Augmented metalloproteinase activity and acute lung injury in copper-deficient rats

2001 ◽  
Vol 281 (2) ◽  
pp. L387-L393 ◽  
Author(s):  
Alex B. Lentsch ◽  
Atsushi Kato ◽  
Jack T. Saari ◽  
Dale A. Schuschke
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Copper Deficiency ◽  
Cell Function ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Normal Function ◽  
Neutrophil Accumulation ◽  
Dietary Copper ◽  
Cardiovascular Defects

Dietary copper is required for normal function of >30 mammalian enzyme systems. Copper deficiency causes a number of cardiovascular defects as well as impaired immune cell function. Little is known regarding the effects of copper deficiency on acute inflammatory responses, but this topic is relevant because many members of the Western population receive less than the recommended dietary allowance of copper. In the current studies, we investigated the effects of dietary copper deficiency on acute lung injury induced by intrapulmonary deposition of IgG immune complexes. Weanling male Long-Evans rats were fed diets either adequate (5.6 μg/g) or deficient (0.3 μg/g) in copper. IgG immune complex lung injury was greatly increased in copper-deficient rats as determined by lung vascular leakage of albumin and histopathology. However, no change was observed in either the lung content of tumor necrosis factor-α or lung neutrophil accumulation. Lungs from copper-deficient rats had much higher levels of matrix metalloproteinase (MMP)-2 and MMP-9 than did copper-adequate control animals. This increased activity was not attributable to alveolar macrophages or neutrophils. These data suggest that the augmented lung injury caused by copper deficiency is due to increased pulmonary MMP-2 and MMP-9 activity and not a generalized amplification of the inflammatory response.

scholarly journals Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets

2017 ◽  
Vol 312 (5) ◽  
pp. L625-L637 ◽  
Author(s):  
Mark J. McVey ◽  
Michael Kim ◽  
Arata Tabuchi ◽  
Victoria Srbely ◽  
Lukasz Japtok ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Pulmonary Complications ◽  
Acid Sphingomyelinase ◽  
Blood Products ◽  
Barrier Dysfunction ◽  
Neutrophil Accumulation ◽  
Characteristic Features ◽  
Underlying Mechanisms ◽  
Stored Blood

Pulmonary complications from stored blood products are the leading cause of mortality related to transfusion. Transfusion-related acute lung injury is mediated by antibodies or bioactive mediators, yet underlying mechanisms are incompletely understood. Sphingolipids such as ceramide regulate lung injury, and their composition changes as a function of time in stored blood. Here, we tested the hypothesis that aged platelets may induce lung injury via a sphingolipid-mediated mechanism. To assess this hypothesis, a two-hit mouse model was devised. Recipient mice were treated with 2 mg/kg intraperitoneal lipopolysaccharide (priming) 2 h before transfusion of 10 ml/kg stored (1–5 days) platelets treated with or without addition of acid sphingomyelinase inhibitor ARC39 or platelets from acid sphingomyelinase-deficient mice, which both reduce ceramide formation. Transfused mice were examined for signs of pulmonary neutrophil accumulation, endothelial barrier dysfunction, and histological evidence of lung injury. Sphingolipid profiles in stored platelets were analyzed by mass spectrophotometry. Transfusion of aged platelets into primed mice induced characteristic features of lung injury, which increased in severity as a function of storage time. Ceramide accumulated in platelets during storage, but this was attenuated by ARC39 or in acid sphingomyelinase-deficient platelets. Compared with wild-type platelets, transfusion of ARC39-treated or acid sphingomyelinase-deficient aged platelets alleviated lung injury. Aged platelets elicit lung injury in primed recipient mice, which can be alleviated by pharmacological inhibition or genetic deletion of acid sphingomyelinase. Interventions targeting sphingolipid formation represent a promising strategy to increase the safety and longevity of stored blood products.

scholarly journals LncRNA HOTAIR Increases Inflammatory Responses by Activating NF-κB Pathway in LPS-Induced Acute Lung Injury

2020 ◽  
Author(s):  
XiaoMei Huang ◽  
ZeXun Mo ◽  
YuJun Li ◽  
Hua He ◽  
KangWei Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Noncoding Rna ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
A549 Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Qrt Pcr ◽  
Tnf Α ◽  
Lncrna Hotair

Abstract Background Nuclear factor kappa-B (NF-κB) activation increased the expression of cytokines and further lead to lung injury was considered the main mechanism of acute lung injury (ALI). Here, we focus on exploring the potential regulatory mechanism between long noncoding RNA (LncRNA) HOX transcript antisense RNA (HOTAIR) and NF-κB on LPS-induced ALI. Methods A549 cells were then divided into 4 groups: HOTAIR group, NC group, si-HOTAIR group and si-NC group. These 4 groups were then treated with 1μg/mL lipopolysaccharides (LPS) or without LPS at 37°C for 24 h. The expression level of cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6) and LncRNA HOTAIR were evaluated by quantitative Real Time Polymerase Chain Reaction (qRT-PCR) and Enzyme-linked immunosorbent assay (ELISA). Western Blot analysis was adopted for evaluating the level of p-IκBα/IκBα and p-p65/p65. Nuclear translocation of p65 was observed by immunofluorescence staining. Results qRT-PCR and ELISA assay showed that the expression of cytokines (IL-1β, IL-6 and TNF-α) and inflammatory gene HOTAIR was remarkably increased with LPS treatment (p < 0.01). Over-expression of HOTAIR significantly increased the expression of cytokines (including IL-1β, IL-6 and TNF-α) and NF-κB pathway associated proteins (including p-IκBα/IκBα and p-p65/p65), while knockdown of HOTAIR had the opposite effect (p < 0.01). The immunofluorescence assay showed that the level of p65 in the nucleus was significantly higher in the HOTAIR group and significantly lowers in the si-HOTAIR group (p < 0.01). Conclusion HOTAIR may play a pro-inflammatory response through NF-κB pathway in LPS-induced ALI, which may provide a perspective for further understanding the pathogenic mechanism of ALI.

scholarly journals Levonadifloxacin, a Novel Benzoquinolizine Fluoroquinolone, Modulates Lipopolysaccharide-Induced Inflammatory Responses in Human Whole-Blood Assay and Murine Acute Lung Injury Model

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Anasuya Patel ◽  
Ganesh V. Sangle ◽  
Jinal Trivedi ◽  
Sushant A. Shengule ◽  
Deepak Thorve ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Whole Blood ◽  
Inflammatory Responses ◽  
Immunomodulatory Activity ◽  
Human Whole Blood ◽  
Injury Model ◽  
Cytokine Levels ◽  
Lung Injury Model ◽  
Clinical Benefits

ABSTRACT Fluoroquinolones are reported to possess immunomodulatory activity; hence, a novel benzoquinolizine fluoroquinolone, levonadifloxacin, was evaluated in lipopolysaccharide-stimulated human whole-blood (HWB) and mouse acute lung injury (ALI) models. Levonadifloxacin significantly mitigated the inflammatory responses in an HWB assay through inhibition of proinflammatory cytokines and in the ALI model by lowering lung total white blood cell count, myeloperoxidase, and cytokine levels. The immunomodulatory effect of levonadifloxacin, along with promising antibacterial activity, is expected to provide clinical benefits in the treatment of infections.

Umbelliferone Alleviates Lipopolysaccharide-Induced Inflammatory Responses in Acute Lung Injury by Down-Regulating TLR4/MyD88/NF-κB Signaling

Inflammation ◽  
2019 ◽  
Vol 42 (2) ◽  
pp. 440-448 ◽  
Author(s):  
Dongqiu Wang ◽  
Xia Wang ◽  
Wen Tong ◽  
Yuhong Cui ◽  
Xiuxian Li ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Responses

Src protein tyrosine kinase family and acute inflammatory responses

2006 ◽  
Vol 291 (2) ◽  
pp. L129-L141 ◽  
Author(s):  
Daisuke Okutani ◽  
Monika Lodyga ◽  
Bing Han ◽  
Mingyao Liu
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Tyrosine Kinase ◽  
Reperfusion Injury ◽  
Protein Tyrosine Kinase ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Protein Tyrosine

Acute inflammatory responses are one of the major underlying mechanisms for tissue damage of multiple diseases, such as ischemia-reperfusion injury, sepsis, and acute lung injury. By use of cellular and molecular approaches and transgenic animals, Src protein tyrosine kinase (PTK) family members have been identified to be essential for the recruitment and activation of monocytes, macrophages, neutrophils, and other immune cells. Src PTKs also play a critical role in the regulation of vascular permeability and inflammatory responses in tissue cells. Importantly, animal studies have demonstrated that small chemical inhibitors for Src PTKs attenuate tissue injury and improve survival from a variety of pathological conditions related to acute inflammatory responses. Further investigation may lead to the clinical application of these inhibitors as drugs for ischemia-reperfusion injury (such as stroke and myocardial infarction), sepsis, acute lung injury, and multiple organ dysfunction syndrome.

Late Breaking Abstract - Aging impairs alveolar epithelial type II cell function in acute lung injury

2019 ◽  
Author(s):  
Christina Brandenberger ◽  
Tolga Yazicioglu ◽  
Cheng-Kai Huang ◽  
Christian Bär ◽  
Christian Mühlfeld
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Cell Function ◽  
Type Ii ◽  
Alveolar Epithelial ◽  
Type Ii Cell

Effect of MiR-16 on Acute Lung Injury in Neonatal Rats Through Regulating NF-κB Pathway

2020 ◽  
Vol 10 (3) ◽  
pp. 360-364
Author(s):  
Yan Xing ◽  
Yuan Liang ◽  
Changsong Shi ◽  
Yudong Miao ◽  
Jianqin Gu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Correlation Analysis ◽  
Western Blotting ◽  
Inflammatory Responses ◽  
Morphological Changes ◽  
Pearson Correlation ◽  
Mrna Levels ◽  
Low Oxygen ◽  
Pearson Correlation Analysis

Acute lung injury represents a widespread, variable type of lung injury characterized by a low oxygen level in the blood, non cardiogenic pulmonary edema, low lung compliance and extensive capillary leakage. In our study, the Wistar rat mode of ALI was established using lipopolysaccharide (LPS). The rats were randomly divided into normal control (NC) group (n = 12) and miR-16 overex-pression group (n = 12), and they were transfected with empty vector and miR-16 overexpression virus, respectively. The lung tissues were extracted in both groups, and then the expression levels of miR-16 and NF-κB were detected via fluorescence quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and the association between their expressions was analyzed via Pearson correlation analysis. Moreover, the morphological changes in lung tissues were detected via hematoxylin-eosin (HE) staining, and the differences in the wet/dry weight (W/D) ratio and the pathomorphological score of lung tissues were compared between the two groups. The expression level of NF-κB was detected via immunohistochemistry (IHC) and Western blotting. Our results showed that, there were different degrees of lung injury in lung tissues in both groups. In miR-16 overexpression group, the W/D ratio was significantly higher than that in NC group (P < 0.05), and the pathomorphological score was also significantly higher than that in NC group (P < 0.05). The results of RT-PCR revealed that the mRNA levels of miR-16 and NF-κB in miR-16 overexpression group were 2.5 and 3.7 times higher than those in NC group. The results of Western blotting and IHC also showed that the activity of NF-κB in lung tissues was evidently enhanced in miR-16 overexpression group compared with that in NC group. According to the Pearson correlation analysis, there was a significant positive correlation between the mRNA levels of miR-16 and NF-κB in lung tissues (r = 0.705, P = 0.012). In conclusion, miR-16 activates the NF-κB pathway to initiate a series of inflammatory responses, thereby contributing to the occurrence of ALI in rats.

scholarly journals Fibrocytes Ameliorate Acute Lung Injury by Decreasing Inflammatory Cytokine and Chemokine Levels and Reducing Neutrophil Accumulation in the Lung

2017 ◽  
Vol 44 (4) ◽  
pp. 1526-1536 ◽  
Author(s):  
Wenlin Tai ◽  
Yiheng Xu ◽  
Jiawei Ding ◽  
Hanxin Wu ◽  
Ming Du ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mononuclear Cells ◽  
Human Life ◽  
Severe Disease ◽  
Lavage Fluid ◽  
Neutrophil Accumulation ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Ifn Γ

Background/Aims: Acute lung injury (ALI) remains a severe disease that threatens human life around the world. To decrease the mortality of ALI and improve ALI treatment efficacy, the development of more ALI treatments is urgently needed. Whether fibrocytes directly participate in ALI has not been studied. Therefore, a mouse model of ALI was induced with lipopolysaccharide (LPS). Methods: Fibrocytes were harvested from peripheral blood mononuclear cells of bleomycin mice and identified by using flow cytometry to detect the expression of molecular makers. The fibrocytes were injected for the treatment of acute lung injury mice. The curative effects were evaluated by using ELISA to determine the cytokines (including TNF-α, IL-6 and IFN-γ) concentrations in bronchoalveolar lavage fluid (BALF) supernatant. Results: The concentrations of cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) were increased in mice with ALI induced with LPS. The concentrations of TNF-α, IL-6, and IFN-γ as well as their mRNA and protein expression levels were decreased by administration of fibrocytes. The effect of fibrocytes in ameliorating ALI was time dependent. LPS treatment induced an increase in myeloperoxidase (MPO) activity, whereas the fibrocyte treatment caused inhibition of MPO activity as well as expression of the neutrophil-chemoattractant chemokine macrophage inflammatory protein 2 (MIP-2). Conclusion: Taken together, these data suggest that fibrocytes ameliorated ALI by suppressing inflammatory cytokines and chemokines as well as by decreasing the accumulation of neutrophils in the lung.

scholarly journals Transcriptional Profiling of Lipopolysaccharide-Induced Acute Lung Injury

2004 ◽  
Vol 72 (12) ◽  
pp. 7247-7256 ◽  
Author(s):  
Samithamby Jeyaseelan ◽  
Hong Wei Chu ◽  
Scott K. Young ◽  
G. Scott Worthen
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Transcriptional Profiling ◽  
Lung Damage ◽  
Neutrophil Accumulation ◽  
Transcriptional Responses ◽  
Necrosis Factor Alpha ◽  
Neutrophil Influx ◽  
Inflammatory Genes ◽  
Proinflammatory Mediators

ABSTRACT Mortality associated with acute lung injury (ALI) induced by lipopolysaccharide (LPS) remains high in humans, warranting improved treatment and prevention strategies. ALI is characterized by the expression of proinflammatory mediators and extensive neutrophil influx into the lung, followed by severe lung damage. Understanding the pathogenesis of LPS-induced ALI is a prerequisite for designing better therapeutic strategies. In the present study, we used microarrays to gain a global view of the transcriptional responses of the lung to LPS in a mouse model of ALI that mimics ALI in humans. A total of 71 inflammation-associated genes were up-regulated in LPS-treated lungs, including a chemokine, LPS-induced CXC chemokine (LIX), whose role in the induction of ALI is unknown. Most of the inflammatory genes peaked at 2 h post-LPS treatment. Real-time reverse transcription-PCR confirmed the LPS-induced up-regulation of selected genes identified by microarray analysis, including LIX. The up-regulation of LIX, tumor necrosis factor alpha, and macrophage inflammatory protein 2 was confirmed at the protein level by enzyme-linked immunosorbent assays. To determine the role of LIX in the induction of ALI, we used both exogenous LIX and a LIX blocking antibody. Exogenous LIX alone elicited a neutrophil influx in the lungs, and the anti-LIX antibody attenuated the LPS-induced neutrophil accumulation in the lungs. Taken together, the results of our study demonstrate for the first time the temporal expression of inflammatory genes during LPS-induced ALI and suggest that early therapeutic intervention is crucial to attenuate lung damage. Moreover, we identified a role for LIX in the induction of ALI, and therefore LIX may serve as a novel therapeutic target for the minimization of ALI.

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