Targeted delivery of pulmonary arterial endothelial cells overexpressing interleukin-8 receptors attenuates monocrotaline-induced pulmonary vascular remodeling.
OBJECTIVE
Interleukin-8 (IL-8) receptors IL8RA and IL8RB (IL8RA/B) on neutrophil membranes bind to IL-8 with high affinity and play a critical role in neutrophil recruitment to sites of injury and inflammation. This study tested the hypothesis that administration of rat pulmonary arterial endothelial cells (ECs) overexpressing IL8RA/B can accelerate the adhesion of ECs to the injured lung and inhibit monocrotaline-induced pulmonary inflammation, arterial thickening and hypertension, and right ventricular hypertrophy.


RESULTS
The treatment groups included 10-week-old ovariectomized Sprague-Dawley rats that received subcutaneous injection of PBS (vehicle), a single injection of monocrotaline (monocrotaline alone, 60 mg/kg, SC), monocrotaline followed by intravenous transfusion of ECs transduced with the empty adenoviral vector (null-EC), and monocrotaline followed by intravenous transfusion of ECs overexpressing IL8RA/B (1.5 × 10(6) cells/rat). Two days or 4 weeks after monocrotaline treatment, endothelial nitric oxide synthase, inducible nitric oxide synthase, cytokine-induced neutrophil chemoattractant-2β (IL-8 equivalent in rat), and monocyte chemoattractant protein-1 expression, neutrophil and macrophage infiltration into pulmonary arterioles, and arteriolar and alveolar morphology were measured by histological and immunohistochemical techniques. Proinflammatory cytokine/chemokine protein levels were measured by Multiplex rat-specific magnetic bead-based sandwich immunoassay in total lung homogenates. Transfusion of ECs overexpressing IL8RA/B significantly reduced monocrotaline-induced neutrophil infiltration and proinflammatory mediator (IL-8, monocyte chemoattractant protein-1, inducible nitric oxide synthase, cytokine-induced neutrophil chemoattractant, and macrophage inflammatory protein-2) expression in lungs and pulmonary arterioles and alveoli, pulmonary arterial pressure, and pulmonary arterial and right ventricular hypertrophy and remodeling.


CONCLUSIONS
These provocative findings suggest that targeted delivery of ECs overexpressing IL8RA/B is effective in repairing the injured pulmonary vasculature.
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (J.F., Y.-F.C., X.Z., Y.G., F.G.H., S.O., D.D.X.) and Department of Anesthesiology, University of Alabama at Birmingham (J.R.C.); Department of Biochemistry and the Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Xinjiang, China (J.F.); and Section of Cardiology, Birmingham Veteran's Administration Medical Center, AL (F.G.H.).
Jinyan
J
Fu
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (J.F., Y.-F.C., X.Z., Y.G., F.G.H., S.O., D.D.X.) and Department of Anesthesiology, University of Alabama at Birmingham (J.R.C.); Department of Biochemistry and the Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Xinjiang, China (J.F.); and Section of Cardiology, Birmingham Veteran's Administration Medical Center, AL (F.G.H.).
Yiu-Fai
YF
Chen
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (J.F., Y.-F.C., X.Z., Y.G., F.G.H., S.O., D.D.X.) and Department of Anesthesiology, University of Alabama at Birmingham (J.R.C.); Department of Biochemistry and the Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Xinjiang, China (J.F.); and Section of Cardiology, Birmingham Veteran's Administration Medical Center, AL (F.G.H.).
Xiangmin
X
Zhao
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (J.F., Y.-F.C., X.Z., Y.G., F.G.H., S.O., D.D.X.) and Department of Anesthesiology, University of Alabama at Birmingham (J.R.C.); Department of Biochemistry and the Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Xinjiang, China (J.F.); and Section of Cardiology, Birmingham Veteran's Administration Medical Center, AL (F.G.H.).
Judy R
JR
Creighton
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (J.F., Y.-F.C., X.Z., Y.G., F.G.H., S.O., D.D.X.) and Department of Anesthesiology, University of Alabama at Birmingham (J.R.C.); Department of Biochemistry and the Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Xinjiang, China (J.F.); and Section of Cardiology, Birmingham Veteran's Administration Medical Center, AL (F.G.H.).
Yuanyuan
Y
Guo
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (J.F., Y.-F.C., X.Z., Y.G., F.G.H., S.O., D.D.X.) and Department of Anesthesiology, University of Alabama at Birmingham (J.R.C.); Department of Biochemistry and the Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Xinjiang, China (J.F.); and Section of Cardiology, Birmingham Veteran's Administration Medical Center, AL (F.G.H.).
Fadi G
FG
Hage
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (J.F., Y.-F.C., X.Z., Y.G., F.G.H., S.O., D.D.X.) and Department of Anesthesiology, University of Alabama at Birmingham (J.R.C.); Department of Biochemistry and the Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Xinjiang, China (J.F.); and Section of Cardiology, Birmingham Veteran's Administration Medical Center, AL (F.G.H.).
Suzanne
S
Oparil
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (J.F., Y.-F.C., X.Z., Y.G., F.G.H., S.O., D.D.X.) and Department of Anesthesiology, University of Alabama at Birmingham (J.R.C.); Department of Biochemistry and the Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Xinjiang, China (J.F.); and Section of Cardiology, Birmingham Veteran's Administration Medical Center, AL (F.G.H.). dqxing@uab.edu.
Daisy D
DD
Xing
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D062186:Arterial Pressure; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D008264:Macrophages / Q000378:metabolism; D016686:Monocrotaline; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010052:Ovariectomy; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D053700:Receptors, Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D014161:Transduction, Genetic; D015854:Up-Regulation; D016278:Ventricular Function, Right; D020257:Ventricular Remodeling
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D019743:Chemokines, CXC; C513294:Cxcl3 protein, rat; D053700:Receptors, Interleukin-8; D016686:Monocrotaline; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat
cell- and tissue-based therapy; receptors, interleukin-8