ABSTRACT
BACKGROUND: Mouse models are useful for studying cigarette smoke (CS)-induced chronic pulmonary pathologies such as lung emphysema. To enhance translation of large-scale omics data from mechanistic studies into pathophysiological changes, we have developed computational tools based on reverse causal reasoning (RCR). OBJECTIVE: In the present study we applied a systems biology approach leveraging RCR to identify molecular mechanistic explanations of pathophysiological changes associated with CS-induced lung emphysema in susceptible mice. METHODS: The lung transcriptomes of five mouse models (C57BL/6, ApoE (-/-) , A/J, CD1, and Nrf2 (-/-) ) were analyzed following 5-7 months of CS exposure. RESULTS: We predicted 39 molecular changes mostly related to inflammatory processes including known key emphysema drivers such as NF-κB and TLR4 signaling, and increased levels of TNF-α, CSF2, and several interleukins. More importantly, RCR predicted potential molecular mechanisms that are less well-established, including increased transcriptional activity of PU.1, STAT1, C/EBP, FOXM1, YY1, and N-COR, and reduced protein abundance of ITGB6 and CFTR. We corroborated several predictions using targeted proteomic approaches, demonstrating increased abundance of CSF2, C/EBPα, C/EBPß, PU.1, BRCA1, and STAT1. CONCLUSION: These systems biology-derived candidate mechanisms common to susceptible mouse models may enhance understanding of CS-induced molecular processes underlying emphysema development in mice and their relevancy for human chronic obstructive pulmonary disease.
Subject(s)
Nicotiana , Pulmonary Emphysema/genetics , Pulmonary Emphysema/pathology , Smoke , Animals , Apolipoproteins E/genetics , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Causality , Gene Expression Profiling , Inhalation Exposure , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Inbred CFTR , Mice, Knockout , Polymerase Chain Reaction , Proteomics , Pulmonary Emphysema/chemically induced , Smoking , Species SpecificityABSTRACT
In this study, we postulated that acute mechanical strain of the arterial wall induces changes in syndecan-4 expression that in turn may modulate cellular events, which promote neointima formation. Correlative in vivo and in vitro studies were performed to determine whether: (1) balloon injury of the rat carotid artery induces spatially and temporally regulated changes in syndecan-4 messenger RNA (mRNA) and protein expression; (2) the application of biaxial mechanical strain to cultured vascular wall cells regulates the expression of syndecan-4 mRNA and protein and its cell surface distribution and surface shedding; and (3) shed syndecan-4 directly effects cell motility behavior. We observed that syndecan-4 mRNA and protein expression were regulated in a temporally and spatially specific manner, such that initial expression of syndecan-4 was localized to adventitial cells followed by later expression in the neointima. Notably, in vitro stimulation of isolated adventitial fibroblasts with a mechanical stretch protocol that was designed to mimic in vivo balloon injury produced a rapid increase in syndecan-4 (4.3-fold increase; P <.001) that was accompanied both by enhanced protein shedding and by the disassembly of focal adhesions. Also significant was that shed syndecan-4, induced with mechanically conditioned media, appeared to be responsible for a chemotactic response of adventitial fibroblasts (P =.005). These results indicate that mechanical strain tightly regulates syndecan-4 expression, which may, in part, provide a mechanism for the activation of myofibroblast migration from the tunica adventitia into the neointima.
Subject(s)
Angioplasty, Balloon , Membrane Glycoproteins/metabolism , Proteoglycans/metabolism , Tunica Intima/pathology , Animals , Carotid Arteries/metabolism , Carotid Arteries/pathology , Cells, Cultured , Chemotaxis , Culture Media, Conditioned , Fibroblasts/metabolism , Fibroblasts/physiology , Immunohistochemistry , In Situ Hybridization , Male , Rats , Rats, Sprague-Dawley , Stress, Mechanical , Syndecan-4 , Up-RegulationABSTRACT
La vía de acceso femoral es utilizada desde hace muchos años para realizar cateterismos cardíacos y angioplastias coronarias con excelentes resultados. Si bien este acceso tiene ventajas en su utilización, las complicaciones vasculares representan un riesgo potencial cuya incidencia se aproxima a 4 por ciento, requiriendo en ciertos casos reparación quirúrgica. La vía transradial ha sido propuesta recientemente como una alternativa técnica para evitar dichas complicaciones. Presentamos nuestra experiencia inicial con los primeros 1.000 procedimientos por esta vía de acceso
