemokine ligand (CCL) 3, and its receptors, CC chemokine receptor (CCR) 1 and CCR5, can prevent radiation-induced lung inflammation and fibrosis. C57BL/6J mice received thoracic radiation, and the interaction of CCL3 with CCR1 or CCR5 was blocked using genetic techniques, or by pharmacologic intervention. Lung inflammation was assessed by histochemical staining of lung tissue and by flow cytometry. Fibrosis was measured by hydroxyproline assays and collagen staining, and lung function was studied by invasive procedures. Irradiated mice lacking CCL3 or its receptor, CCR1, did not develop the lung inflammation, fibrosis, and decline in lung function seen in irradiated wild-type mice. Pharmacologic treatment of wild-type mice with a small molecule inhibitor of CCR1 also prevented lung inflammation and fibrosis. By contrast, mice lacking CCR5 were not protected from radiation-induced injury and fibrosis. The selective interaction of CCL3 with its receptor, CCR1, is critical for radiation-induced lung inflammation and fibrosis, and these conditions can be largely prevented by a small molecule inhibitor of CCR1.
Yang
Xuebin
X
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Walton
William
W
Cook
Donald N
DN
Hua
Xiaoyang
X
Tilley
Stephen
S
Haskell
Christopher A
CA
Horuk
Richard
R
Blackstock
A William
AW
Kirby
Suzanne L
SL
D000818:Animals; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism*; D005720:Gamma Rays / Q000009:adverse effects*; D006909:Hydroxyproline / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010671:Phenylurea Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D017564:Radiation Pneumonitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism
C496534:Ccl3 protein, mouse; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D010671:Phenylurea Compounds; D010880:Piperidines; D054389:Receptors, CCR1; D019713:Receptors, CCR5; C411885:BX 471; D006909:Hydroxyproline