Neutrophils and Eosinophils: Clinical Implications of their Appearance, Presence and Disappearance in Asthma and COPD

Watt, Alison; Schock, Bettina; Ennis, Madeleine

doi:10.2174/1568010054526313

Cited by 49 publications

(46 citation statements)

References 128 publications

(178 reference statements)

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“…Neutrophil-dominant pulmonary inflammation is an important feature of COPD (Watt et al, 2005;Quint and Wedzicha, 2007), and we found that CHF6001 was highly potent in inhibiting fMLP-evoked ROS production from human neutrophils (IC 50 5 0.005 nM) and C5a-induced chemotaxis in mouse neutrophils (IC 50 5 0.093 nM). Overall, these findings suggest that CHF6001 targets neutrophils both through direct inhibition of oxidative burst and chemotaxis, two biologic responses known to be scarcely sensitive to glucocorticoids (Kubo et al, 2012).…”

Section: Discussionmentioning

confidence: 92%

CHF6001 I: A Novel Highly Potent and Selective Phosphodiesterase 4 Inhibitor with Robust Anti-Inflammatory Activity and Suitable for Topical Pulmonary Administration

Moretto

Caruso

Bosco

et al. 2015

The Journal of Pharmacology and Experimental Therapeutics

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This study examined the pharmacologic characterization of CHF6001 [(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) phenyl)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)ethyl)pyridine 1-oxide], a novel phosphodiesterase (PDE) 4 inhibitor designed for treating pulmonary inflammatory diseases via inhaled administration. CHF6001 was 7-and 923-fold more potent than roflumilast and cilomilast, respectively, in inhibiting PDE4 enzymatic activity (IC 50 5 0.026 6 0.006 nM). CHF6001 inhibited PDE4 isoforms A-D with equal potency, showed an elevated ratio of high-affinity rolipram binding site versus low-affinity rolipram binding site (i.e., .40) and displayed .20,000-fold selectivity versus PDE4 compared with a panel of PDEs. CHF6001 effectively inhibited (subnanomolar IC 50 values) the release of tumor necrosis factor-a from human peripheral blood mononuclear cells, human acute monocytic leukemia cell line macrophages (THP-1), and rodent macrophages (RAW264.7 and NR8383). Moreover, CHF6001 potently inhibited the activation of oxidative burst in neutrophils and eosinophils, neutrophil chemotaxis, and the release of interferon-g from CD4 1 T cells. In all these functional assays, CHF6001 was more potent than previously described PDE4 inhibitors, including roflumilast, UK-500,001 [2-(3,4-difluorophenoxy)-5-fluoro-N-((1S,4S)-4-(2-hydroxy-5-methylbenzamido)cyclohexyl)nicotinamide], and cilomilast, and it was comparable to GSK256066 [6-((3-(dimethylcarbamoyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide]. When administered intratracheally to rats as a micronized dry powder, CHF6001 inhibited liposaccharide-induced pulmonary neutrophilia (ED 50 5 0.205 mmol/kg) and leukocyte infiltration (ED 50 5 0.188 mmol/kg) with an efficacy comparable to a high dose of budesonide (1 mmol/kg i. p.). In sum, CHF6001 has the potential to be an effective topical treatment of conditions associated with pulmonary inflammation, including asthma and chronic obstructive pulmonary disease.

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Section: Discussionmentioning

confidence: 92%

CHF6001 I: A Novel Highly Potent and Selective Phosphodiesterase 4 Inhibitor with Robust Anti-Inflammatory Activity and Suitable for Topical Pulmonary Administration

Moretto

Caruso

Bosco

et al. 2015

The Journal of Pharmacology and Experimental Therapeutics

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“…Thus, during diseases such as allergic asthma, priming cytokines such as IL-5 prolong the life span of the infiltrating eosinophils by delaying apoptosis, thereby heightening their potential to cause tissue damage. This concept has been supported by in vivo studies that show that reduced apoptosis of sputum eosinophils is related to increased clinical severity of allergic asthma (5), and also by observations of apoptotic airway eosinophils in vivo (6). Together, these findings provide evidence that the regulation of eosinophil apoptosis plays a critical role in the resolution of inflammation in diseases such as asthma.…”

mentioning

confidence: 74%

Regulation of Arachidonate Remodeling Enzymes Impacts Eosinophil Survival during Allergic Asthma

Seeds¹,

Peachman²,

Bowton³

et al. 2009

Am J Respir Cell Mol Biol

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Although the role of arachidonic acid (AA) metabolism to eicosanoids has been well established in allergy and asthma, recent studies in neoplastic cells have revealed that AA remodeling through phospholipids impacts cell survival. This study tests the hypothesis that regulation of AA/phospholipid-remodeling enzymes, cytosolic phospholipase A 2 a(cPLA 2 -a, gIVaPLA 2 ) and CoA-independent transacylase (CoA-IT), provides a mechanism for altered eosinophil survival during allergic asthma. In vitro incubation of human eosinophils (from donors without asthma) with IL-5 markedly increased cell survival, induced gIVaPLA 2 phosphorylation, and increased both gIVaPLA 2 and CoA-IT activity. Furthermore, treatment of eosinophils with nonselective (ET18-O-CH 3 ) and selective (SK&F 98625) inhibitors of CoA-IT triggered apoptosis, measured by changes in morphology, membrane phosphatidylserine exposure, and caspase activation, completely reversing IL-5-induced eosinophil survival. To determine if similar activation occurs in vivo, human blood eosinophils were isolated from either normal individuals at baseline or from subjects with mild asthma, at both baseline and 24 hours after inhaled allergen challenge. Allergen challenge of subjects with allergic asthma induced a marked increase in cPLA 2 phosphorylation, augmented gIVaPLA 2 activity, and increased CoA-IT activity. These findings indicate that both in vitro and in vivo challenge of eosinophils activated gIVaPLA 2 and CoA-IT, which may play a key role in enhanced eosinophil survival.

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“…This demonstration is the first on the involvement of PARP-1 in the process of eosinophil recruitment, although most reports have shown an effect on neutrophil infiltration in a variety of animal models (16, 30 -33). This novel finding is particularly important because recruitment of eosinophils differs greatly from that of neutrophils in terms of the mechanism of the recruitment process as well as the disease state for which they are associated (34).…”

Section: Discussionmentioning

confidence: 98%

“…Such modulation correlates with PARP-1 inhibition on eosinophil recruitment in our experimental model. Because IL-5 is the major maturation and differentiation factor for eosinophils and may also be responsible for the activation and degranulation of these inflammatory cells during asthma (8,9,34), we have primarily focused our research on the relationship between PARP-1 and IL-5. Recently, Tavernier et al (35) have shown that only IL-5, not GM-CSF or IL-13, up-regulates the ␣ subunit of the IL-5R and that human eosinophil development is largely IL-5 dependent.…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) Polymerase-1 Inhibition Prevents Eosinophil Recruitment by Modulating Th2 Cytokines in a Murine Model of Allergic Airway Inflammation: A Potential Specific Effect on IL-5

Oumouna¹,

Datta²,

Oumouna-Benachour³

et al. 2006

The Journal of Immunology

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We recently used a murine model of allergic airway inflammation to show that poly(ADP-ribose) polymerase-1 (PARP-1) plays an important role in the pathogenesis of asthma-related lung inflammation. In this study, we show that PARP-1 inhibition, by a novel inhibitor (TIQ-A) or by gene deletion, prevented eosinophilic infiltration into the airways of OVA-challenged mice. Such impairment of eosinophil recruitment appeared to take place after IgE production. OVA challenge of wild-type mice resulted in a significant increase in IL-4, IL-5, IL-10, IL-13, and GM-CSF secretions. Although IL-4 production was moderately affected in OVA-challenged PARP-1−/− mice, the production of IL-5, IL-10, IL-13, and GM-CSF was completely inhibited in ex vivo OVA-challenged lung cells derived from these animals. A single TIQ-A injection before OVA challenge in wild-type mice mimicked the latter effects. The marked effect PARP-1 inhibition exerted on mucus production corroborated the effects observed on the Th2 response. Although PARP-1 inhibition by gene knockout increased the production of the Th1 cytokines IL-2 and IL-12, the inhibition by TIQ-A exerted no effect on these two cytokines. The failure of lung cells derived from OVA-challenged PARP-1−/− mice to synthesize GM-CSF, a key cytokine in eosinophil recruitment, was reestablished by replenishment of IL-5. Furthermore, intranasal administration of IL-5 restored the impairment of eosinophil recruitment and mucus production in OVA-challenged PARP-1−/− mice. The replenishment of either IL-4 or IgE, however, did not result in such phenotype reversals. Altogether, these results suggest that PARP-1 plays a critical role in eosinophil recruitment by specifically regulating the cascade leading to IL-5 production.

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Neutrophils and Eosinophils: Clinical Implications of their Appearance, Presence and Disappearance in Asthma and COPD

Cited by 49 publications

References 128 publications

CHF6001 I: A Novel Highly Potent and Selective Phosphodiesterase 4 Inhibitor with Robust Anti-Inflammatory Activity and Suitable for Topical Pulmonary Administration

CHF6001 I: A Novel Highly Potent and Selective Phosphodiesterase 4 Inhibitor with Robust Anti-Inflammatory Activity and Suitable for Topical Pulmonary Administration

Regulation of Arachidonate Remodeling Enzymes Impacts Eosinophil Survival during Allergic Asthma

Poly(ADP-ribose) Polymerase-1 Inhibition Prevents Eosinophil Recruitment by Modulating Th2 Cytokines in a Murine Model of Allergic Airway Inflammation: A Potential Specific Effect on IL-5

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