PAD4 Deficiency Improves Bleomycin-induced Neutrophil Extracellular Traps and Fibrosis in Mouse Lung

Suzuki, Masaki; Ikari, Jun; Anazawa, Rie; Tanaka, Nozomi; Katsumata, Yusuke; Shimada, Ayako; Suzuki, Eiko; Tatsumi, Koichiro

doi:10.1165/rcmb.2019-0433oc

Cited by 64 publications

(44 citation statements)

References 50 publications

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“…PAD2 and PAD4 are potential biomarkers and therapeutic targets of sepsis [ 45 ]. PAD4 inhibitor block neutrophil extracellular trap formation [ 46 ], reducing bleomycin fibrosis [ 47 , 48 ]. Simultaneous inhibition of PAD2 and PAD4 ameliorates neutrophil extracellular trap formation and reduces inflammatory cytokine production [ 49 ].…”

Section: Neutrophils In Immunitymentioning

confidence: 99%

Role of Neutrophils on the Ocular Surface

Mun

Hwang

Shin

2021

IJMS

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The ocular surface is a gateway that contacts the outside and receives stimulation from the outside. The corneal innate immune system is composed of many types of cells, including epithelial cells, fibroblasts, natural killer cells, macrophages, neutrophils, dendritic cells, mast cells, basophils, eosinophils, mucin, and lysozyme. Neutrophil infiltration and degranulation occur on the ocular surface. Degranulation, neutrophil extracellular traps formation, called NETosis, and autophagy in neutrophils are involved in the pathogenesis of ocular surface diseases. It is necessary to understand the role of neutrophils on the ocular surface. Furthermore, there is a need for research on therapeutic agents targeting neutrophils and neutrophil extracellular trap formation for ocular surface diseases.

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Section: Neutrophils In Immunitymentioning

confidence: 99%

Role of Neutrophils on the Ocular Surface

Mun

Hwang

Shin

2021

IJMS

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“…*p < 0.05, **p < 0.01, ***p < 0.001 vs. control cells; # p < 0.05, & p < 0.01, $ p < 0.001 compromised TGFβ signalling in PAD4 -/-CFs might partially explain improved cardiac compliance and function after MI 21 as well as reduced organ fibrosis. 19,21,23 Previous as well as unpublished data of our group revealed reduced cardiac remodelling in PAD4 -/mice subjected to MI, as evidenced by decreased end-diastolic volume and diameter, increased contractility and EF. 21 However, because we did not investigate the impact of PAD4 deficiency on other cardiac cell types, such as cardiomyocytes, additional aspects may merit In summary, this study is, to our knowledge, the first demonstrating that PAD4 is involved in the regulation of TGFβ-induced profibrotic pathways.…”

Section: Discussionmentioning

confidence: 55%

“…PAD4 deficiency has previously been described to protect against organ fibrosis. 19 , 23 Therefore, we next investigated whether there are any differences in the expression of fibrosis markers between WT and PAD4 ‐/‐ hearts. Whereas the expression of α ‐ smooth muscle actin (α ‐ SMA) , collagen I , collagen III , TGF ‐ β and MMP ‐ 2 did not differ between the different genotypes, significant downregulation of MMP ‐ 9 could be detected in PAD4 ‐/‐ hearts (Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

Impaired non‐canonical transforming growth factor‐β signalling prevents profibrotic phenotypes in cultured peptidylarginine deiminase 4‐deficient murine cardiac fibroblasts

Akboua

Eghbalzadeh

Keser

et al. 2021

J Cellular Molecular Medi

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Ischaemic heart disease (IHD) and its consequences are major underlying pathogenic factors of heart failure and contribute significantly to morbidity and mortality worldwide. 1 Elective percutaneous coronary intervention has revolutionized the outcome after acute myocardial infarction (MI) resulting in a remarkable decrease in inhospital heart failure. 2 On the contrary, insufficient reestablishment of blood flow and late or unsuccessful reperfusion drive cardiomyocyte death, ventricular remodelling and increase in late heart failure

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“…Neutrophils release NETs-associated cytotoxic proteases such as histone, elastase and MPO, which was associated with in ammatory response, collagen production ECM deposition [14,15]. NETs could also promote differentiation and function of broblasts, that contribute to organ brosis [15,16].…”

Section: Discussionmentioning

confidence: 99%

NETs Enhance STING To Promote Surgical Adhesion

Shen

Wang

et al. 2021

Preprint

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Background Postoperative adhesion (PA) following abdominal surgery may cause bowel obstruction, chronic pain, infertility, or even death. Knowledge of adhesion biology is limited, and preventive agents in clinical trials have failed to achieve efficacy. Results In the present study, we showed that neutrophils accumulate in the injured peritoneum at early stage of PA, and neutrophils within the ischemic buttons undergo cell death and form neutrophil extracellular traps (NETs) that contribute to PA. Neutrophil depletion reduces adhesion burden at 7 days after adhesion induction. Peptidylarginine deiminase 4 (PAD4), an essential enzyme for NET formation, is increased in ischemic buttons. Degradation of NETs by DNase 1 and suppression of NET formation by pharmacologic inhibition of PAD4 alleviated adhesion burden, collogen deposition and fibrosis formation. Mechanistically, administration of DNase I and PAD inhibitor reduces STING-mediated inflammatory response. STING deficiency attenuates adhesion burden, collogen deposition, and α-SMA production in the adhesive tissues at 7 days after surgery. Conclusions Collectively, our findings reveal NETs/STING signaling as a therapeutic target to prevent PA.

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PAD4 Deficiency Improves Bleomycin-induced Neutrophil Extracellular Traps and Fibrosis in Mouse Lung

Cited by 64 publications

References 50 publications

Role of Neutrophils on the Ocular Surface

Role of Neutrophils on the Ocular Surface

Impaired non‐canonical transforming growth factor‐β signalling prevents profibrotic phenotypes in cultured peptidylarginine deiminase 4‐deficient murine cardiac fibroblasts

NETs Enhance STING To Promote Surgical Adhesion

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