Models and mechanisms of acute lung injury caused by direct insults

Background: TLR4 contributes to pulmonary hypertension, a disease of endothelial dysfunction. The role of HMGB1, one endogenous ligand of TLR4, remains unexplored. Results: HMGB1 inhibited pulmonary artery endothelial cell migration, which was reversed by TLR4 or IRF3 siRNA. Conclusion: HMGB1 inhibits pulmonary artery endothelial cell migration via TLR4-and IRF3-dependent mechanism(s). Significance: HMGB1, via TLR4, inhibits a critical process for pulmonary vascular regeneration.

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“…Again, in contrast to the reported literature on HUVECs (18,19), hypoxia inhibited VEGF induced-HPAEC migration (Fig. 4A).…”

Section: Hypoxia-induced Hmgb1 Release Leads To Inhibition Of Hpaec Mcontrasting

confidence: 54%

High Mobility Group Box 1 Inhibits Human Pulmonary Artery Endothelial Cell Migration via a Toll-like Receptor 4- and Interferon Response Factor 3-dependent Mechanism(s)

Bauer

Shapiro

Billiar

et al. 2013

Journal of Biological Chemistry

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“…The results showed that compared with OA-treated rats, OA þ SO 2 donor rats showed an increased SO 2 content in lung tissue and an alleviated ALI, suggesting that possibly the pathogenesis of OA-induced ALI at least partially involved downregulation of endogenous SO 2 production.…”

Section: Discussionmentioning

confidence: 72%

“…1,2 Since the first description of ALI/ARDS, in 1967, numerous studies have been conducted to better understand the pathogenesis. 3,4 Exposure to hazardous factors such as acid, lipopolysaccharide, hyperoxia, or overinflation generates excessive levels of reactive oxygen species (ROS) and recruitment of considerable amounts of neutrophils in lung tissue, thus resulting in proinflammatory processes and eventually cellular, and tissue dysfunction, which contributes to increased vascular permeability, leukocyte infiltration, plasma exudation and impaired arterial oxygenation.…”

mentioning

confidence: 99%

Endogeous sulfur dioxide protects against oleic acid-induced acute lung injury in association with inhibition of oxidative stress in rats

Chen

Zheng

Liu

et al. 2015

Laboratory Investigation

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The role of endogenous sulfur dioxide (SO 2 ), an efficient gasotransmitter maintaining homeostasis, in the development of acute lung injury (ALI) remains unidentified. We aimed to investigate the role of endogenous SO 2 in the pathogenesis of ALI. An oleic acid (OA)-induced ALI rat model was established. Endogenous SO 2 levels, lung injury, oxidative stress markers and apoptosis were examined. OA-induced ALI rats showed a markedly downregulated endogenous SO 2 /aspartate aminotransferase 1 (AAT1)/AAT2 pathway and severe lung injury. Chemical colorimetry assays demonstrated upregulated reactive oxygen species generation and downregulated antioxidant capacity in OA-induced ALI rats. However, SO 2 increased endogenous SO 2 levels, protected against oxidative stress and alleviated ALI. Moreover, compared with OA-treated cells, in human alveolar epithelial cells SO 2 downregulated O 2 À and OH À generation. In contrast, L-aspartic acid-b-hydroxamate (HDX, Sigma-Aldrich Corporation), an inhibitor of endogenous SO 2 generating enzyme, promoted free radical generation, upregulated poly (ADP-ribose) polymerase expression, activated caspase-3, as well as promoted cell apoptosis. Importantly, apoptosis could be inhibited by the free radical scavengers glutathione (GSH) and N-acetyl-L-cysteine (NAC). The results suggest that SO 2 /AAT1/AAT2 pathway might protect against the development of OA-induced ALI by inhibiting oxidative stress.

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“…In both instances, the lack of TNF shedding has been made responsible for the observed protection. TNF is considered a cardinal proinflammatory cytokine that also contributes to inflammatory lung damage and edema formation (155,216). However, in LPS-induced lung inflammation, mice lacking ADAM17 in hematopoietic cells (driven by Vav-Cre) were not protected against lung inflammation, as measured by edema formation (146).…”

Section: Adam17mentioning

confidence: 99%

ADAM-family metalloproteinases in lung inflammation: potential therapeutic targets

Dreymueller

Uhlig

Ludwig

2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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117

107

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-Acute and chronic lung inflammation is driven and controlled by several endogenous mediators that undergo proteolytic conversion from surface-expressed proteins to soluble variants by a disintegrin and metalloproteinase (ADAM)-family members. TNF and epidermal growth factor receptor ligands are just some of the many substrates by which these proteases regulate inflammatory or regenerative processes in the lung. ADAM10 and ADAM17 are the most prominent members of this protease family. They are constitutively expressed in most lung cells and, as recent research has shown, are the pivotal shedding enzymes mediating acute lung inflammation in a cell-specific manner. ADAM17 promotes endothelial and epithelial permeability, transendothelial leukocyte migration, and inflammatory mediator production by smooth muscle and epithelial cells. ADAM10 is critical for leukocyte migration and alveolar leukocyte recruitment. ADAM10 also promotes allergic asthma by driving B cell responses. Additionally, ADAM10 acts as a receptor for Staphylococcus aureus (S. aureus) ␣-toxin and is crucial for bacterial virulence. ADAM8, ADAM9, ADAM15, and ADAM33 are upregulated during acute or chronic lung inflammation, and recent functional or genetic analyses have linked them to disease development. Pharmacological inhibitors that allow us to locally or systemically target and differentiate ADAM-family members in the lung suppress acute and asthmatic inflammatory responses and S. aureus virulence. These promising results encourage further research to develop therapeutic strategies based on selected ADAMs. These studies need also to address the role of the ADAMs in repair and regeneration in the lung to identify further therapeutic opportunities and possible side effects. metalloproteinase; shedding; inflammation; edema; asthma ACUTE OR CHRONIC INFLAMMATION in the lung can lead to a fatal loss of lung functions. Acute inflammation resulting from infection, aspiration of gastric juice, or overventilation during intensive care is initially characterized by enhanced inflammatory mediator production, edema formation, and recruitment of innate immune cells with the risk of lung damage. Asthma, chronic obstructive pulmonary disease (COPD), and lung fibrosis are fatal chronic diseases that are driven by persistent inflammation with a lack of resolution and impaired tissue regeneration. Targeting the immune response is the underlying principle of many treatment strategies against these diseases (reviewed in Ref. 7).The cytokines, growth factors, receptors, and adhesion molecules that drive the inflammatory process are all under intensive scrutiny. Many of these molecules undergo functional modulation by limited proteolysis, bringing the participating proteases into the focus of attention. Among these proteases is a class of metalloproteinases that subdivides into the matrix metalloproteinases (MMP) and the families of a disintegrin and metalloproteinases (ADAM) and ADAM with trombospondin motif. MMPs have already been intensively investigated with resp...

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Models and mechanisms of acute lung injury caused by direct insults

Cited by 144 publications

References 164 publications

High Mobility Group Box 1 Inhibits Human Pulmonary Artery Endothelial Cell Migration via a Toll-like Receptor 4- and Interferon Response Factor 3-dependent Mechanism(s)

High Mobility Group Box 1 Inhibits Human Pulmonary Artery Endothelial Cell Migration via a Toll-like Receptor 4- and Interferon Response Factor 3-dependent Mechanism(s)

Endogeous sulfur dioxide protects against oleic acid-induced acute lung injury in association with inhibition of oxidative stress in rats

ADAM-family metalloproteinases in lung inflammation: potential therapeutic targets

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