scholarly journals Akt1 regulates pulmonary fibrosis via modulating IL-13 expression in macrophages

2019 ◽  
Vol 25 (7) ◽  
pp. 451-461 ◽  
Author(s):  
Yunjuan Nie ◽  
Yudong Hu ◽  
Kaikai Yu ◽  
Dan Zhang ◽  
Yinze Shi ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Smooth Muscle Actin ◽  
In Vivo Studies ◽  
Muscle Actin ◽  
Alpha Smooth Muscle Actin ◽  
Fibrosis Progression ◽  
Matrix Components ◽  
Deficient Mice

Idiopathic pulmonary fibrosis is a progressive interstitial pneumonia characterised by fibroblast accumulation, collagen deposition and extracellular matrix (ECM) remodelling. It was reported that Akt1 mediated idiopathic pulmonary fibrosis progression through regulating the apoptosis of alveolar macrophage, while its effect on macrophage-produced cytokines remains largely unknown. In the present study, we first examined the phosphorylation of Akt1 in lung sections from idiopathic pulmonary fibrosis patients by immunohistochemistry before applying a bleomycin-induced idiopathic pulmonary fibrosis model using Akt1−/− mice and Akt1+/+ littermates. The results showed that Akt1 was remarkably up-regulated in idiopathic pulmonary fibrosis patients, while in vivo studies revealed that Akt1-deficient mice had well-preserved alveolar structure and fewer collagens, secreted fewer matrix components, including alpha smooth-muscle actin and fibronectin and survived significantly longer than Akt1+/+ littermates. Additionally, the pro-fibrogenic cytokine IL-13 was down-regulated at least twofold in Akt1−/−mice compared to the Akt1+/+group on d 3 and 7 after bleomycin treatment. Furthermore, it was found that Akt1–/– macrophages displayed down-regulation of IL-13 compared to Akt1+/+ macrophages in which Akt1 was phosphorylated in response to IL-33 stimulation. These findings indicate that Akt1 modulates pulmonary fibrosis through inducing IL-13 production by macrophages, suggesting that targeting Akt1 may simultaneously block the fibrogenic processes of idiopathic pulmonary fibrosis.

The Strain Response of Lung Myofibroblasts Cultured on Electrospun Polycaprolactone Nanofibers

2013 ◽  
Author(s):  
Timothy J. Fee ◽  
Yong Zhou ◽  
Lauren E. Marshall ◽  
Joel L. Berry
Keyword(s):  
Smooth Muscle ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Smooth Muscle Actin ◽  
Strain Response ◽  
Muscle Actin ◽  
Alpha Smooth Muscle Actin

Idiopathic Pulmonary Fibrosis is a devastating condition characterized by excessive localized production of collagen in the lungs. Over 131,000 people are living with IPF in America (1, 2). There is currently no known treatment or cure for the disease. It has recently been shown that IPF myofibroblasts are sensitive to the stiffness of their substrate. Specifically, alpha Smooth Muscle Actin (alpha-SMA), a known indicator of IPF activity, was differentially produced on soft vs. stiff substrates (3). This suggests a mechanotransduction pathway within the IPF myofibroblasts.

scholarly journals Influence of Laminin Coating on the Autologous In Vivo Recellularization of Decellularized Vascular Protheses

Materials ◽  
2019 ◽  
Vol 12 (20) ◽  
pp. 3351 ◽  
Author(s):  
Mahfuza Toshmatova ◽  
Sentaro Nakanishi ◽  
Yukiharu Sugimura ◽  
Vera Schmidt ◽  
Artur Lichtenberg ◽  
...  
Keyword(s):  
Inflammatory Cell ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Similar Extent ◽  
Alpha Smooth Muscle Actin ◽  
Promising Strategy ◽  
Biological Implants ◽  
Significant Acceleration ◽  
The Media

Decellularization of non-autologous biological implants reduces the immune response against foreign tissue. Striving for in vivo repopulation of aortic prostheses with autologous cells, thereby improving the graft biocompatibility, we examined surface coating with laminin in a standardized rat implantation model. Detergent-decellularized aortic grafts from donor rats (n = 37) were coated with laminin and systemically implanted into Wistar rats. Uncoated implants served as controls. Implant re-colonization and remodeling were examined by scanning electron microscopy (n = 10), histology and immunohistology (n = 18). Laminin coating persisted over eight weeks. Two weeks after implantation, no relevant neoendothelium formation was observed, whereas it was covering the whole grafts after eight weeks, with a significant acceleration in the laminin group (p = 0.0048). Remarkably, the intima-to-media ratio, indicating adverse hyperplasia, was significantly diminished in the laminin group (p = 0.0149). No intergroup difference was detected in terms of medial recellularization (p = 0.2577). Alpha-smooth muscle actin-positive cells originating from the adventitial surface invaded the media in both groups to a similar extent. The amount of calcifying hydroxyapatite deposition in the intima and the media did not differ between the groups. Inflammatory cell markers (CD3 and CD68) proved negative in coated as well as uncoated decellularized implants. The coating of decellularized aortic implants with bioactive laminin caused an acceleration of the autologous recellularization and a reduction of the intima hyperplasia. Thereby, laminin coating seems to be a promising strategy to enhance the biocompatibility of tissue-engineered vascular implants.

Alpha-smooth muscle actin in pathological human disc nucleus pulposus cells in vivo and in vitro

2004 ◽  
Vol 12 (4) ◽  
pp. 430-438 ◽  
Author(s):  
Dawn Hastreiter ◽  
Jeannie Chao ◽  
QI Wang ◽  
Richard M. Ozuna ◽  
Myron Spector
Keyword(s):  
Smooth Muscle ◽  
Nucleus Pulposus ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Nucleus Pulposus Cells ◽  
Alpha Smooth Muscle Actin

scholarly journals The specific NH2-terminal sequence Ac-EEED of alpha-smooth muscle actin plays a role in polymerization in vitro and in vivo.

1995 ◽  
Vol 130 (4) ◽  
pp. 887-895 ◽  
Author(s):  
C Chaponnier ◽  
M Goethals ◽  
P A Janmey ◽  
F Gabbiani ◽  
G Gabbiani ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Actin Polymerization ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Alpha Smooth Muscle Actin ◽  
Fab Fragment ◽  
Acetyl Group ◽  
Antibody Complex

The blocking effect of the NH2-terminal decapeptide of alpha-smooth muscle (SM) actin AcEEED-STALVC on the binding of the specific monoclonal antibody anti-alpha SM-1 (Skalli, O., P. Ropraz, A. Trzeviak, G. Benzonana, D. Gillessen, and G. Gabbiani. 1986. J. Cell Biol. 103:2787-2796) was compared with that of synthetic peptides modified by changing the acetyl group or by substituting an amino acid in positions 1 to 5. Using immunofluorescence and immunoblotting techniques, anti-alpha SM-1 binding was abolished by the native peptide and by peptides with a substitution in position 5, indicating that AcEEED is the epitope for anti-alpha SM-1. Incubation of anti-alpha SM-1 (or of its Fab fragment) with arterial SM actin increased polymerization in physiological salt conditions; the antibody binding did not hinder the incorporation of the actin antibody complex into the filaments. This action was not exerted on skeletal muscle actin. After microinjection of the alpha-SM actin NH2-terminal decapeptide or of the epitopic peptide into cultured aortic smooth muscle cells, double immunofluorescence for alpha-SM actin and total actin showed a selective disappearance of alpha-SM actin staining, detectable at approximately 30 min. When a control peptide (e.g. alpha-skeletal [SK] actin NH2-terminal peptide) was microinjected, this was not seen. This effect is compatible with the possibility that the epitopic peptide traps a protein involved in alpha-SM actin polymerization during the dynamic filament turnover in stress fibers. Whatever the mechanism, this is the first evidence that the NH2 terminus of an actin isoform plays a role in the regulation of polymerization in vitro and in vivo.

scholarly journals Targeting MAP3K19 prevents human lung myofibroblast activation both in vitro and in a humanized SCID model of idiopathic pulmonary fibrosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Isabelle C. Jones ◽  
Milena S. Espindola ◽  
Rohan Narayanan ◽  
Ana L. Coelho ◽  
David M. Habiel ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Smooth Muscle Actin ◽  
Mitogen Activated Protein Kinase ◽  
Lung Fibroblasts ◽  
Alpha Smooth Muscle Actin ◽  
Biochemical Assays ◽  
Mitogen Activated Protein ◽  
Si Rna

AbstractIdiopathic Pulmonary Fibrosis (IPF) is a disease with a devastating prognosis characterized by unrelenting lung scarring. Aberrant activation of lung fibroblasts is a key feature of this disease, yet the key pathways responsible for this are poorly understood. Mitogen-activated protein kinase, kinase, kinase- 19 (MAP3K19) was recently shown to be upregulated in IPF and this MAPK has a key role in target gene transcription in the TGF-β pathway. Herein, we further investigate the role of MAP3K19 in cultured normal and IPF fibroblasts and in a humanized SCID mouse model of IPF employing both short interfering (si) RNA and novel small-molecule inhibitors directed at this kinase. Targeting MAP3K19 had significant inhibitory effects on the expression of both alpha smooth muscle actin and extracellular matrix in cultured human IPF fibroblasts. Quantitative protein and biochemical assays, as well as histological analysis, showed that MAP3K19 was required for the development of lung fibrosis in SCID mice humanized with IPF lung fibroblasts. MAP3K19 was required for IPF myofibroblast differentiation, and targeting its activity attenuated the profibrotic activity of these cells both in vitro and in an adoptive transfer SCID model of pulmonary fibrosis.

scholarly journals RXFP1 expression is regulated by miR-144-3p in Fibroblasts from Patients with Idiopathic Pulmonary Fibrosis

2017 ◽  
Author(s):  
Harinath Bahudhanapati ◽  
Jiangning Tan ◽  
Justin A Dutta ◽  
Stephen B Strock ◽  
Yingze Zhang ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Smooth Muscle Actin ◽  
Negative Regulator ◽  
Lung Fibroblasts ◽  
Luciferase Reporter ◽  
Alpha Smooth Muscle Actin ◽  
Protein Levels ◽  
Donor Lung ◽  
Luciferase Reporter Vector

ABSTRACTRelaxin has been considered as a potential therapy for patients with pulmonary fibrosis. We have previously shown, however, that a potential limitation of relaxin-based therapy for Idiopathic Pulmonary Fibrosis (IPF) is the loss of expression of the relaxin receptor Relaxin/Insulin Like Receptor 1 (RXFP1) expression in fibroblasts. The molecular mechanism for RXFP1 down-regulation in IPF patients remains unclear. To determine whether microRNAs play a role in RXFP1 gene expression, we employed a bioinformatics approach to identify microRNAs (miRs) that are predicted to target RXFP1. By in silico analysis, we identified a putative target site in the RXFP1 mRNA for the miR-144 family. We found that miR-144-3p was upregulated in IPF fibroblasts compared to donor lung fibroblast controls. Forced miR-144-3p mimic expression reduced RXFP1 mRNA and protein levels and increased expression of the myofibroblast marker alpha-smooth muscle actin (α-SMA) in donor lung fibroblasts. IPF lung fibroblasts transfected with a miR-144-3p inhibitor increased RXFP1 expression and reduced α-SMA expression. A lentiviral luciferase reporter vector carrying the WT 3’UTR of RXFP1 was repressed more in lung fibroblasts whereas vector carrying a mutated miR-144-3p binding site exhibited less sensitivity to endogenous miR-144-3p expression, suggesting that RXFP1 is a direct target of miR-144-3p. Thus, miR-144-3p is highly expressed in IPF fibroblasts and acts as a negative regulator of RXFP1 protein expression.

scholarly journals Fat, Cartilage, and Bone Metaplasia in Lungs of Cattle With Caudal Pleural Lesions and Subjacent Interstitial Fibrosis

2019 ◽  
Vol 56 (4) ◽  
pp. 599-603
Author(s):  
Cecilia Ramírez-Hernández ◽  
Luis Jorge García-Márquez ◽  
Horacio Decanini-Arcaute ◽  
Julio Martínez-Burnes ◽  
Rafael Ramírez-Romero
Keyword(s):  
Wilms Tumor ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Mesothelial Cells ◽  
Osseous Metaplasia ◽  
Muscle Actin ◽  
Alpha Smooth Muscle Actin ◽  
Bone Metaplasia ◽  
Histology And Immunohistochemistry

The changes associated with condemned lungs in cattle with chronic pleural lesions of the caudal lobes were characterized by histology and immunohistochemistry (IHC). Fibroproliferative pleural lesions were microscopically confirmed. Occasionally, the pleural lesions also included adipose, chondroid, and osseous metaplasia that were covered by mesothelial cells, mostly in the absence of inflammation. Other lungs also showed fibrosis in the subpleural interstitium and interlobular septa. In both condemned and noncondemned lungs, immunoreactivity to Wilms tumor 1 (WT1) was normally observed on surface mesothelial cells but not on the submesothelial fibroblasts and myofibroblasts. Conversely, the myofibroblasts beneath the pleura, but not the mesothelial cells, showed immunoreactivity to alpha smooth muscle actin and calponin. However, in the lungs with myofibroblastic foci in the pleura, the proliferated cells maintained WT1 immunoreactivity similar to those of some metaplastic cells. These findings may reflect the plasticity of mesothelial cells in vivo.

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