Remodeling In Murine Model Research Articles

Speckle tracking echocardiography in the assessment of mouse models of cardiac dysfunction

Two-dimensional (2-D) speckle tracking echocardiography (STE) accurately quantifies circumferential strain (S(circ)) and radial strain (S(rad)) in humans and in large and small animals. This study was performed to assess sensitivity of S(circ) and S(rad) to left ventricular (LV) dysfunction in mouse models. We performed 2-D and M-mode echocardiography 1) in 6 mice during superficial and profound isoflurane anesthesia, 2) serially in 12 mice to monitor the development of heart failure induced by transverse aortic constriction (TAC) and in 8 corresponding control mice, and 3) in 26 mice with varying degrees of TAC-induced heart failure and 12 corresponding control mice immediately before euthanasia. Fractional shortening (FS) and LV mass were measured from standard M-mode tracings, whereas S(circ) and S(rad) were derived by STE. Percent fibrosis and myocyte diameters were assessed from whole heart cross-sectional specimens stained by Masson trichrome. Profound isoflurane anesthesia decreased S(circ) (P = 0.027) but not S(rad) (P > 0.05). Mice subjected to TAC showed an immediate and sustained decrease in FS (P = 0.035), S(circ) (P = 0.016), and S(rad) (P = 0.012). S(circ) showed better correlation with FS (r = 0.56 and P < 0.0001) and LV mass (r = 0.42 and P = 0.0003) than S(rad) (r = 0.54 and P < 0.0001 for FS and r = 0.37 and P = 0.014 for LV mass, respectively). Percent fibrosis correlated better with S(circ) (r = 0.46 and P = 0.004) than with S(rad) (r = -0.32 and P = 0.05), whereas myocyte diameter showed similar correlation with both strains (r = 0.45 and r = -0.44, respectively, and P = 0.006 for both). STE correctly identifies LV dysfunction and histological changes in mice and can be used for the serial assessment of cardiac remodeling in murine models.

Evidence for Inflammatory Signaling in Idiopathic Pulmonary Artery Hypertension

Knowledge of molecular mechanisms underlying pulmonary arterial hypertension (PAH) continues to increase with the emerging theme that PAH is a heterogeneous disease involving multiple molecular abnormalities. Mutations in several genes have been identified in subsets of patients with PAH, and multiple signaling systems that influence vascular tone, function, and remodeling have been associated with PAH.1,2,3 In addition to mutations in BMPR2 , serotonin ( 5-HT ) and polymorphisms in its transporter ( SERT ) play a critical role in the pulmonary vascular smooth muscle hyperplasia and vascular remodeling found in PAH.4,5 Other genes and signals thought to contribute to the development of idiopathic pulmonary arterial hypertension (IPAH) include somatic mutations of BAX ,5 upregulation of Angiopoietin 1 ,6 transforming growth factor β1 polymorphisms,7 ALK1 mutation,8 SMAD8 mutation,9 and increased hyaluronic acid content associated with increased Hyaluronan Synthase 1 and decreased Hyaluronoglucosaminidase 1 gene expression.10 A recent observation also suggests that the noncanonical Wnt pathway is activated in IPAH.11 Article see p 2313 Several transient receptor potential canonical (TRPC) family …

Time course of lung parenchyma remodeling in pulmonary and extrapulmonary acute lung injury

The aim of this study is to test the hypothesis that the early changes in lung mechanics and the amount of type III collagen fiber do not predict the evolution of lung parenchyma remodeling in pulmonary and extrapulmonary acute lung injury (ALI). For this purpose, we analyzed the time course of lung parenchyma remodeling in murine models of pulmonary and extrapulmonary ALI with similar degrees of mechanical compromise at the early phase of ALI. Lung histology (light and electron microscopy), the amount of elastic and collagen fibers in the alveolar septa, the expression of matrix metalloproteinase-9, and mechanical parameters (lung-resistive and viscoelastic pressures, and static elastance) were analyzed 24 h, 1, 3, and 8 wk after the induction of lung injury. In control (C) pulmonary (p) and extrapulmonary (exp) groups, saline was intratracheally (it; 0.05 ml) instilled and intraperitoneally (ip; 0.5 ml) injected, respectively. In ALIp and ALIexp groups, mice received Escherichia coli lipopolysaccharide (10 microg it and 125 microg ip, respectively). At 24 h, all mechanical and morphometrical parameters, as well as type III collagen fiber content, increased similarly in ALIp and ALIexp groups. In ALIexp, all mechanical and histological data returned to control values at 1 wk. However, in ALIp, static elastance returned to control values at 3 wk, whereas resistive and viscoelastic pressures, as well as type III collagen fibers and elastin, remained elevated until week 8. ALIp showed higher expression of matrix metalloproteinase-9 than ALIexp. In conclusion, insult in pulmonary epithelium yielded fibroelastogenesis, whereas mice with ALI induced by endothelial lesion developed only fibrosis that was repaired early in the course of lung injury. Furthermore, early functional and morphological changes did not predict lung parenchyma remodeling.