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Fatty acid binding protein 4 regulates VEGF-induced airway angiogenesis and inflammation in a transgenic mouse model: implications for asthma.

ABSTRACT: Neovascularization of the airways occurs in several inflammatory lung diseases, including asthma. Vascular endothelial growth factor (VEGF) plays an important role in vascular remodeling in the asthmatic airways. Fatty acid binding protein 4 (FABP4 or aP2) is an intracellular lipid chaperone that is induced by VEGF in endothelial cells. FABP4 exhibits a proangiogenic function in vitro, but whether it plays a role in modulation of angiogenesis in vivo is not known. We hypothesized that FABP4 promotes VEGF-induced airway angiogenesis and investigated this hypothesis with the use of a transgenic mouse model with inducible overexpression of VEGF165 under a CC10 promoter [VEGF-TG (transgenic) mice]. We found a significant increase in FABP4 mRNA levels and density of FABP4-expressing vascular endothelial cells in mouse airways with VEGF overexpression. FABP4(-/-) mouse airways showed a significant decrease in neovessel formation and endothelial cell proliferation in response to VEGF overexpression. These alterations in airway vasculature were accompanied by attenuated expression of proinflammatory mediators. Furthermore, VEGF-TG/FABP4(-/-) mice showed markedly decreased expression of endothelial nitric oxide synthase, a well-known mediator of VEGF-induced responses, compared with VEGF-TG mice. Finally, the density of FABP4-immunoreactive vessels in endobronchial biopsy specimens was significantly higher in patients with asthma than in control subjects. Taken together, these data unravel FABP4 as a potential target of pathologic airway remodeling in asthma.

SUBMITTER: Ghelfi E

PROVIDER: S-EPMC3620401 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Fatty acid binding protein 4 regulates VEGF-induced airway angiogenesis and inflammation in a transgenic mouse model: implications for asthma.

Ghelfi Elisa E Yu Chen-Wei CW Elmasri Harun H Terwelp Matthew M Lee Chun G CG Bhandari Vineet V Comhair Suzy A SA Erzurum Serpil C SC Hotamisligil Gökhan S GS Elias Jack A JA Cataltepe Sule S

The American journal of pathology 20130204 4

Neovascularization of the airways occurs in several inflammatory lung diseases, including asthma. Vascular endothelial growth factor (VEGF) plays an important role in vascular remodeling in the asthmatic airways. Fatty acid binding protein 4 (FABP4 or aP2) is an intracellular lipid chaperone that is induced by VEGF in endothelial cells. FABP4 exhibits a proangiogenic function in vitro, but whether it plays a role in modulation of angiogenesis in vivo is not known. We hypothesized that FABP4 prom ...[more]

PMID: 23391391

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Project description:BackgroundAirway remodeling in patients with asthma, which leads to a decline in pulmonary function, is likely the result of repeated exacerbations often provoked by aeroallergen exposures. Aeroallegen exposure triggers a stereotypic response orchestrated by growth factor cytokines and other protein mediators. This results in a late-phase allergic reaction characterized by vascular permeability, recruitment of activated leukocytes, and activation of structural cells of the airway. The spectrum of protein mediators and their functions are incompletely understood.MethodsBronchoalveolar lavage fluid (BALF) samples were obtained from 12 volunteers who exhibited robust eosinophilic recruitment following segmental bronchial provocation with allergen (SBP-Ag). We systematically identified and quantified proteins in BALF using high-performance liquid chromatography-high-resolution mass spectrometry (LC-MS/MS) followed by pathway analysis and correlations with airway physiology.ResultsPairwise analysis of protein abundance in BALF pre- vs post-SBP-Ag revealed that 55 proteins were upregulated and 103 proteins were downregulated. We observed enrichment of groups of proteins mapping to hemostasis/fibrin clot, platelet activation, lipoprotein assembly, neutrophil degranulation proteins, and acute-phase inflammation-airway remodeling pathways. The abundances of F2 and Fibrinogen γ (FGG) correlated with eosinophil numbers, whereas SERPINA3 negatively correlated with change in FeNO. The coagulation proteins F2 and KNG negatively correlated with FN1 an index of airway remodeling. Interestingly, patients with lower FEV1 showed distinct allergen-induced patterns of 8 BALF proteins, including MUC1, alarmins (HSPB1), and actin polymerization factors.ConclusionsProtein abundance of the fibrin formation cascade, platelet activation and remodeling are associated with late-phase leukocyte numbers and markers of remodeling. Patients with lower FEV1 have distinct dynamic responses to allergen.

Project description:BackgroundLoki zupa (Luooukezupa) decoction, consisting of the roots of Hyssopuscuspidatus Boriss (Shenxiangcao) and Irishalophila Pall root (Yuanweigen), is commonly used in Uygur medicine to treat asthma. However, the mode of action of this material has yet to be elucidated. This study aims to investigate the effects of Loki zupa decoction on the airway inflammation of an ovalbumin (OVA)-induced asthma mouse model.MethodsMice were divided into normal control (NC), asthma (A), high, medium and low doses of Loki zupa decoction (L 14.0, L 7.0, L 3.5), water extract (LW), n-butanol extract (LN), ethyl acetate extract (LE) and dexamethasone (DEX) groups. Antiasthmatic model was induced by OVA sensitization and challenged using BALB/c mice. Airway hyperresponsiveness (AHR) toward methacholine (Mch) was assessed using Buxco equipment. Lung inflammation was measured by hematoxylin and eosin staining and bronchoalveolar lavage fluid (BALF) cell count and classification. Inflammatory cytokines in BALF and serum were analyzed by Bio-Plex assay, and mRNA levels were investigated by qPCR analysis. The roots of H. Boriss (250 g) and I. Pall (250 g) were decocted, concentrated and diluted to 14.0, 7.0 and 3.5 g crude herb/kg body weight. The LW, LN and LE of the Loki zupa decoction were prepared and diluted to a dose equivalent to 7 g of crude herb/kg body weight.ResultsLoki zupa decoction and its extracts significantly attenuated the AHR towards Mch (all P < 0.05). Treatment with Loki zupa decoction and its extracts relieved the infiltration of inflammatory cells in and around the airways, and reduced the total white blood cell (all P < 0.05), neutrophil (all P < 0.05), monocyte (all P < 0.05) and eosinophil (all P < 0.05) counts in the BALF. The BALF samples collected from the mice treated with the Loki zupa decoction and its extracts had lower levels of IL-1β (all P < 0.05), TNF-α (all P < 0.05), IL-2 (all P < 0.05), IL-4 (P = 0.047) and IL-5 (all P < 0.05). The serum samples of these mice also had lower IL-1β (all P < 0.05), TNF-α (all P < 0.05), IL-4 (all P < 0.05) and IL-5 (all P < 0.05) levels and higher levels of IFN-γ (P < 0.001) compared with the OVA-induced asthma mouse model. qPCR analysis revealed that Loki zupa decoction and its extracts inhibited mRNA expression of IL-4 (all P < 0.05), IL-5 (all P < 0.05) and IL-13 (all P < 0.05) and promoted mRNA expression of IFN-γ (all P < 0.05) in asthmatic mice.ConclusionLoki zupa decoction reduced AHR, attenuated airway inflammation, promoted Th1 and suppressed Th2 cell functions in an OVA-induced asthma mouse model.

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Fatty acid binding protein 4 regulates VEGF-induced airway angiogenesis and inflammation in a transgenic mouse model: implications for asthma.

Publications

Fatty acid binding protein 4 regulates VEGF-induced airway angiogenesis and inflammation in a transgenic mouse model: implications for asthma.

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