Table 1 Drugs that target a phase of the process of eosinophil extracellular traps (EETs) release
From: Eosinophil extracellular traps in asthma: implications for pathogenesis and therapy
Therapy | First author [ref.] | Study description | Related Findings |
|---|---|---|---|
DNase treatments | Lu [10] | Mouse model | DNase I treatment ameliorates asthma in mice |
Cunha [75] | Mouse model | rhDNase decreased significantly airway resistance, EETs formation, and globet cells hyperplasia | |
Chia [76] Hull [77] Harrison [78] | Case report | Successful weaning from mechanical ventilation and ongoing recovery | |
Boogaard [79] | 121 children with moderate to severe worsening asthma were randomly assigned to receive a single 5 mg dose of nebulized rhDNase or a second dose of bronchodilator followed by placebo | Compared to the placebo group, rhDNase did not significantly improve patients’ asthma scores, duration of oxygenation, or number of bronchodilator treatments within 24 h | |
Silverman [80] | 50 patients aged 18–55 years with FEV1 < 60% and symptomatic asthma were randomly assigned to the 2.5 mg, 5.0 mg, 7.5 mg, or placebo treatment groups | Compared to the placebo group, rhDNase failed to significantly improve FEV1% | |
Krug [87] | 40 patients aged 18–64 years with mild asthma were randomly assigned to either the 10 mg SB010 or placebo treatment group | Treatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma | |
Anti-TSLP antibody | Choi [11] | Mouse model | EET-mediated airway inflammation in OVA-challenged mice resulted in significantly increased airway hyperresponsiveness and levels of type 2 cytokines in BALF. Treatment with anti-IL33 and anti-TSLP antibodies significantly reduced AHR |
NCT05280418 | Thirty patients > 18 years of age with moderate or severe asthma were randomly assigned to the tespilizumab 210 mg subcutaneous injection every 4 weeks or placebo treatment group. | On-going | |
Anti-IL-5 antibody | Sasaki [95] Masaki [96] | Case report | Benralizumab reduces the expression levels of EETs |
PAD4 inhibitors | Sim [46] | Purified eosinophils isolated from human peripheral blood | EETs formation induced by PMA, A23187 and its activated platelets can be significantly inhibited by the PAD4 inhibitor GSK484 |
Kim [102] | Purified eosinophils isolated from human peripheral blood | LysoPS-mediated EETs formation is partially blocked by the PAD4 inhibitor GSK484 | |
Barroso [103] | Purified eosinophils isolated from human peripheral blood | Aspergillus fumigatus-induced EETs release occurs in a mechanism independent of PAD4 histone guanylation, and the PAD4 inhibitor GSK484 fails to inhibit Aspergillus fumigatus-mediated release of EETs | |
NADPH/ROS inhibitors | Yousefi [32] | Purified eosinophils isolated from human peripheral blood | DNA release can be detected within 5Â min of stimulation of eosinophils with C5a or LPS, reaching maximum levels after 20Â min, and the effect can be blocked by inhibitors of reactive oxygen species production |
Ueki [38] | Purified eosinophils isolated from human peripheral blood | IgG, IgA, PAF containing IL-5 or GM-CSF, and non-physiological stimulants, calcium carrier A23187 and PMA can cause EETosis, and this effect can be inhibited by DPI | |
Sim [46] | Purified eosinophils isolated from human peripheral blood | PMA-induced EETs formation was completely inhibited by DPI, and A23187-induced EETs formation was partially inhibited by DPI. In contrast, conditioned medium and pellet-formed EETs from A23187-activated platelet cultures were completely insensitive to DPI | |
Silveira [117] | Mouse model | DPI and NAC treatment reduced EPO, goblet cell proliferation, pro-inflammatory cytokines, NFκB p65 immune content, and lung oxidative stress, and decreased the release of EETs in the airways | |
Kim [102] | Purified eosinophils isolated from human peripheral blood | LysoPS-induced EETs are not affected by DPI | |
SP-D treatment | Yousefi [143] | Purified eosinophils isolated from human and mouse peripheral blood | SP-D binds directly to membranes and inhibits human and murine eosinophil-forming EETs in a concentration- and carbohydrate-dependent manner |
cysLT synthase/receptor inhibitor | Cunha [137] | Mouse model | MK-886 or/and MK-571 treatment reduced cysLT production or inhibited cysLT1 receptors and reduced EETs formation in BALF, respectively |
Autophagy Inhibitors | Silveira [145] | Mouse model | 3-Methyladenine treatment reduced the number of eosinophils, EPO activity, goblet cell proliferation, pro-inflammatory cytokines and NFκB p65 immune content in the lung, improved oxidative stress, mitochondrial energy metabolism and Na + and K+-ATPase activity, and reduced EETs formation in the airways |
Anti-TIMP-1 antibody | Cao [149] | Cellular model | TIMP-1 directly activates eosinophils and induces EET release. Anti-TIMP-1 antibody inhibits EET release. |
miR-155 Inhibitor | Kim [151] | Mouse model | miR-155 contributes to the extracellular release of dsDNA and exacerbates allergic lung inflammation. Mixed neutrophil/eosinophil asthma lung inflammation and severe airway hyperresponsiveness can be reduced with miR-155 inhibitors. |