scholarly journals FMS-Like Tyrosine Kinase 3 Ligand Treatment of Mice Aggravates Acute Lung Injury in Response to Streptococcus pneumoniae: Role of Pneumolysin

2012 ◽  
Vol 80 (12) ◽  
pp. 4281-4290 ◽  
Author(s):  
Christina Brumshagen ◽  
Regina Maus ◽  
Andrea Bischof ◽  
Bianca Ueberberg ◽  
Jennifer Bohling ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Streptococcus Pneumoniae ◽  
Lung Injury ◽  
Tyrosine Kinase ◽  
Protective Immunity ◽  
Content Type ◽  
Lung Permeability ◽  
Immunization Strategies ◽  
The Impact

ABSTRACTFMS-like tyrosine kinase-3 ligand (Flt3L) is a dendritic cell (DC) growth and differentiation factor with potential in antitumor therapies and antibacterial immunization strategies. However, the effect of systemic Flt3L treatment on lung-protective immunity against bacterial infection is incompletely defined. Here, we examined the impact of deficient (in Flt3L knockout [KO] mice), normal (in wild-type [WT] mice), or increased Flt3L availability (in WT mice pretreated with Flt3L for 3, 5, or 7 days) on lung DC subset profiles and lung-protective immunity against the major lung-tropic pathogen,Streptococcus pneumoniae. Although in Flt3L-deficient mice the numbers of DCs positive for CD11b (CD11bposDCs) and for CD103 (CD103posDCs) were diminished, lung permeability, a marker of injury, was unaltered in response toS. pneumoniae. In contrast, WT mice pretreated with Flt3L particularly responded with increased numbers of CD11bposDCs and with less pronounced numbers of CD103posDCs and impaired bacterial clearance and with increased lung permeability followingS. pneumoniae challenge. Notably, infection of Flt3L-pretreated mice withS. pneumoniaelacking the pore-forming toxin, pneumolysin (PLY), resulted in substantially less lung CD11bposDCs activation and reduced lung permeability. Collectively, this study establishes that Flt3L treatment enhances the accumulation of proinflammatory activated lung CD11bposDCs which contribute to acute lung injury in response to PLY released byS. pneumoniae.

The Role of the Receptor Tyrosine Kinase Ron in Nickel-Induced Acute Lung Injury

2002 ◽  
Vol 26 (1) ◽  
pp. 99-104 ◽  
Author(s):  
Susan A. McDowell ◽  
Ali Mallakin ◽  
Cindy J. Bachurski ◽  
Kenya Toney-Earley ◽  
Daniel R. Prows ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase

scholarly journals Proline-rich tyrosine kinase 2 mediates transforming growth factor-beta-induced hepatic stellate cell activation and liver fibrosis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jonghwa Kim ◽  
Wonseok Kang ◽  
So Hee Kang ◽  
Su Hyun Park ◽  
Ji Young Kim ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Tyrosine Kinase ◽  
Focal Adhesion ◽  
Transforming Growth Factor ◽  
Family Members ◽  
Type I ◽  
Tyrosine Kinase 2 ◽  
The Impact ◽  
Tgf Β1

AbstractHepatic fibrogenesis is characterized by activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix (ECM). The impact of ECM on TGF-β-mediated fibrogenic signaling pathway in HSCs has remained obscure. We studied the role of non-receptor tyrosine kinase focal adhesion kinase (FAK) family members in TGF-β-signaling in HSCs. We used a CCl4-induced liver fibrosis mice model to evaluate the effect of FAK family kinase inhibitors on liver fibrosis. RT-PCR and Western blot were used to measure the expression of its target genes; α-SMA, collagen, Nox4, TGF-β1, Smad7, and CTGF. Pharmacological inhibitors, siRNA-mediated knock-down, and plasmid-based overexpression were adopted to modulate the function and the expression level of proteins. Association of PYK2 activation with liver fibrosis was confirmed in liver samples from CCl4-treated mice and patients with significant fibrosis or cirrhosis. TGF-β treatment up-regulated expression of α-SMA, type I collagen, NOX4, CTGF, TGF-β1, and Smad7 in LX-2 cells. Inhibition of FAK family members suppressed TGF-β-mediated fibrogenic signaling. SiRNA experiments demonstrated that TGF-β1 and Smad7 were upregulated via Smad-dependent pathway through FAK activation. In addition, CTGF induction was Smad-independent and PYK2-dependent. Furthermore, RhoA activation was essential for TGF-β-mediated CTGF induction, evidenced by using ROCK inhibitor and dominant negative RhoA expression. We identified that TGF-β1-induced activation of PYK2-Src-RhoA triad leads to YAP/TAZ activation for CTGF induction in liver fibrosis. These findings provide new insights into the role of focal adhesion molecules in liver fibrogenesis, and targeting PYK2 may be an attractive target for developing novel therapeutic strategies for the treatment of liver fibrosis.

scholarly journals Leukocyte immunoglobulin-like receptor B4 deficiency exacerbates acute lung injury via NF-κB signaling in bone marrow-derived macrophages

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Tao Qiu ◽  
Jiangqiao Zhou ◽  
Tianyu Wang ◽  
Zhongbao Chen ◽  
Xiaoxiong Ma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Stromal Cells ◽  
Marrow Cell ◽  
Marrow Transplant ◽  
Cell Source ◽  
Transplant Model ◽  
Acute Inflammatory Disease

AbstractAcute lung injury (ALI) is an acute inflammatory disease. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing inhibitory receptor that is implicated in various pathological processes. However, the function of LILRB4 in ALI remains largely unknown. The aim of the present study was to explore the role of LILRB4 in ALI. LILRB4 knockout mice (LILRB4 KO) were used to construct a model of ALI. Bone marrow cell transplantation was used to identify the cell source of the LILRB4 deficiency-aggravated inflammatory response in ALI. The effect on ALI was analyzed by pathological and molecular analyses. Our results indicated that LILRB4 KO exacerbated ALI triggered by LPS. Additionally, LILRB4 deficiency can enhance lung inflammation. According to the results of our bone marrow transplant model, LILRB4 regulates the occurrence and development of ALI by bone marrow-derived macrophages (BMDMs) rather than by stromal cells in the lung. The observed inflammation was mainly due to BMDM-induced NF-κB signaling. In conclusion, our study demonstrates that LILRB4 deficiency plays a detrimental role in ALI-associated BMDM activation by prompting the NF-κB signal pathway.

H2O2 inhibits alveolar epithelial wound repair in vitro by induction of apoptosis

2004 ◽  
Vol 287 (2) ◽  
pp. L448-L453 ◽  
Author(s):  
Thomas Geiser ◽  
Masanobu Ishigaki ◽  
Coretta van Leer ◽  
Michael A. Matthay ◽  
V. Courtney Broaddus
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Cell Viability ◽  
Wound Repair ◽  
Wound Edge ◽  
Alveolar Epithelial ◽  
Induction Of Apoptosis

Reactive oxygen species (ROS) are released into the alveolar space and contribute to alveolar epithelial damage in patients with acute lung injury. However, the role of ROS in alveolar repair is not known. We studied the effect of ROS in our in vitro wound healing model using either human A549 alveolar epithelial cells or primary distal lung epithelial cells. We found that H2O2 inhibited alveolar epithelial repair in a concentration-dependent manner. At similar concentrations, H2O2 also induced apoptosis, an effect seen particularly at the edge of the wound, leading us to hypothesize that apoptosis contributes to H2O2-induced inhibition of wound repair. To learn the role of apoptosis, we blocked caspases with the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (zVAD). In the presence of H2O2, zVAD inhibited apoptosis, particularly at the wound edge and, most importantly, maintained alveolar epithelial wound repair. In H2O2-exposed cells, zVAD also maintained cell viability as judged by improved cell spreading and/or migration at the wound edge and by a more normal mitochondrial potential difference compared with cells not treated with zVAD. In conclusion, H2O2 inhibits alveolar epithelial wound repair in large part by induction of apoptosis. Inhibition of apoptosis can maintain wound repair and cell viability in the face of ROS. Inhibiting apoptosis may be a promising new approach to improve repair of the alveolar epithelium in patients with acute lung injury.

Social capital and national innovation system: a cross-country analysis

2014 ◽  
Vol 21 (4) ◽  
pp. 453-475 ◽  
Author(s):  
Sepehr Ghazinoory ◽  
Ali Bitaab ◽  
Ardeshir Lohrasbi
Keyword(s):  
Social Capital ◽  
National Level ◽  
Innovation System ◽  
Negative Effects ◽  
Content Type ◽  
Research Findings ◽  
Different Dimensions ◽  
The Impact ◽  
Positive Effect

Purpose – In the last two decades, researchers have paid much attention to the role of cultural values on economic and social development. In particular, the crucial role of different aspects of culture on the development of innovation has been stressed in the literature. Consequently, it is vital to understand how social capital, as a core cultural value, affects the innovation process and the innovative performance at the national level. However, to date, the impact of different dimensions of social capital and innovation has not been properly portrayed or explained. Thus, the purpose of this paper is to investigate the influence of four different dimensions of social capital (institutional and interpersonal, associational life and norms) on two of the main functions of national innovation system (NIS) (entrepreneurship and knowledge creation) based on over 50,000 observations in 34 countries. Design/methodology/approach – In this regard, national-level data from the World Values Survey database was employed to quantify social capital. Entrepreneurship is, in turn, assumed to consist of three sub-indexes and 14 indicators based on the Global Entrepreneurship Index. Knowledge creation is also measured through US Patent Office applications. Also, exploratory factor analysis and structural equation modeling approach were used to build the measurement model and investigate the impact that each factor of social capital had on entrepreneurship and knowledge application, respectively. Measurement and structural models were built and their reliability and validity were tested using various fit indices. Research findings suggest the strong positive effect of institutional trust and networking on entrepreneurship. Also, interpersonal trust and networks were shown to have high influence on knowledge development at the national level. Norms appear to have naïve to medium negative effects on both functions. Findings – Research findings suggest the strong positive effect of institutional trust and networking on entrepreneurship. Also, interpersonal trust and networks were shown to have high influence on knowledge development at the national level. Norms appear to have naïve to medium negative effects on both functions. Originality/value – However, to date, the impact of different dimensions of social capital and innovation has not been properly portrayed or explained.

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