scholarly journals Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

2019 ◽  
Author(s):  
A. Rahman ◽  
K. M. Henry ◽  
K. D. Herman ◽  
A. A. R Thompson ◽  
H. M. Isles ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Human Neutrophils ◽  
Chronic Obstructive ◽  
Neutrophil Apoptosis ◽  
Obstructive Pulmonary Disease ◽  
Neutrophilic Inflammation ◽  
Injury Model ◽  
Neutrophil Survival

AbstractNeutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafishin vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown ofegfraanderbb2by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.

scholarly journals Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Atiqur Rahman ◽  
Katherine M Henry ◽  
Kimberly D Herman ◽  
Alfred AR Thompson ◽  
Hannah M Isles ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Human Neutrophils ◽  
Chronic Obstructive ◽  
Neutrophil Apoptosis ◽  
Obstructive Pulmonary Disease ◽  
Neutrophilic Inflammation ◽  
Injury Model ◽  
Neutrophil Survival

Neutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafish in vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown of egfra and erbb2 by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.

scholarly journals Dexamethasone and RU24858 Induce Survival and Growth Factor Receptor Bound protein 2, Leukotriene B4 Receptor 1 and Annexin-1 expression in primary Human Neutrophils

2012 ◽  
Vol 5 ◽  
pp. JCD.S9097 ◽  
Author(s):  
Mirkka Janka-Junttila ◽  
Hannele Hasala ◽  
Ian Adcock ◽  
Eeva Moilanen ◽  
Hannu Kankaanranta
Keyword(s):  
Growth Factor Receptor ◽  
Leukotriene B4 ◽  
Human Neutrophils ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Gm Csf ◽  
Annexin 1 ◽  
Inducible Genes ◽  
Neutrophil Survival ◽  
Leukotriene B4 Receptor

Glucocorticoids are widely used anti-inflammatory medication in diseases like asthma and chronic obstructive pulmonary disease. Glucocorticoids can either activate (transactivation) or inhibit (transrepression) transcription. RU24858 was introduced as a “dissociated” glucocorticoid and it has been reported to transrepress but not to transactivate. The aim of this study was to compare the effects of RU24858 and dexamethasone in human neutrophils. RU24858 delayed spontaneous neutrophil apoptosis and further enhanced GM-CSF- induced neutrophil survival to a similar extent as dexamethasone. Like dexamethasone RU24858 also reduced CXCL8 and MIP-1α. Unexpectedly however, RU24858 increased the expression of the glucocorticoid-inducible genes BLT-1, Annexin-1 and Grb-2 in neutrophils to a similar level as seen with dexamethasone. We have shown here that dexamethasone and RU24858 both increase Grb-2, BLT1 and Annexin-1 expression and inhibit CXCL8 and MIP-1α production. This suggests that RU24858 was not able to dissociate between transactivation and transrepression in human neutrophils but enhanced neutrophil survival.

scholarly journals Crizotinib acts as ABL1 inhibitor combining ATP-binding with allosteric inhibition and is active against native BCR-ABL1 and its resistance and compound mutants BCR-ABL1T315I and BCR-ABL1T315I-E255K

2021 ◽  
Author(s):  
Afsar Ali Mian ◽  
Isabella Haberbosch ◽  
Hazem Khamaisie ◽  
Abed Agbarya ◽  
Larissa Pietsch ◽  
...  
Keyword(s):  
Binding Site ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Binding Pocket ◽  
Atp Binding ◽  
Atp Binding Site ◽  
Lung Cancer Patients

AbstractResistance remains the major clinical challenge for the therapy of Philadelphia chromosome–positive (Ph+) leukemia. With the exception of ponatinib, all approved tyrosine kinase inhibitors (TKIs) are unable to inhibit the common “gatekeeper” mutation T315I. Here we investigated the therapeutic potential of crizotinib, a TKI approved for targeting ALK and ROS1 in non-small cell lung cancer patients, which inhibited also the ABL1 kinase in cell-free systems, for the treatment of advanced and therapy-resistant Ph+ leukemia. By inhibiting the BCR-ABL1 kinase, crizotinib efficiently suppressed growth of Ph+ cells without affecting growth of Ph− cells. It was also active in Ph+ patient-derived long-term cultures (PD-LTCs) independently of the responsiveness/resistance to other TKIs. The efficacy of crizotinib was confirmed in vivo in syngeneic mouse models of BCR-ABL1- or BCR-ABL1T315I-driven chronic myeloid leukemia–like disease and in BCR-ABL1-driven acute lymphoblastic leukemia (ALL). Although crizotinib binds to the ATP-binding site, it also allosterically affected the myristol binding pocket, the binding site of GNF2 and asciminib (former ABL001). Therefore, crizotinib has a seemingly unique double mechanism of action, on the ATP-binding site and on the myristoylation binding pocket. These findings strongly suggest the clinical evaluation of crizotinib for the treatment of advanced and therapy-resistant Ph+ leukemia.

Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental animal model of sepsis

Blood ◽  
2021 ◽  
Author(s):  
Jia-feng Wang ◽  
Yun-peng Wang ◽  
Jian Xie ◽  
Zhen-zhen Zhao ◽  
Sahil Gupta ◽  
...  
Keyword(s):  
Animal Model ◽  
Lung Injury ◽  
Cecal Ligation ◽  
Human Neutrophils ◽  
Experimental Sepsis ◽  
Akt Phosphorylation ◽  
Effect Of Pd ◽  
Knockout Animals ◽  
Neutrophil Survival

PD-L1 is a ligand for PD-1 and its expression has been shown to be upregulated in neutrophils harvested from septic patients. However, the effect of PD-L1 on neutrophil survival and sepsis-induced lung injury remains largely unknown. Here we show PD-L1 expression negatively correlates with rates of apoptosis in human neutrophils harvested from patients with sepsis. Using co-immunoprecipitation assays on control neutrophils challenged with IFN-γ and LPS, we show PD-L1 complexes with the p85 subunit of PI3-K to activate AKT-dependent survival signaling. Conditional CRE/LoxP deletion of neutrophil PD-L1 in vivo further protected against lung injury and reduced neutrophil lung infiltration in a cecal ligation and puncture (CLP) experimental sepsis animal model. Compared to wild-type animals, PD-L1-deficient animals presented lower plasma levels of plasma TNF-α and IL-6 and higher IL-10 following CLP, and reduced seven-day mortality in CLP PD-L1 knockout animals. Taken together, our data suggest that increased PD-L1 expression on human neutrophils delays cellular apoptosis by triggering PI-3K-dependent AKT phosphorylation to drive lung injury and increase mortality during clinical and experimental sepsis.

In vivo characterization of the transitional bronchioles by aerosol-derived airway morphometry

1999 ◽  
Vol 87 (3) ◽  
pp. 920-927 ◽  
Author(s):  
Kirby L. Zeman ◽  
Gerhard Scheuch ◽  
Knut Sommerer ◽  
James S. Brown ◽  
William D. Bennett
Keyword(s):  
Ex Vivo ◽  
Normal Subjects ◽  
Characteristic Line ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Lung Capacity ◽  
Single Breath ◽  
In Vivo Characterization

Effective airway dimensions (EADs) were determined in vivo by aerosol-derived airway morphometry as a function of volumetric lung depth (VLD) to identify and characterize, noninvasively, the caliber of the transitional bronchiole region of the human lung and to compare the EADs by age, gender, and disease. By logarithmically plotting EAD vs. VLD, two distinct regions of the lung emerged that were identified by characteristic line slopes. The intersection of proximal and distal segments was defined as VLDtransand associated EADtrans. In our normal subjects ( n = 20), VLDtrans [345 ± 83 (SD) ml] correlated significantly with anatomic dead space (224 ± 34 ml) and end of phase II of single-breath nitrogen washout (360 ± 53 ml). The corresponding EADtranswas 0.42 ± 0.07 mm, in agreement with other ex vivo measurements of the transitional bronchioles. VLDtrans was smaller (216 ± 64 ml) and EADtrans was larger (0.83 ± 0.04 mm) in our patients with chronic obstructive pulmonary disease ( n = 13). VLDtrans increased with age for children (age 8–18 yr; P = 0.006, n = 26) and with total lung capacity for age 8–81 yr ( P < 0.001, n = 61). This study extends the usefulness of aerosol-derived airway morphometry to in vivo measurements of the transitional bronchioles.

Voluntary feed intake and apparent digestibility in vivo in ponies given ad libitum access to de-hydrated grass or hay harvested from the same grass crop

1998 ◽  
Vol 1998 ◽  
pp. 131-131
Author(s):  
J. J. Hyslop ◽  
A. Bayley ◽  
A. L. Tomlinson ◽  
D. Cuddeford
Keyword(s):  
Feed Intake ◽  
Chronic Obstructive ◽  
Apparent Digestibility ◽  
Obstructive Pulmonary Disease ◽  
Respiratory Problems ◽  
Voluntary Feed Intake ◽  
Grass Hay ◽  
Ad Libitum ◽  
The Uk

De-hydrated forages are often fed to equids in the UK in place of more traditional grass hay, particularly where individual animals are known to have a sensitivity to dusty, mouldy hay which may play a part inducing respiratory problems such as chronic obstructive pulmonary disease (COPD). One such alternative forage is short-chop de-hydrated grass. However, there is very little information available on voluntary feed intake (VFI), apparent digestibility and nutrient intake parameters when de-hydrated grass is offered to equids compared with traditional grass hay. This study examines the VFI and apparent digestibility in vivo of a short-chop de-hydrated grass compared with a traditional grass hay and determines their ability to meet the predicted energy and protein needs of mature ponies.Six mature Welsh-cross pony geldings with a mean liveweight (LW) of 281 kg (s.e.d. 0.89) were individually housed and offered ad libitum access to either short-chop de-hydrated grass (DHG) or traditional grass hay (HAY) plus 60 g/h/d minerals. The DHG and HAY were made from the same 2nd cut perennial ryegrass sward cut on the same day.

scholarly journals Asthma‐chronic obstructive pulmonary disease overlap: A clinical entity?

2020 ◽  
Vol 3 (1) ◽  
pp. 2-8
Author(s):  
Robert A. Wise
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Lung Function ◽  
Middle Age ◽  
Clinical Manifestations ◽  
Normal Lung ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Neutrophilic Inflammation ◽  
Normal Lung Function

Asthma and COPD are easily recognizable clinical entities in their characteristic presentations. Asthma is an early-onset disorder characterized by Type 2, eosinophil-predominant, inflammation of the airways and is associated with atopy. COPD presents in middle age and is characterized by neutrophilic inflammation of the airways and is associated with cigarette smoking or biomass fuel exposure. Between exacerbations, asthma typically has normal lung function whereas COPD has incompletely reversible lung function. Approximately one in five patients with either of these disorders will show some features of both COPD and Asthma. This overlap is far more common than can be accounted for by chance concurrence of two common diseases. There are likely genetic and environmental susceptibilities to both disorders, but there is no single pathobiological mechanism that identifies all such overlap patients. Most likely there are numerous predispositions that lead to Asthma-COPD overlap that may be grounded in early childhood or even pre-natal events. Thus, Asthma-COPD overlap is best considered a family of diseases with overlapping clinical manifestations. The future elucidation of these different pathways to Asthma-COPD overlap, in conjunction with highly targeted therapies will aid clinicians in treating these patients.

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