A disintegrin and metalloprotease (ADAM) 33 protein in patients with pulmonary sarcoidosis

Shaffiq, A S; Haitchi, Hans Michael; Pang, Yun Yung; Alangari, Abdullah; Jones, Mark G.; Marshall, Ben G.; Howarth, Peter H.; Davies, Donna E.; O’Reilly, Katherine Ma

doi:10.1111/j.1440-1843.2011.02098.x

Cited by 7 publications

(7 citation statements)

References 31 publications

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“…The 52-kDa band was confirmed as the unprocessed Pro-MP domain using an antibody against the Pro domain ( Supplemental Figure 1A ; supplemental material available online with this article; doi: 10.1172/jci.insight.87632DS1 ). The bands were similar to those previously characterized in BALF from sarcoid patients ( 28 ) and were significantly increased in asthma ( Figure 1B and Supplemental Figure 1B ). Neither ADAM33 antibody cross-reacted with recombinant ADAM8 and ADAM12 ( Supplemental Figure 2, A–C ), which have been associated with asthma ( 29 – 31 ) and show high homology with ADAM33.…”

Section: Resultssupporting

confidence: 86%

“…The transferred protein was assessed by Ponceau staining to ensure similar protein loading prior to blocking and Western blotting. Membranes were probed with polyclonal rabbit antibodies against the MP (ab39191, Abcam; 1:5,000) or the Pro (ab39190, Abcam; 1:5,000) domains of ADAM33 ( Supplemental Figure 1 ) or a polyclonal goat antibody against the ectodomain of mouse ADAM33 (AF2434, R&D Systems; 1:1,000) as described previously ( 26 , 28 ). Secondary antibodies were rabbit TrueBlot anti-rabbit IgG HRP antibody (18-8816, eBioscience; 1: 5,000) or rabbit anti-goat IgG HRP antibody (Calbiochem, Merck; 1:10,000).…”

Section: Methodsmentioning

confidence: 99%

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Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life

Davies¹,

Kelly²,

Howarth³

et al. 2016

JCI Insight

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Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene a disintegrin and metalloprotease 33 (ADAM33) acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble ADAM33 (sADAM33) is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33-null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances postnatal airway eosinophilia and bronchial hyperresponsiveness following subthreshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma.

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Section: Resultssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life

Davies¹,

Kelly²,

Howarth³

et al. 2016

JCI Insight

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“…Because gymnotically delivered oligonucleotides showed no toxicity and high efficiency in cultured cells, they are ideal for further ADAM33 studies. We are exploring the delivery of anti- Adam33 oligonucleotides to mouse airways and the therapeutic potential of ASO-mediated inhibition of ADAM33 for reversing pathological airway remodeling in asthma and other chronic lung diseases, including chronic obstructive pulmonary disease (COPD)66, 67 and sarcoidosis 68 …”

Section: Discussionmentioning

confidence: 99%

Locked Nucleic Acid Gapmers and Conjugates Potently Silence ADAM33, an Asthma-Associated Metalloprotease with Nuclear-Localized mRNA

Pendergraff

Krishnamurthy

Debacker

et al. 2017

Molecular Therapy - Nucleic Acids

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Two mechanisms dominate the clinical pipeline for oligonucleotide-based gene silencing, namely, the antisense approach that recruits RNase H to cleave target RNA and the RNAi approach that recruits the RISC complex to cleave target RNA. Multiple chemical designs can be used to elicit each pathway. We compare the silencing of the asthma susceptibility gene ADAM33 in MRC-5 lung fibroblasts using four classes of gene silencing agents, two that use each mechanism: traditional duplex small interfering RNAs (siRNAs), single-stranded small interfering RNAs (ss-siRNAs), locked nucleic acid (LNA) gapmer antisense oligonucleotides (ASOs), and novel hexadecyloxypropyl conjugates of the ASOs. Of these designs, the gapmer ASOs emerged as lead compounds for silencing ADAM33 expression: several gapmer ASOs showed subnanomolar potency when transfected with cationic lipid and low micromolar potency with no toxicity when delivered gymnotically. The preferential susceptibility of ADAM33 mRNA to silencing by RNase H may be related to the high degree of nuclear retention observed for this mRNA. Dynamic light scattering data showed that the hexadecyloxypropyl ASO conjugates self-assemble into clusters. These conjugates showed reduced potency relative to unconjugated ASOs unless the lipophilic tail was conjugated to the ASO using a biocleavable linkage. Finally, based on the lead ASOs from (human) MRC-5 cells, we developed a series of homologous ASOs targeting mouse Adam33 with excellent activity. Our work confirms that ASO-based gene silencing of ADAM33 is a useful tool for asthma research and therapy.

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“…Shaffiq et al . presented data demonstrating that the soluble form of A Disintegrin and Metalloprotease (ADAM) 33 protein is raised in the bronchoalveolar lavage fluid of individuals with sarcoid when compared with controls . ADAM 33 forms part of a family of transmembrane glycoproteins that play diverse roles in modulating cell surface remodelling, mediation of cell–cell and cell–matrix interactions and ectodomain shedding of growth factors and receptors.…”

Section: Interstitial Lung Diseasesmentioning

confidence: 99%

Year in review 2012: Acute lung injury, interstitial lung diseases, sleep and physiology

et al. 2013

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A disintegrin and metalloprotease (ADAM) 33 protein in patients with pulmonary sarcoidosis

Abstract: Release of sADAM33 is increased in sarcoid and may be associated with abnormal lung function. sADAM33 may be a biomarker of lung tissue inflammation and remodelling in sarcoid.

Cited by 7 publications

References 31 publications

Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life

Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life

Locked Nucleic Acid Gapmers and Conjugates Potently Silence ADAM33, an Asthma-Associated Metalloprotease with Nuclear-Localized mRNA

Year in review 2012: Acute lung injury, interstitial lung diseases, sleep and physiology

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