ADAM8 signaling drives neutrophil migration and ARDS severity

Conrad, Catharina; Yildiz, Daniela; Cleary, Simon J.; Margraf, Andreas; Cook, Lena; Schlomann, Uwe; Panaretou, Barry; Bowser, Jessica L.; Karmouty‐Quintana, Harry; Li, Jiwen; Berg, Nathaniel K.; Martin, Samuel C.; Aljohmani, Ahmad; Moussavi-Harami, S. Farshid; Wang, Kristin M.; Tian, Jennifer J.; Magnen, Mélia; Valet, Colin; Qiu, Longhui; Singer, Jonathan P.; Eltzschig, Holger K.; Bertrams, Wilhelm; Herold, Susanne; Suttorp, N; Schmeck, Bernd; Ball, Zachary T.; Zarbock, Alexander; Looney, Mark R.; Bartsch, Jörg W.

doi:10.1172/jci.insight.149870

Cited by 25 publications

(14 citation statements)

References 72 publications

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“…had shown that an increase in C5a during sepsis inhibits neutrophil IL-8 secretion, resulting in neutrophil migration dysfunction through downstream signaling pathways mediated by C5aR and C5L2 ( 173 ). It is concluded that GPCR-mediated aggregation, activation, and apoptosis of the accumulated neutrophils in the lung of septic patients are important causes of ARDS and are related to the release of tissue-destructive immune mediators ( 174 , 175 ).…”

Section: The Contribution Of Neutrophils and Gpcrs In Sepsis-induced ...mentioning

confidence: 99%

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

Wang

Zhu²,

Liu³

et al. 2023

Front. Immunol.

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Sepsis is defined as a life-threatening dysfunction due to a dysregulated host response to infection. It is a common and complex syndrome and is the leading cause of death in intensive care units. The lungs are most vulnerable to the challenge of sepsis, and the incidence of respiratory dysfunction has been reported to be up to 70%, in which neutrophils play a major role. Neutrophils are the first line of defense against infection, and they are regarded as the most responsive cells in sepsis. Normally, neutrophils recognize chemokines including the bacterial product N-formyl-methionyl-leucyl-phenylalanine (fMLP), complement 5a (C5a), and lipid molecules Leukotriene B4 (LTB4) and C-X-C motif chemokine ligand 8 (CXCL8), and enter the site of infection through mobilization, rolling, adhesion, migration, and chemotaxis. However, numerous studies have confirmed that despite the high levels of chemokines in septic patients and mice at the site of infection, the neutrophils cannot migrate to the proper target location, but instead they accumulate in the lungs, releasing histones, DNA, and proteases that mediate tissue damage and induce acute respiratory distress syndrome (ARDS). This is closely related to impaired neutrophil migration in sepsis, but the mechanism involved is still unclear. Many studies have shown that chemokine receptor dysregulation is an important cause of impaired neutrophil migration, and the vast majority of these chemokine receptors belong to the G protein-coupled receptors (GPCRs). In this review, we summarize the signaling pathways by which neutrophil GPCR regulates chemotaxis and the mechanisms by which abnormal GPCR function in sepsis leads to impaired neutrophil chemotaxis, which can further cause ARDS. Several potential targets for intervention are proposed to improve neutrophil chemotaxis, and we hope that this review may provide insights for clinical practitioners.

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Section: The Contribution Of Neutrophils and Gpcrs In Sepsis-induced ...mentioning

confidence: 99%

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

Wang

Zhu²,

Liu³

et al. 2023

Front. Immunol.

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“…The proliferation and differentiation of AECs may be indicated by the level of growth factors, such as hepatocyte growth factor (HGF) acting as a mitogen for AECs II, the increased level of which was associated with poor outcome for ALI patients [ 388 ] ( Table 3 ). Moreover, ECM regulators can be used as markers of the proliferative phase of ALI: high expression levels of genes, responsible for the ECM regulation (PTX3 [ 363 , 389 ], TIMP1 [ 364 ], TNC [ 365 ], MMP8 [ 366 ], PLAUR [ 390 ], ADAM8 [ 368 ]), are associated with increased severity and rapid progression of ALI with different etiologies, including COVID-19 ( Table 3 ).…”

Section: Prognostic Markers Of Acute Lung Injury and Pulmonary Fibrosismentioning

confidence: 99%

Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches

Savin

Zenkova

Sen’kova

2022

IJMS

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Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over time and causing the deposition of fibrotic tissue in the lungs. Despite a long history of study and good coverage of the problem in the scientific literature, the effective therapeutic approaches for pulmonary fibrosis treatment are currently lacking. Thus, the study of the molecular mechanisms underlying the transition from acute lung inflammation to pulmonary fibrosis, and the search for new molecular markers and promising therapeutic targets to prevent pulmonary fibrosis development, remain highly relevant tasks. This review focuses on the etiology, pathogenesis, morphological characteristics and outcomes of acute lung inflammation as a precursor of pulmonary fibrosis; the pathomorphological changes in the lungs during fibrosis development; the known molecular mechanisms and key players of the signaling pathways mediating acute lung inflammation and pulmonary fibrosis, as well as the characteristics of the most common in vivo models of these processes. Moreover, the prognostic markers of acute lung injury severity and pulmonary fibrosis development as well as approved and potential therapeutic approaches suppressing the transition from acute lung inflammation to fibrosis are discussed.

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“…A disintegrin and metalloproteinase 8 Adam8 is an enzyme that participates in the recruitment of leukocytes from the pulmonary blood vessels into the lung tissue during acute lung inflammation [ 67 , 68 , 69 ]. Adam8 is not regulated by Timp1 or other Timps [ 70 , 71 ] such as matrix metalloproteinases and thus may a represent relatively independent way of regulating of inflammation.…”

Section: Resultsmentioning

confidence: 99%

siRNA-Mediated Timp1 Silencing Inhibited the Inflammatory Phenotype during Acute Lung Injury

Chernikov

Staroseletz

Татарникова

et al. 2023

IJMS

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Acute lung injury is a complex cascade process that develops in response to various damaging factors, which can lead to acute respiratory distress syndrome. Within this study, based on bioinformatics reanalysis of available full-transcriptome data of acute lung injury induced in mice and humans by various factors, we selected a set of genes that could serve as good targets for suppressing inflammation in the lung tissue, evaluated their expression in the cells of different origins during LPS-induced inflammation, and chose the tissue inhibitor of metalloproteinase Timp1 as a promising target for suppressing inflammation. We designed an effective chemically modified anti-TIMP1 siRNA and showed that Timp1 silencing correlates with a decrease in the pro-inflammatory cytokine IL6 secretion in cultured macrophage cells and reduces the severity of LPS-induced acute lung injury in a mouse model.

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ADAM8 signaling drives neutrophil migration and ARDS severity

Cited by 25 publications

References 72 publications

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches

siRNA-Mediated Timp1 Silencing Inhibited the Inflammatory Phenotype during Acute Lung Injury

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