scholarly journals ADAM17 inhibition prevents neutrophilia and lung injury in a mouse model of Covid-19

2021 ◽  
Author(s):  
Nathaniel L. Lartey ◽  
Salvador Valle-Reyes ◽  
Hilda Vargas-Robles ◽  
Karina E. Jiménez-Camacho ◽  
Idaira M. Guerrero-Fonseca ◽  
...  
Keyword(s):  
Lung Injury ◽  
Mouse Model ◽  
Inflammatory Responses ◽  
Specific Treatment ◽  
Lung Damage ◽  
Poly I:C ◽  
Leukocyte Infiltration ◽  
Vascular Congestion ◽  
Current Therapies ◽  
Endothelial Adhesion Molecules

Severe coronavirus disease 2019 (Covid-19) is characterized by lung injury, cytokine storm and increased neutrophil-to-lymphocyte ratio (NLR). Current therapies focus on reducing viral replication and inflammatory responses, but no specific treatment exists to prevent the development of severe Covid-19 in infected individuals. Angiotensin-converting enzyme-2 ACE-2) is the receptor for SARS-CoV-2, the virus causing Covid-19, but it is also critical for maintaining the correct functionality of lung epithelium and endothelium. Coronaviruses induce activation of a disintegrin and metalloprotease 17 (ADAM17) and shedding of ACE-2 from the cell surface resulting in exacerbated inflammatory responses. Thus, we hypothesized that ADAM17 inhibition ameliorates Covid-19-related lung inflammation. We employed a pre-clinical mouse model using intra-tracheal instillation of a combination of polyinosinic:polycytidylic acid (poly-I:C) and the receptor-binding domain of the SARS-CoV-2 spike protein (RBD-S) to mimic lung damage associated with Covid-19. Histological analysis of inflamed mice confirmed the expected signs of lung injury including edema, fibrosis, vascular congestion and leukocyte infiltration. Moreover, inflamed mice also showed an increased NLR as observed in critically ill Covid-19 patients. Administration of the ADAM17 inhibitors apratastat and TMI-1 significantly improved lung histology and prevented leukocyte infiltration. Reduced leukocyte recruitment could be explained by reduced production of pro-inflammatory cytokines and lower levels of the endothelial adhesion molecules ICAM-1 and VCAM-1. Additionally, the NLR was significantly reduced by ADAM17 inhibition. Thus, we propose inhibition of ADAM17 as a novel promising treatment strategy in SARS-CoV-2-infected individuals to prevent the progression towards severe Covid-19.

CYCLIN-DEPENDENT KINASE INHIBITION REDUCES LUNG DAMAGE IN A MOUSE MODEL OF VENTILATOR-INDUCED LUNG INJURY

Shock ◽  
2012 ◽  
Vol 38 (4) ◽  
pp. 375-380 ◽  
Author(s):  
Arie J. Hoogendijk ◽  
Maria T. Kuipers ◽  
Tom van der Poll ◽  
Marcus J. Schultz ◽  
Catharina W. Wieland
Keyword(s):  
Lung Injury ◽  
Mouse Model ◽  
Lung Damage ◽  
Cyclin Dependent Kinase ◽  
Kinase Inhibition ◽  
Ventilator Induced Lung Injury

scholarly journals Hydrogen Sulfide Prevents Formation of Reactive Oxygen Species through PI3K/Akt Signaling and Limits Ventilator-Induced Lung Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Sashko Georgiev Spassov ◽  
Rosa Donus ◽  
Paul Mikael Ihle ◽  
Helen Engelstaedter ◽  
Alexander Hoetzel ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Hydrogen Sulfide ◽  
Lung Injury ◽  
Inflammatory Responses ◽  
Reactive Oxygen ◽  
Akt Signaling ◽  
Lung Damage ◽  
Oxygen Species ◽  
Ventilator Induced Lung Injury ◽  
Oxidative Processes

The development of ventilator-induced lung injury (VILI) is still a major problem in mechanically ventilated patients. Low dose inhalation of hydrogen sulfide (H2S) during mechanical ventilation has been proven to prevent lung damage by limiting inflammatory responses in rodent models. However, the capacity of H2S to affect oxidative processes in VILI and its underlying molecular signaling pathways remains elusive. In the present study we show that ventilation with moderate tidal volumes of 12 ml/kg for 6 h led to an excessive formation of reactive oxygen species (ROS) in mice lungs which was prevented by supplemental inhalation of 80 parts per million of H2S. In addition, phosphorylation of the signaling protein Akt was induced by H2S. In contrast, inhibition of Akt by LY294002 during ventilation reestablished lung damage, neutrophil influx, and proinflammatory cytokine release despite the presence of H2S. Moreover, the ability of H2S to induce the antioxidant glutathione and to prevent ROS production was reversed in the presence of the Akt inhibitor. Here, we provide the first evidence that H2S-mediated Akt activation is a key step in protection against VILI, suggesting that Akt signaling limits not only inflammatory but also detrimental oxidative processes that promote the development of lung injury.

Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

2015 ◽  
Vol 60 (8) ◽  
pp. 1217-1225 ◽  
Author(s):  
Su-Yeon Joo ◽  
Mi-Ju Park ◽  
Kyun-Ha Kim ◽  
Hee-Jung Choi ◽  
Tae-Wook Chung ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Cold Stress ◽  
Inflammatory Responses

scholarly journals Luteolin Suppresses Inflammatory Mediator Expression by Blocking the Akt/NFκB Pathway in Acute Lung Injury Induced by Lipopolysaccharide in Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Yi-Ching Li ◽  
Chung-Hsin Yeh ◽  
Ming-Ling Yang ◽  
Yu-Hsiang Kuan
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Responses ◽  
Specific Treatment ◽  
Severe Illness ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Protection Mechanism ◽  
Tissue Edema ◽  
Nfκb Pathway

Acute lung injury (ALI), instilled by lipopolysaccharide (LPS), is a severe illness with excessive mortality and has no specific treatment strategy. Luteolin is an anti-inflammatory flavonoid and widely distributed in the plants. Pretreatment with luteolin inhibited LPS-induced histological changes of ALI and lung tissue edema. In addition, LPS-induced inflammatory responses, including increased vascular permeability, tumor necrosis factor (TNF)-αand interleukin (IL)-6 production, and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), were also reduced by luteolin in a concentration-dependent manner. Furthermore, luteolin suppressed activation of NFκB and its upstream molecular factor, Akt. These results suggest that the protection mechanism of luteolin is by inhibition of NFκB activation possibly via Akt.

scholarly journals ZFP36 protects lungs from intestinal I/R-induced injury and fibrosis through the CREBBP/p53/p21/Bax pathway

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Yongmei Cao ◽  
Weifeng Huang ◽  
Fang Wu ◽  
Jiawei Shang ◽  
Feng Ping ◽  
...  
Keyword(s):  
Lung Injury ◽  
Zinc Finger Protein ◽  
Inflammatory Responses ◽  
Binding Protein ◽  
Ischemia Reperfusion ◽  
Negative Regulator ◽  
Lung Damage ◽  
Mouse Lung ◽  
Creb Binding Protein ◽  
Element Binding Protein

AbstractAcute lung injury induced by ischemia–reperfusion (I/R)-associated pulmonary inflammation is associated with high rates of morbidity. Despite advances in the clinical management of lung disease, molecular therapeutic options for I/R-associated lung injury are limited. Zinc finger protein 36 (ZFP36) is an AU-rich element-binding protein that is known to suppress the inflammatory response. A ZFP36 binding site occurs in the 3ʹ UTR of the cAMP‐response element-binding protein (CREB) binding protein (CREBBP) gene, which is known to interact with apoptotic proteins to promote apoptosis. In this study, we investigate the involvement of ZFP36 and CREBBP on I/R-induced lung injury in vivo and in vitro. Intestinal ischemia/reperfusion (I/R) activates inflammatory responses, resulting in injury to different organs including the lung. Lung tissues from ZFP36-knockdown mice and mouse lung epithelial (MLE)-2 cells were subjected to either Intestinal I/R or hypoxia/reperfusion, respectively, and then analyzed by Western blotting, immunohistochemistry, and real-time PCR. Silico analyses, pull down and RIP assays were used to analyze the relationship between ZFP36 and CREBBP. ZFP36 deficiency upregulated CREBBP, enhanced I/R-induced lung injury, apoptosis, and inflammation, and increased I/R-induced lung fibrosis. In silico analyses indicated that ZFP36 was a strong negative regulator of CREBBP mRNA stability. Results of pull down and RIP assays confirmed that ZFP36 direct interacted with CREBBP mRNA. Our results indicated that ZFP36 can mediate the level of inflammation-associated lung damage following I/R via interactions with the CREBBP/p53/p21/Bax pathway. The downregulation of ZFP36 increased the level of fibrosis.

scholarly journals Protective effects of sialylated oligosaccharides in immune complex-induced acute lung injury.

1993 ◽  
Vol 178 (2) ◽  
pp. 623-631 ◽  
Author(s):  
M S Mulligan ◽  
J B Lowe ◽  
R D Larsen ◽  
J Paulson ◽  
Z L Zheng ◽  
...  
Keyword(s):  
Lung Injury ◽  
Immune Complex ◽  
Inflammatory Responses ◽  
Complex Model ◽  
Lung Damage ◽  
Physical Contact ◽  
Protective Effects ◽  
Tissue Accumulation ◽  
Pulmonary Vascular Endothelium

Using sialyl Lewisx (SLX) oligosaccharides derived from fucosyl transferase-expressing cells or generated synthetically, the ability of these compounds to protect against acute lung damage after deposition of immunoglobulin (Ig)G or IgA immune complexes has been determined. The synthetic compounds were tetra- and pentasaccharide derivates of SLX as well as the nonfucosylated forms of SLX as controls. In the IgG immune complex model of lung injury, which is E-selectin dependent, SLX preparations provided dose-dependent protective effects, as assessed by changes in lung vascular permeability and hemorrhage. Protective effects were associated with diminished tissue accumulation of neutrophils in lungs (as assessed by myeloperoxidase). Morphological assessment revealed reduced physical contact of neutrophils with the pulmonary vascular endothelium and reduced tissue accumulation of neutrophils. In the model of IgA immune complex-induced lung injury, which does not involve participation of neutrophils and is independent of the requirement for E-selectin, SLX preparations were not protective. These data suggest that, in neutrophil-mediated and E-selectin-dependent lung injury, SLX preparations provide significant, protective effects against inflammatory vascular injury. The ability to achieve antiinflammatory outcomes in vivo with appropriate oligosaccharides suggests a new approach to the blocking of acute inflammatory responses.

Callicarpa japonica Thunb. reduces inflammatory responses: A mouse model of lipopolysaccharide-induced acute lung injury

2015 ◽  
Vol 26 (1) ◽  
pp. 174-180 ◽  
Author(s):  
Na-Rae Shin ◽  
In-Sik Shin ◽  
Hyuk-Hwan Song ◽  
Ju-Mi Hong ◽  
Ok-Kyoung Kwon ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Inflammatory Responses

scholarly journals A new experimental model of acid- and endotoxin-induced acute lung injury in rats

2016 ◽  
Vol 311 (2) ◽  
pp. L229-L237 ◽  
Author(s):  
F. Puig ◽  
R. Herrero ◽  
R. Guillamat-Prats ◽  
M. N. Gómez ◽  
J. Tijero ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Aspiration Pneumonia ◽  
Inflammatory Responses ◽  
Diffuse Alveolar Damage ◽  
Intratracheal Instillation ◽  
Lung Damage ◽  
Long Term Effects ◽  
Protein Permeability

The majority of the animal models of acute lung injury (ALI) are focused on the acute phase. This limits the studies of the mechanisms involved in later phases and the effects of long-term treatments. Thus the goal of this study was to develop an experimental ALI model of aspiration pneumonia, in which diffuse alveolar damage continues for 72 h. Rats were intratracheally instilled with one dose of HCl (0.1 mol/l) followed by another instillation of one dose of LPS (0, 10, 20, 30, or 40 μg/g body weight) 2 h later, which models aspiration of gastric contents that progresses to secondary lung injury from bacteria or bacterial products. The rats were euthanized at 24, 48, and 72 h after the last instillation. The results showed that HCl and LPS at all doses caused activation of inflammatory responses, increased protein permeability and apoptosis, and induced mild hypoxemia in rat lungs at 24 h postinstillation. However, this lung damage was present at 72 h only in rats receiving HCl and LPS at the doses of 30 and 40 μg/g body wt. Mortality (∼50%) occurred in the first 48 h and only in the rats treated with HCl and LPS at the highest dose (40 μg/g body wt). In conclusion, intratracheal instillation of HCl followed by LPS at the dose of 30 μg/g body wt results in severe diffuse alveolar damage that continues at least 72 h. This rat model of aspiration pneumonia-induced ALI will be useful for testing long-term effects of new therapeutic strategies in ALI.

scholarly journals Elevated inflammatory responses and targeted therapeutic intervention in a preclinical mouse model of ataxia-telangiectasia lung disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rudel A. Saunders ◽  
Thomas F. Michniacki ◽  
Courtney Hames ◽  
Hilary A. Moale ◽  
Carol Wilke ◽  
...  
Keyword(s):  
Lung Injury ◽  
Mouse Model ◽  
Lung Disease ◽  
Pulmonary Disease ◽  
Immune Cells ◽  
Ataxia Telangiectasia ◽  
Inflammatory Responses ◽  
Neutrophil Recruitment ◽  
Therapeutic Interventions ◽  
The Impact

AbstractAtaxia-telangiectasia (A-T) is an autosomal recessive, multisystem disorder characterized by cerebellar degeneration, cancer predisposition, and immune system defects. A major cause of mortality in A-T patients is severe pulmonary disease; however, the underlying causes of the lung complications are poorly understood, and there are currently no curative therapeutic interventions. In this study, we examined the lung phenotypes caused by ATM-deficient immune cells using a mouse model of A-T pulmonary disease. In response to acute lung injury, ATM-deficiency causes decreased survival, reduced blood oxygen saturation, elevated neutrophil recruitment, exaggerated and prolonged inflammatory responses and excessive lung injury compared to controls. We found that ATM null bone marrow adoptively transferred to WT recipients induces similar phenotypes that culminate in impaired lung function. Moreover, we demonstrated that activated ATM-deficient macrophages exhibit significantly elevated production of harmful reactive oxygen and nitrogen species and pro-inflammatory cytokines. These findings indicate that ATM-deficient immune cells play major roles in causing the lung pathologies in A-T. Based on these results, we examined the impact of inhibiting the aberrant inflammatory responses caused by ATM-deficiency with reparixin, a CXCR1/CXCR2 chemokine receptor antagonist. We demonstrated that reparixin treatment reduces neutrophil recruitment, edema and tissue damage in ATM mutant lungs. Thus, our findings indicate that targeted inhibition of CXCR1/CXCR2 attenuates pulmonary phenotypes caused by ATM-deficiency and suggest that this treatment approach represents a viable therapeutic strategy for A-T lung disease.

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