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Hans Michael Haitchi - One of the best experts on this subject based on the ideXlab platform.

  • s130 maternal allergic airway inflammation during pregnancy alters offspring s airway hyperresponsiveness dependent on muscarinic receptor and ADAM33 mediated mechanisms
    Thorax, 2019
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Donna E Davies, Jeffrey A Whitsett, Jfc Kelly, S T Holgate, Hans Michael Haitchi
    Abstract:

    Background Maternal allergic asthma is a strong risk factor for the development of asthma and airway hyperresponsiveness (AHR) in children. ADAM33, an asthma susceptibility gene, has been associated with AHR and impaired lung function in early life. Our aim was to investigate how the maternal allergic environment during pregnancy interacts with the ADAM33 status of their offspring, and the effects this has on the lungs of offspring after birth. We hypothesised that the effects of maternal allergy will be different in ADAM33 knock-out (KO) compared to wild-type (WT) offspring Methods Allergic airway inflammation (AAI) during pregnancy was induced in heterozygous (ADAM33±) mice through intranasal house dust mite (HDM) challenges. Control mice were challenged with saline. WT and KO (ADAM33-/-) offspring from the same litters were studied 4 weeks post partum (pp). Lung function was measured in response to increasing doses of methacholine. Bronchoalveolar lavage fluid (BALF) and lung tissue were obtained for RTqPCR, Western Blots and immunostainings. Precision-cut lung slices (PCLS) from 4-weeks old offspring were investigated for airway contraction in response to different agonists and antagonists in vitro. Results Allergen-naive WT offspring of allergic mothers showed AHR 4 weeks pp compared to those of control mothers, whereas KO offspring from the same litter were protected. Expression of the muscarinic M1 receptor was elevated in both KO and WT offspring lungs of HDM-challenged dams. Experiments using muscarinic receptor antagonists and methacholine in PCLS confirmed that maternal AAI causes increased bronchoconstriction through vagal reflexes in WT offspring. KO offspring were protected from this effect due to decreased sensitivity of airway smooth muscle, suggested by a delayed response to a thromboxane-receptor agonist in PCLS. Conclusions Our studies show how gene-environment interactions between ADAM33 and maternal AAI determine development of AHR in early life. While the AAI of the mother leads to an increased pulmonary muscarinic M1 receptor expression, the absence of ADAM33 alters the airway smooth muscle function in the offspring. Together these changes manifest in AHR only in WT offspring, but not in KO offspring. Further studies are needed to determine how ADAM33 KO changes smooth muscle function in the lungs.

  • s27 ADAM33 knockout mice have an altered metabolic transcriptional profile in response to house dust mite when compared to wild type mice
    Thorax, 2018
    Co-Authors: Jfc Kelly, Elizabeth R Davies, Donna E Davies, Jeffrey A Whitsett, Joseph Bell, S T Holgate, Hans Michael Haitchi
    Abstract:

    Rationale ADAM33 is an asthma susceptibility gene that plays a role in both airway remodelling and susceptibility to allergic airways disease. To study the role of ADAM33 in asthma we have exposed an ADAM33 Knockout (KO) mouse to a house dust mite (HDM) sensitisation and challenge protocol. We have found that these mice exhibit less remodelling, bronchial hyperresponsiveness (BHR) and eosinophilic inflammation than wild type (WT) mice (ER Davies et al., JCI-Insight 2016), however the mechanisms which contribute to this protective phenotype are not well understood. Methods To study how the response to HDM is altered by loss of ADAM33 we challenged WT and KO mice with HDM or saline and took whole lung RNA samples for next generation RNA sequencing (RNAseq). Gene set enrichment analysis was used to identify pathways and gene ontology terms associated with the differential response to HDM between KO and WT mice. Results Control WT and KO mice were found to have very similar gene expression profiles at baseline (5 differentially expressed genes, including ADAM33, FDR p Discussion The alteration in the pulmonary metabolic gene signature may underpin a shift in immune cell activation and/or modification of smooth muscle energy expenditure during airway contraction. These changes may explain why the KO mouse is protected from both allergic responses and BHR. Further work will aim to identify the source of the different metabolic behaviour at a cellular level and to assess oxidative stress in lungs of normal and ADAM33 KO mice.

  • ADAM33 is involved in post natal airway hyperresponsiveness caused by maternal allergic airway inflammation
    European Respiratory Journal, 2018
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Joanne Kelly, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Hans Michael Haitchi
    Abstract:

    Maternal allergy is a strong risk factor for developing asthma and airway hyperresponsiveness (AHR). The asthma susceptibility gene ADAM33 is associated with AHR and impaired lung function in early life. Our aim was to investigate gene-environment interactions involving ADAM33 by determining the effects of maternal murine allergic airway inflammation on the lungs of offspring. We hypothesised that this will be modified in ADAM33 knock out (KO) compared to wild-type (WT) offspring. Allergic airway inflammation was induced by exposure to house dust mite (HDM) allergen in pregnant heterozygous ADAM33 mice. WT and KO offspring from the same litters were studied on embryonic day (ED)17.5 and 2 and 4 weeks post partum. Lung function was performed in response to methacholine, bronchoalveolar lavage fluid (BALF) collected for differential cell counts and lung tissue for RTqPCR. Compared with saline challenged mothers, 4-week-old WT offspring of HDM challenged mothers showed significantly enhanced AHR; KO offspring of HDM challenged mothers were protected against development of AHR. No inflammatory genes were up-regulated in the lungs and no inflammatory cells were present in the BALF at 2 or 4 weeks. While typical remodelling genes were not up-regulated at the time points studied, ADAM33 mRNA expression was significantly increased in WT lungs at ED17.5 and Cholinergic Receptor Muscarinic 1 (Chrm1) mRNA at 4 weeks in offspring of HDM challenged mothers. This study identifies an in utero gene-environment interaction involving ADAM33 that has implications for the development of AHR in early life. Further studies are needed to elucidate the mechanisms whereby ADAM33 mediates this.

  • s89 soluble ADAM33 augments the pulmonary immune response promoting allergic airway sensitivity
    Thorax, 2017
    Co-Authors: Jfc Kelly, Elizabeth R Davies, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Hans Michael Haitchi
    Abstract:

    Rational A disintegrin and metalloproteinase 33 (ADAM33) was discovered in 2002 as an asthma susceptibility gene. Genetic associations have been made between ADAM33 polymorphisms and asthma disease severity, bronchial hyperresponsivenss (BHR) and rate of lung function decline in both adults and children. A soluble, catalytically active form of the protein (sADAM33) has been identified in the bronchoalveolar lavage fluid of patients, levels of which correlate with disease severity (Lee JY et al, AJRCCM 2006). To study the role sADAM33, a lung specific, doxycycline (Dox) inducible, transgenic mouse, expressing the human pro and metalloproteinase domains of the full-length protein was generated (Ccsp-rtTA/Otet-ADAM33-Pro-MP). Induction of sADAM33, followed by house dust mite (HDM) sensitisation and challenge, resulted in increased BHR and airway inflammation (Davies ER et al, JCI-Insight 2016). The mechanisms by which ADAM33 promotes this susceptibility are unclear. The aim of this work is to identify pathways that are augmented by the induction of sADAM33, which promote increased sensitivity to allergen. Methods RNA samples from whole lung of adult mice, where sADAM33 had been induced for 4 or 8 weeks, were analysed by next generation RNA sequencing. Identified genes were confirmed across experimental time points (72 hour, 7 day, 4 and 8 weeks on Dox) in wider sample cohorts of Ccsp-rtTA/Otet-ADAM33-Pro-MP and control mice through RTqPCR. Results The predominant signal from the RNAseq output was for modulation of immune response genes at 4 weeks of sADAM33 expression (GO:0006955 Immune response: 31 genes, 58.49% coverage, FDR p value=7.09 E-22). Genes associated with an immune activation signature (Ccl5, Irgm1, Gm12250, Gzmb, Ncr1) were validated at least one time point. By 8 weeks of sADAM33 expression genes associated with negative regulation of the response were also validated (Ido1, Cd274). Conclusion Induction of sADAM33 in murine lungs, without allergic sensitisation, augmented underlying immune processes in this transgenic mouse model, which may contribute to increased susceptibility to allergic airway inflammation and BHR when challenged with allergen. Further work is required to delineate how sADAM33 affects immune cell populations and their behaviour in the lung.

  • locked nucleic acid gapmers and conjugates potently silence ADAM33 an asthma associated metalloprotease with nuclear localized mrna
    Molecular therapy. Nucleic acids, 2017
    Co-Authors: Hannah Pendergraff, Hans Michael Haitchi, Pranathi Meda Krishnamurthy, Alexandre J Debacker, Michael P Moazami, Vivek Sharma, Liisa Niitsoo, Yen Nee Tan, Jonathan K Watts
    Abstract:

    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.

Donna E Davies - One of the best experts on this subject based on the ideXlab platform.

  • s130 maternal allergic airway inflammation during pregnancy alters offspring s airway hyperresponsiveness dependent on muscarinic receptor and ADAM33 mediated mechanisms
    Thorax, 2019
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Donna E Davies, Jeffrey A Whitsett, Jfc Kelly, S T Holgate, Hans Michael Haitchi
    Abstract:

    Background Maternal allergic asthma is a strong risk factor for the development of asthma and airway hyperresponsiveness (AHR) in children. ADAM33, an asthma susceptibility gene, has been associated with AHR and impaired lung function in early life. Our aim was to investigate how the maternal allergic environment during pregnancy interacts with the ADAM33 status of their offspring, and the effects this has on the lungs of offspring after birth. We hypothesised that the effects of maternal allergy will be different in ADAM33 knock-out (KO) compared to wild-type (WT) offspring Methods Allergic airway inflammation (AAI) during pregnancy was induced in heterozygous (ADAM33±) mice through intranasal house dust mite (HDM) challenges. Control mice were challenged with saline. WT and KO (ADAM33-/-) offspring from the same litters were studied 4 weeks post partum (pp). Lung function was measured in response to increasing doses of methacholine. Bronchoalveolar lavage fluid (BALF) and lung tissue were obtained for RTqPCR, Western Blots and immunostainings. Precision-cut lung slices (PCLS) from 4-weeks old offspring were investigated for airway contraction in response to different agonists and antagonists in vitro. Results Allergen-naive WT offspring of allergic mothers showed AHR 4 weeks pp compared to those of control mothers, whereas KO offspring from the same litter were protected. Expression of the muscarinic M1 receptor was elevated in both KO and WT offspring lungs of HDM-challenged dams. Experiments using muscarinic receptor antagonists and methacholine in PCLS confirmed that maternal AAI causes increased bronchoconstriction through vagal reflexes in WT offspring. KO offspring were protected from this effect due to decreased sensitivity of airway smooth muscle, suggested by a delayed response to a thromboxane-receptor agonist in PCLS. Conclusions Our studies show how gene-environment interactions between ADAM33 and maternal AAI determine development of AHR in early life. While the AAI of the mother leads to an increased pulmonary muscarinic M1 receptor expression, the absence of ADAM33 alters the airway smooth muscle function in the offspring. Together these changes manifest in AHR only in WT offspring, but not in KO offspring. Further studies are needed to determine how ADAM33 KO changes smooth muscle function in the lungs.

  • s28 ADAM33 knock out is protective against post natal airway hyperresponsiveness caused by maternal allergy
    Thorax, 2018
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Jfc Kelly, H M Haitchi
    Abstract:

    Background Maternal allergy is a strong risk factor for developing asthma and airway hyperresponsiveness (AHR). ADAM33 has been identified as an asthma susceptibility gene and is associated with AHR and impaired lung function in early life. Our aim was to investigate the effects of maternal murine allergic airway inflammation on the lungs of offspring before and after birth. We hypothesised that the effects of maternal allergy will be modified in ADAM33 knock out (KO) compared to wild-type (WT) offspring. Methods Allergic airway inflammation in pregnant heterozygous (ADAM33±) mice was induced by exposure to house dust mite (HDM) through intranasal challenges during pregnancy. Control mice were challenged with saline. WT (ADAM33+/+) and KO (ADAM33-/-) offspring from the same litters were studied on embryonic day (ED)17.5 and 2 or 4 weeks post partum (pp). Lung function was measured in response to increasing doses of methacholine and bronchoalveolar lavage fluid (BALF) was collected for differential cell counts. Lung tissue was obtained for RTqPCR, Western blot and immunohistochemistry. Results At 4 weeks pp, WT offspring of HDM challenged mothers showed significantly enhanced AHR compared to WT offspring of control mothers. KO of ADAM33 protected against AHR in the offspring of allergic mothers. ADAM33 mRNA expression was significantly enhanced in WT lungs of HDM challenged mothers at ED17.5, but unchanged pp. Differential cell counts in the BALF and mRNA expression of inflammatory mediators indicated an absence of allergic airway inflammation in all of the offspring. Remodelling genes were not affected at any time point studied. In contrast, Cholinergic Receptor Muscarinic 1 (Chrm1) mRNA was increased at 4 weeks in all offspring of HDM challenged mothers. Conclusions This study identifies an in utero gene-environment interaction involving ADAM33. This interaction has implications for the subsequent development of AHR in early life. Further studies are needed to elucidate the precise mechanism(s) whereby ADAM33 mediates its effects. Our data suggest modulation of the contractility of the airways, possibly involving muscarinic receptors.

  • s27 ADAM33 knockout mice have an altered metabolic transcriptional profile in response to house dust mite when compared to wild type mice
    Thorax, 2018
    Co-Authors: Jfc Kelly, Elizabeth R Davies, Donna E Davies, Jeffrey A Whitsett, Joseph Bell, S T Holgate, Hans Michael Haitchi
    Abstract:

    Rationale ADAM33 is an asthma susceptibility gene that plays a role in both airway remodelling and susceptibility to allergic airways disease. To study the role of ADAM33 in asthma we have exposed an ADAM33 Knockout (KO) mouse to a house dust mite (HDM) sensitisation and challenge protocol. We have found that these mice exhibit less remodelling, bronchial hyperresponsiveness (BHR) and eosinophilic inflammation than wild type (WT) mice (ER Davies et al., JCI-Insight 2016), however the mechanisms which contribute to this protective phenotype are not well understood. Methods To study how the response to HDM is altered by loss of ADAM33 we challenged WT and KO mice with HDM or saline and took whole lung RNA samples for next generation RNA sequencing (RNAseq). Gene set enrichment analysis was used to identify pathways and gene ontology terms associated with the differential response to HDM between KO and WT mice. Results Control WT and KO mice were found to have very similar gene expression profiles at baseline (5 differentially expressed genes, including ADAM33, FDR p Discussion The alteration in the pulmonary metabolic gene signature may underpin a shift in immune cell activation and/or modification of smooth muscle energy expenditure during airway contraction. These changes may explain why the KO mouse is protected from both allergic responses and BHR. Further work will aim to identify the source of the different metabolic behaviour at a cellular level and to assess oxidative stress in lungs of normal and ADAM33 KO mice.

  • s29 the effect of soluble ADAM33 on allergic airway inflammation in early life is age dependent
    Thorax, 2018
    Co-Authors: Elizabeth R Davies, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Jfc Kelly, Marieke Wandel, H M Haitchi
    Abstract:

    Introduction Most asthma has its origin in early life and probably involves gene-environment interactions. The asthma susceptibility gene ADAM33 is associated with bronchial hyperresponsiveness (BHR) and reduced lung function in young children. It encodes a membrane-anchored metalloprotease, which is shed as a soluble protein (sADAM33) whose levels are increased in asthma. We have previously shown that sADAM33, promotes airway remodelling and augments allergic airway inflammation in juvenile mice (Davies ER et al, JCI Insight 2016). This might be initiated by ADAM33 induced innate lymphocytes (Kelly JFC et al, Thorax 2017). The aim of this work was to evaluate the effect of sADAM33 on the allergic airway responses of neonates. Methods Human sADAM33 was induced in lungs of double transgenic (Ccsp/ADAM33) (dTg) mice from in utero up to 4 weeks post-partum. dTg mice or single transgenic (sTg) controls were challenged with house dust mite extract (HDM) 3 times a week for 2 weeks from 3 or 14 days post-partum. BHR and inflammation were quantified. Lung tissue was analysed by RT-qPCR and immunohistochemistry (IHC). Results After HDM challenge from day 3, Type 2-responsive genes Il-5, Ccl11/Eotaxin and Muc5ac were significantly increased. Whilst an increase in BHR was observed after HDM challenge, there was no significant difference between sADAM33-expressing and control mice. In contrast, when challenged from day 14, sADAM33-expressing mice had a more robust eosinophilic inflammatory response in the bronchoalveolar lavage fluid with increased Il-5 and Ccl11/Eotaxin mRNA expression compared to littermate controls. This was also associated with increased Acta2 mRNA expression and BHR. Conclusion These data indicate that sADAM33 does not augment allergic responses in neonatal mice as robustly as in older mice. This suggests that the immune microenvironment in neonates is not sufficiently mature to respond to the pro-allergic effects of sADAM33 that may induce innate lymphocytes to make the airways more susceptible to allergic airway inflammation.

  • ADAM33 is involved in post natal airway hyperresponsiveness caused by maternal allergic airway inflammation
    European Respiratory Journal, 2018
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Joanne Kelly, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Hans Michael Haitchi
    Abstract:

    Maternal allergy is a strong risk factor for developing asthma and airway hyperresponsiveness (AHR). The asthma susceptibility gene ADAM33 is associated with AHR and impaired lung function in early life. Our aim was to investigate gene-environment interactions involving ADAM33 by determining the effects of maternal murine allergic airway inflammation on the lungs of offspring. We hypothesised that this will be modified in ADAM33 knock out (KO) compared to wild-type (WT) offspring. Allergic airway inflammation was induced by exposure to house dust mite (HDM) allergen in pregnant heterozygous ADAM33 mice. WT and KO offspring from the same litters were studied on embryonic day (ED)17.5 and 2 and 4 weeks post partum. Lung function was performed in response to methacholine, bronchoalveolar lavage fluid (BALF) collected for differential cell counts and lung tissue for RTqPCR. Compared with saline challenged mothers, 4-week-old WT offspring of HDM challenged mothers showed significantly enhanced AHR; KO offspring of HDM challenged mothers were protected against development of AHR. No inflammatory genes were up-regulated in the lungs and no inflammatory cells were present in the BALF at 2 or 4 weeks. While typical remodelling genes were not up-regulated at the time points studied, ADAM33 mRNA expression was significantly increased in WT lungs at ED17.5 and Cholinergic Receptor Muscarinic 1 (Chrm1) mRNA at 4 weeks in offspring of HDM challenged mothers. This study identifies an in utero gene-environment interaction involving ADAM33 that has implications for the development of AHR in early life. Further studies are needed to elucidate the mechanisms whereby ADAM33 mediates this.

Stephen T Holgate - One of the best experts on this subject based on the ideXlab platform.

  • s28 ADAM33 knock out is protective against post natal airway hyperresponsiveness caused by maternal allergy
    Thorax, 2018
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Jfc Kelly, H M Haitchi
    Abstract:

    Background Maternal allergy is a strong risk factor for developing asthma and airway hyperresponsiveness (AHR). ADAM33 has been identified as an asthma susceptibility gene and is associated with AHR and impaired lung function in early life. Our aim was to investigate the effects of maternal murine allergic airway inflammation on the lungs of offspring before and after birth. We hypothesised that the effects of maternal allergy will be modified in ADAM33 knock out (KO) compared to wild-type (WT) offspring. Methods Allergic airway inflammation in pregnant heterozygous (ADAM33±) mice was induced by exposure to house dust mite (HDM) through intranasal challenges during pregnancy. Control mice were challenged with saline. WT (ADAM33+/+) and KO (ADAM33-/-) offspring from the same litters were studied on embryonic day (ED)17.5 and 2 or 4 weeks post partum (pp). Lung function was measured in response to increasing doses of methacholine and bronchoalveolar lavage fluid (BALF) was collected for differential cell counts. Lung tissue was obtained for RTqPCR, Western blot and immunohistochemistry. Results At 4 weeks pp, WT offspring of HDM challenged mothers showed significantly enhanced AHR compared to WT offspring of control mothers. KO of ADAM33 protected against AHR in the offspring of allergic mothers. ADAM33 mRNA expression was significantly enhanced in WT lungs of HDM challenged mothers at ED17.5, but unchanged pp. Differential cell counts in the BALF and mRNA expression of inflammatory mediators indicated an absence of allergic airway inflammation in all of the offspring. Remodelling genes were not affected at any time point studied. In contrast, Cholinergic Receptor Muscarinic 1 (Chrm1) mRNA was increased at 4 weeks in all offspring of HDM challenged mothers. Conclusions This study identifies an in utero gene-environment interaction involving ADAM33. This interaction has implications for the subsequent development of AHR in early life. Further studies are needed to elucidate the precise mechanism(s) whereby ADAM33 mediates its effects. Our data suggest modulation of the contractility of the airways, possibly involving muscarinic receptors.

  • s29 the effect of soluble ADAM33 on allergic airway inflammation in early life is age dependent
    Thorax, 2018
    Co-Authors: Elizabeth R Davies, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Jfc Kelly, Marieke Wandel, H M Haitchi
    Abstract:

    Introduction Most asthma has its origin in early life and probably involves gene-environment interactions. The asthma susceptibility gene ADAM33 is associated with bronchial hyperresponsiveness (BHR) and reduced lung function in young children. It encodes a membrane-anchored metalloprotease, which is shed as a soluble protein (sADAM33) whose levels are increased in asthma. We have previously shown that sADAM33, promotes airway remodelling and augments allergic airway inflammation in juvenile mice (Davies ER et al, JCI Insight 2016). This might be initiated by ADAM33 induced innate lymphocytes (Kelly JFC et al, Thorax 2017). The aim of this work was to evaluate the effect of sADAM33 on the allergic airway responses of neonates. Methods Human sADAM33 was induced in lungs of double transgenic (Ccsp/ADAM33) (dTg) mice from in utero up to 4 weeks post-partum. dTg mice or single transgenic (sTg) controls were challenged with house dust mite extract (HDM) 3 times a week for 2 weeks from 3 or 14 days post-partum. BHR and inflammation were quantified. Lung tissue was analysed by RT-qPCR and immunohistochemistry (IHC). Results After HDM challenge from day 3, Type 2-responsive genes Il-5, Ccl11/Eotaxin and Muc5ac were significantly increased. Whilst an increase in BHR was observed after HDM challenge, there was no significant difference between sADAM33-expressing and control mice. In contrast, when challenged from day 14, sADAM33-expressing mice had a more robust eosinophilic inflammatory response in the bronchoalveolar lavage fluid with increased Il-5 and Ccl11/Eotaxin mRNA expression compared to littermate controls. This was also associated with increased Acta2 mRNA expression and BHR. Conclusion These data indicate that sADAM33 does not augment allergic responses in neonatal mice as robustly as in older mice. This suggests that the immune microenvironment in neonates is not sufficiently mature to respond to the pro-allergic effects of sADAM33 that may induce innate lymphocytes to make the airways more susceptible to allergic airway inflammation.

  • ADAM33 is involved in post natal airway hyperresponsiveness caused by maternal allergic airway inflammation
    European Respiratory Journal, 2018
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Joanne Kelly, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Hans Michael Haitchi
    Abstract:

    Maternal allergy is a strong risk factor for developing asthma and airway hyperresponsiveness (AHR). The asthma susceptibility gene ADAM33 is associated with AHR and impaired lung function in early life. Our aim was to investigate gene-environment interactions involving ADAM33 by determining the effects of maternal murine allergic airway inflammation on the lungs of offspring. We hypothesised that this will be modified in ADAM33 knock out (KO) compared to wild-type (WT) offspring. Allergic airway inflammation was induced by exposure to house dust mite (HDM) allergen in pregnant heterozygous ADAM33 mice. WT and KO offspring from the same litters were studied on embryonic day (ED)17.5 and 2 and 4 weeks post partum. Lung function was performed in response to methacholine, bronchoalveolar lavage fluid (BALF) collected for differential cell counts and lung tissue for RTqPCR. Compared with saline challenged mothers, 4-week-old WT offspring of HDM challenged mothers showed significantly enhanced AHR; KO offspring of HDM challenged mothers were protected against development of AHR. No inflammatory genes were up-regulated in the lungs and no inflammatory cells were present in the BALF at 2 or 4 weeks. While typical remodelling genes were not up-regulated at the time points studied, ADAM33 mRNA expression was significantly increased in WT lungs at ED17.5 and Cholinergic Receptor Muscarinic 1 (Chrm1) mRNA at 4 weeks in offspring of HDM challenged mothers. This study identifies an in utero gene-environment interaction involving ADAM33 that has implications for the development of AHR in early life. Further studies are needed to elucidate the mechanisms whereby ADAM33 mediates this.

  • s89 soluble ADAM33 augments the pulmonary immune response promoting allergic airway sensitivity
    Thorax, 2017
    Co-Authors: Jfc Kelly, Elizabeth R Davies, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Hans Michael Haitchi
    Abstract:

    Rational A disintegrin and metalloproteinase 33 (ADAM33) was discovered in 2002 as an asthma susceptibility gene. Genetic associations have been made between ADAM33 polymorphisms and asthma disease severity, bronchial hyperresponsivenss (BHR) and rate of lung function decline in both adults and children. A soluble, catalytically active form of the protein (sADAM33) has been identified in the bronchoalveolar lavage fluid of patients, levels of which correlate with disease severity (Lee JY et al, AJRCCM 2006). To study the role sADAM33, a lung specific, doxycycline (Dox) inducible, transgenic mouse, expressing the human pro and metalloproteinase domains of the full-length protein was generated (Ccsp-rtTA/Otet-ADAM33-Pro-MP). Induction of sADAM33, followed by house dust mite (HDM) sensitisation and challenge, resulted in increased BHR and airway inflammation (Davies ER et al, JCI-Insight 2016). The mechanisms by which ADAM33 promotes this susceptibility are unclear. The aim of this work is to identify pathways that are augmented by the induction of sADAM33, which promote increased sensitivity to allergen. Methods RNA samples from whole lung of adult mice, where sADAM33 had been induced for 4 or 8 weeks, were analysed by next generation RNA sequencing. Identified genes were confirmed across experimental time points (72 hour, 7 day, 4 and 8 weeks on Dox) in wider sample cohorts of Ccsp-rtTA/Otet-ADAM33-Pro-MP and control mice through RTqPCR. Results The predominant signal from the RNAseq output was for modulation of immune response genes at 4 weeks of sADAM33 expression (GO:0006955 Immune response: 31 genes, 58.49% coverage, FDR p value=7.09 E-22). Genes associated with an immune activation signature (Ccl5, Irgm1, Gm12250, Gzmb, Ncr1) were validated at least one time point. By 8 weeks of sADAM33 expression genes associated with negative regulation of the response were also validated (Ido1, Cd274). Conclusion Induction of sADAM33 in murine lungs, without allergic sensitisation, augmented underlying immune processes in this transgenic mouse model, which may contribute to increased susceptibility to allergic airway inflammation and BHR when challenged with allergen. Further work is required to delineate how sADAM33 affects immune cell populations and their behaviour in the lung.

  • soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life
    JCI insight, 2016
    Co-Authors: Elizabeth R Davies, Joanne Kelly, Peter H Howarth, David I Wilson, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Hans Michael Haitchi
    Abstract:

    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.

Elizabeth R Davies - One of the best experts on this subject based on the ideXlab platform.

  • s130 maternal allergic airway inflammation during pregnancy alters offspring s airway hyperresponsiveness dependent on muscarinic receptor and ADAM33 mediated mechanisms
    Thorax, 2019
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Donna E Davies, Jeffrey A Whitsett, Jfc Kelly, S T Holgate, Hans Michael Haitchi
    Abstract:

    Background Maternal allergic asthma is a strong risk factor for the development of asthma and airway hyperresponsiveness (AHR) in children. ADAM33, an asthma susceptibility gene, has been associated with AHR and impaired lung function in early life. Our aim was to investigate how the maternal allergic environment during pregnancy interacts with the ADAM33 status of their offspring, and the effects this has on the lungs of offspring after birth. We hypothesised that the effects of maternal allergy will be different in ADAM33 knock-out (KO) compared to wild-type (WT) offspring Methods Allergic airway inflammation (AAI) during pregnancy was induced in heterozygous (ADAM33±) mice through intranasal house dust mite (HDM) challenges. Control mice were challenged with saline. WT and KO (ADAM33-/-) offspring from the same litters were studied 4 weeks post partum (pp). Lung function was measured in response to increasing doses of methacholine. Bronchoalveolar lavage fluid (BALF) and lung tissue were obtained for RTqPCR, Western Blots and immunostainings. Precision-cut lung slices (PCLS) from 4-weeks old offspring were investigated for airway contraction in response to different agonists and antagonists in vitro. Results Allergen-naive WT offspring of allergic mothers showed AHR 4 weeks pp compared to those of control mothers, whereas KO offspring from the same litter were protected. Expression of the muscarinic M1 receptor was elevated in both KO and WT offspring lungs of HDM-challenged dams. Experiments using muscarinic receptor antagonists and methacholine in PCLS confirmed that maternal AAI causes increased bronchoconstriction through vagal reflexes in WT offspring. KO offspring were protected from this effect due to decreased sensitivity of airway smooth muscle, suggested by a delayed response to a thromboxane-receptor agonist in PCLS. Conclusions Our studies show how gene-environment interactions between ADAM33 and maternal AAI determine development of AHR in early life. While the AAI of the mother leads to an increased pulmonary muscarinic M1 receptor expression, the absence of ADAM33 alters the airway smooth muscle function in the offspring. Together these changes manifest in AHR only in WT offspring, but not in KO offspring. Further studies are needed to determine how ADAM33 KO changes smooth muscle function in the lungs.

  • s28 ADAM33 knock out is protective against post natal airway hyperresponsiveness caused by maternal allergy
    Thorax, 2018
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Jfc Kelly, H M Haitchi
    Abstract:

    Background Maternal allergy is a strong risk factor for developing asthma and airway hyperresponsiveness (AHR). ADAM33 has been identified as an asthma susceptibility gene and is associated with AHR and impaired lung function in early life. Our aim was to investigate the effects of maternal murine allergic airway inflammation on the lungs of offspring before and after birth. We hypothesised that the effects of maternal allergy will be modified in ADAM33 knock out (KO) compared to wild-type (WT) offspring. Methods Allergic airway inflammation in pregnant heterozygous (ADAM33±) mice was induced by exposure to house dust mite (HDM) through intranasal challenges during pregnancy. Control mice were challenged with saline. WT (ADAM33+/+) and KO (ADAM33-/-) offspring from the same litters were studied on embryonic day (ED)17.5 and 2 or 4 weeks post partum (pp). Lung function was measured in response to increasing doses of methacholine and bronchoalveolar lavage fluid (BALF) was collected for differential cell counts. Lung tissue was obtained for RTqPCR, Western blot and immunohistochemistry. Results At 4 weeks pp, WT offspring of HDM challenged mothers showed significantly enhanced AHR compared to WT offspring of control mothers. KO of ADAM33 protected against AHR in the offspring of allergic mothers. ADAM33 mRNA expression was significantly enhanced in WT lungs of HDM challenged mothers at ED17.5, but unchanged pp. Differential cell counts in the BALF and mRNA expression of inflammatory mediators indicated an absence of allergic airway inflammation in all of the offspring. Remodelling genes were not affected at any time point studied. In contrast, Cholinergic Receptor Muscarinic 1 (Chrm1) mRNA was increased at 4 weeks in all offspring of HDM challenged mothers. Conclusions This study identifies an in utero gene-environment interaction involving ADAM33. This interaction has implications for the subsequent development of AHR in early life. Further studies are needed to elucidate the precise mechanism(s) whereby ADAM33 mediates its effects. Our data suggest modulation of the contractility of the airways, possibly involving muscarinic receptors.

  • s29 the effect of soluble ADAM33 on allergic airway inflammation in early life is age dependent
    Thorax, 2018
    Co-Authors: Elizabeth R Davies, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Jfc Kelly, Marieke Wandel, H M Haitchi
    Abstract:

    Introduction Most asthma has its origin in early life and probably involves gene-environment interactions. The asthma susceptibility gene ADAM33 is associated with bronchial hyperresponsiveness (BHR) and reduced lung function in young children. It encodes a membrane-anchored metalloprotease, which is shed as a soluble protein (sADAM33) whose levels are increased in asthma. We have previously shown that sADAM33, promotes airway remodelling and augments allergic airway inflammation in juvenile mice (Davies ER et al, JCI Insight 2016). This might be initiated by ADAM33 induced innate lymphocytes (Kelly JFC et al, Thorax 2017). The aim of this work was to evaluate the effect of sADAM33 on the allergic airway responses of neonates. Methods Human sADAM33 was induced in lungs of double transgenic (Ccsp/ADAM33) (dTg) mice from in utero up to 4 weeks post-partum. dTg mice or single transgenic (sTg) controls were challenged with house dust mite extract (HDM) 3 times a week for 2 weeks from 3 or 14 days post-partum. BHR and inflammation were quantified. Lung tissue was analysed by RT-qPCR and immunohistochemistry (IHC). Results After HDM challenge from day 3, Type 2-responsive genes Il-5, Ccl11/Eotaxin and Muc5ac were significantly increased. Whilst an increase in BHR was observed after HDM challenge, there was no significant difference between sADAM33-expressing and control mice. In contrast, when challenged from day 14, sADAM33-expressing mice had a more robust eosinophilic inflammatory response in the bronchoalveolar lavage fluid with increased Il-5 and Ccl11/Eotaxin mRNA expression compared to littermate controls. This was also associated with increased Acta2 mRNA expression and BHR. Conclusion These data indicate that sADAM33 does not augment allergic responses in neonatal mice as robustly as in older mice. This suggests that the immune microenvironment in neonates is not sufficiently mature to respond to the pro-allergic effects of sADAM33 that may induce innate lymphocytes to make the airways more susceptible to allergic airway inflammation.

  • s27 ADAM33 knockout mice have an altered metabolic transcriptional profile in response to house dust mite when compared to wild type mice
    Thorax, 2018
    Co-Authors: Jfc Kelly, Elizabeth R Davies, Donna E Davies, Jeffrey A Whitsett, Joseph Bell, S T Holgate, Hans Michael Haitchi
    Abstract:

    Rationale ADAM33 is an asthma susceptibility gene that plays a role in both airway remodelling and susceptibility to allergic airways disease. To study the role of ADAM33 in asthma we have exposed an ADAM33 Knockout (KO) mouse to a house dust mite (HDM) sensitisation and challenge protocol. We have found that these mice exhibit less remodelling, bronchial hyperresponsiveness (BHR) and eosinophilic inflammation than wild type (WT) mice (ER Davies et al., JCI-Insight 2016), however the mechanisms which contribute to this protective phenotype are not well understood. Methods To study how the response to HDM is altered by loss of ADAM33 we challenged WT and KO mice with HDM or saline and took whole lung RNA samples for next generation RNA sequencing (RNAseq). Gene set enrichment analysis was used to identify pathways and gene ontology terms associated with the differential response to HDM between KO and WT mice. Results Control WT and KO mice were found to have very similar gene expression profiles at baseline (5 differentially expressed genes, including ADAM33, FDR p Discussion The alteration in the pulmonary metabolic gene signature may underpin a shift in immune cell activation and/or modification of smooth muscle energy expenditure during airway contraction. These changes may explain why the KO mouse is protected from both allergic responses and BHR. Further work will aim to identify the source of the different metabolic behaviour at a cellular level and to assess oxidative stress in lungs of normal and ADAM33 KO mice.

  • ADAM33 is involved in post natal airway hyperresponsiveness caused by maternal allergic airway inflammation
    European Respiratory Journal, 2018
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Joanne Kelly, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Hans Michael Haitchi
    Abstract:

    Maternal allergy is a strong risk factor for developing asthma and airway hyperresponsiveness (AHR). The asthma susceptibility gene ADAM33 is associated with AHR and impaired lung function in early life. Our aim was to investigate gene-environment interactions involving ADAM33 by determining the effects of maternal murine allergic airway inflammation on the lungs of offspring. We hypothesised that this will be modified in ADAM33 knock out (KO) compared to wild-type (WT) offspring. Allergic airway inflammation was induced by exposure to house dust mite (HDM) allergen in pregnant heterozygous ADAM33 mice. WT and KO offspring from the same litters were studied on embryonic day (ED)17.5 and 2 and 4 weeks post partum. Lung function was performed in response to methacholine, bronchoalveolar lavage fluid (BALF) collected for differential cell counts and lung tissue for RTqPCR. Compared with saline challenged mothers, 4-week-old WT offspring of HDM challenged mothers showed significantly enhanced AHR; KO offspring of HDM challenged mothers were protected against development of AHR. No inflammatory genes were up-regulated in the lungs and no inflammatory cells were present in the BALF at 2 or 4 weeks. While typical remodelling genes were not up-regulated at the time points studied, ADAM33 mRNA expression was significantly increased in WT lungs at ED17.5 and Cholinergic Receptor Muscarinic 1 (Chrm1) mRNA at 4 weeks in offspring of HDM challenged mothers. This study identifies an in utero gene-environment interaction involving ADAM33 that has implications for the development of AHR in early life. Further studies are needed to elucidate the mechanisms whereby ADAM33 mediates this.

Jeffrey A Whitsett - One of the best experts on this subject based on the ideXlab platform.

  • s130 maternal allergic airway inflammation during pregnancy alters offspring s airway hyperresponsiveness dependent on muscarinic receptor and ADAM33 mediated mechanisms
    Thorax, 2019
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Donna E Davies, Jeffrey A Whitsett, Jfc Kelly, S T Holgate, Hans Michael Haitchi
    Abstract:

    Background Maternal allergic asthma is a strong risk factor for the development of asthma and airway hyperresponsiveness (AHR) in children. ADAM33, an asthma susceptibility gene, has been associated with AHR and impaired lung function in early life. Our aim was to investigate how the maternal allergic environment during pregnancy interacts with the ADAM33 status of their offspring, and the effects this has on the lungs of offspring after birth. We hypothesised that the effects of maternal allergy will be different in ADAM33 knock-out (KO) compared to wild-type (WT) offspring Methods Allergic airway inflammation (AAI) during pregnancy was induced in heterozygous (ADAM33±) mice through intranasal house dust mite (HDM) challenges. Control mice were challenged with saline. WT and KO (ADAM33-/-) offspring from the same litters were studied 4 weeks post partum (pp). Lung function was measured in response to increasing doses of methacholine. Bronchoalveolar lavage fluid (BALF) and lung tissue were obtained for RTqPCR, Western Blots and immunostainings. Precision-cut lung slices (PCLS) from 4-weeks old offspring were investigated for airway contraction in response to different agonists and antagonists in vitro. Results Allergen-naive WT offspring of allergic mothers showed AHR 4 weeks pp compared to those of control mothers, whereas KO offspring from the same litter were protected. Expression of the muscarinic M1 receptor was elevated in both KO and WT offspring lungs of HDM-challenged dams. Experiments using muscarinic receptor antagonists and methacholine in PCLS confirmed that maternal AAI causes increased bronchoconstriction through vagal reflexes in WT offspring. KO offspring were protected from this effect due to decreased sensitivity of airway smooth muscle, suggested by a delayed response to a thromboxane-receptor agonist in PCLS. Conclusions Our studies show how gene-environment interactions between ADAM33 and maternal AAI determine development of AHR in early life. While the AAI of the mother leads to an increased pulmonary muscarinic M1 receptor expression, the absence of ADAM33 alters the airway smooth muscle function in the offspring. Together these changes manifest in AHR only in WT offspring, but not in KO offspring. Further studies are needed to determine how ADAM33 KO changes smooth muscle function in the lungs.

  • s28 ADAM33 knock out is protective against post natal airway hyperresponsiveness caused by maternal allergy
    Thorax, 2018
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Jfc Kelly, H M Haitchi
    Abstract:

    Background Maternal allergy is a strong risk factor for developing asthma and airway hyperresponsiveness (AHR). ADAM33 has been identified as an asthma susceptibility gene and is associated with AHR and impaired lung function in early life. Our aim was to investigate the effects of maternal murine allergic airway inflammation on the lungs of offspring before and after birth. We hypothesised that the effects of maternal allergy will be modified in ADAM33 knock out (KO) compared to wild-type (WT) offspring. Methods Allergic airway inflammation in pregnant heterozygous (ADAM33±) mice was induced by exposure to house dust mite (HDM) through intranasal challenges during pregnancy. Control mice were challenged with saline. WT (ADAM33+/+) and KO (ADAM33-/-) offspring from the same litters were studied on embryonic day (ED)17.5 and 2 or 4 weeks post partum (pp). Lung function was measured in response to increasing doses of methacholine and bronchoalveolar lavage fluid (BALF) was collected for differential cell counts. Lung tissue was obtained for RTqPCR, Western blot and immunohistochemistry. Results At 4 weeks pp, WT offspring of HDM challenged mothers showed significantly enhanced AHR compared to WT offspring of control mothers. KO of ADAM33 protected against AHR in the offspring of allergic mothers. ADAM33 mRNA expression was significantly enhanced in WT lungs of HDM challenged mothers at ED17.5, but unchanged pp. Differential cell counts in the BALF and mRNA expression of inflammatory mediators indicated an absence of allergic airway inflammation in all of the offspring. Remodelling genes were not affected at any time point studied. In contrast, Cholinergic Receptor Muscarinic 1 (Chrm1) mRNA was increased at 4 weeks in all offspring of HDM challenged mothers. Conclusions This study identifies an in utero gene-environment interaction involving ADAM33. This interaction has implications for the subsequent development of AHR in early life. Further studies are needed to elucidate the precise mechanism(s) whereby ADAM33 mediates its effects. Our data suggest modulation of the contractility of the airways, possibly involving muscarinic receptors.

  • s29 the effect of soluble ADAM33 on allergic airway inflammation in early life is age dependent
    Thorax, 2018
    Co-Authors: Elizabeth R Davies, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Jfc Kelly, Marieke Wandel, H M Haitchi
    Abstract:

    Introduction Most asthma has its origin in early life and probably involves gene-environment interactions. The asthma susceptibility gene ADAM33 is associated with bronchial hyperresponsiveness (BHR) and reduced lung function in young children. It encodes a membrane-anchored metalloprotease, which is shed as a soluble protein (sADAM33) whose levels are increased in asthma. We have previously shown that sADAM33, promotes airway remodelling and augments allergic airway inflammation in juvenile mice (Davies ER et al, JCI Insight 2016). This might be initiated by ADAM33 induced innate lymphocytes (Kelly JFC et al, Thorax 2017). The aim of this work was to evaluate the effect of sADAM33 on the allergic airway responses of neonates. Methods Human sADAM33 was induced in lungs of double transgenic (Ccsp/ADAM33) (dTg) mice from in utero up to 4 weeks post-partum. dTg mice or single transgenic (sTg) controls were challenged with house dust mite extract (HDM) 3 times a week for 2 weeks from 3 or 14 days post-partum. BHR and inflammation were quantified. Lung tissue was analysed by RT-qPCR and immunohistochemistry (IHC). Results After HDM challenge from day 3, Type 2-responsive genes Il-5, Ccl11/Eotaxin and Muc5ac were significantly increased. Whilst an increase in BHR was observed after HDM challenge, there was no significant difference between sADAM33-expressing and control mice. In contrast, when challenged from day 14, sADAM33-expressing mice had a more robust eosinophilic inflammatory response in the bronchoalveolar lavage fluid with increased Il-5 and Ccl11/Eotaxin mRNA expression compared to littermate controls. This was also associated with increased Acta2 mRNA expression and BHR. Conclusion These data indicate that sADAM33 does not augment allergic responses in neonatal mice as robustly as in older mice. This suggests that the immune microenvironment in neonates is not sufficiently mature to respond to the pro-allergic effects of sADAM33 that may induce innate lymphocytes to make the airways more susceptible to allergic airway inflammation.

  • s27 ADAM33 knockout mice have an altered metabolic transcriptional profile in response to house dust mite when compared to wild type mice
    Thorax, 2018
    Co-Authors: Jfc Kelly, Elizabeth R Davies, Donna E Davies, Jeffrey A Whitsett, Joseph Bell, S T Holgate, Hans Michael Haitchi
    Abstract:

    Rationale ADAM33 is an asthma susceptibility gene that plays a role in both airway remodelling and susceptibility to allergic airways disease. To study the role of ADAM33 in asthma we have exposed an ADAM33 Knockout (KO) mouse to a house dust mite (HDM) sensitisation and challenge protocol. We have found that these mice exhibit less remodelling, bronchial hyperresponsiveness (BHR) and eosinophilic inflammation than wild type (WT) mice (ER Davies et al., JCI-Insight 2016), however the mechanisms which contribute to this protective phenotype are not well understood. Methods To study how the response to HDM is altered by loss of ADAM33 we challenged WT and KO mice with HDM or saline and took whole lung RNA samples for next generation RNA sequencing (RNAseq). Gene set enrichment analysis was used to identify pathways and gene ontology terms associated with the differential response to HDM between KO and WT mice. Results Control WT and KO mice were found to have very similar gene expression profiles at baseline (5 differentially expressed genes, including ADAM33, FDR p Discussion The alteration in the pulmonary metabolic gene signature may underpin a shift in immune cell activation and/or modification of smooth muscle energy expenditure during airway contraction. These changes may explain why the KO mouse is protected from both allergic responses and BHR. Further work will aim to identify the source of the different metabolic behaviour at a cellular level and to assess oxidative stress in lungs of normal and ADAM33 KO mice.

  • ADAM33 is involved in post natal airway hyperresponsiveness caused by maternal allergic airway inflammation
    European Respiratory Journal, 2018
    Co-Authors: Marieke Wandel, Elizabeth R Davies, Joanne Kelly, Stephen T Holgate, Donna E Davies, Jeffrey A Whitsett, Hans Michael Haitchi
    Abstract:

    Maternal allergy is a strong risk factor for developing asthma and airway hyperresponsiveness (AHR). The asthma susceptibility gene ADAM33 is associated with AHR and impaired lung function in early life. Our aim was to investigate gene-environment interactions involving ADAM33 by determining the effects of maternal murine allergic airway inflammation on the lungs of offspring. We hypothesised that this will be modified in ADAM33 knock out (KO) compared to wild-type (WT) offspring. Allergic airway inflammation was induced by exposure to house dust mite (HDM) allergen in pregnant heterozygous ADAM33 mice. WT and KO offspring from the same litters were studied on embryonic day (ED)17.5 and 2 and 4 weeks post partum. Lung function was performed in response to methacholine, bronchoalveolar lavage fluid (BALF) collected for differential cell counts and lung tissue for RTqPCR. Compared with saline challenged mothers, 4-week-old WT offspring of HDM challenged mothers showed significantly enhanced AHR; KO offspring of HDM challenged mothers were protected against development of AHR. No inflammatory genes were up-regulated in the lungs and no inflammatory cells were present in the BALF at 2 or 4 weeks. While typical remodelling genes were not up-regulated at the time points studied, ADAM33 mRNA expression was significantly increased in WT lungs at ED17.5 and Cholinergic Receptor Muscarinic 1 (Chrm1) mRNA at 4 weeks in offspring of HDM challenged mothers. This study identifies an in utero gene-environment interaction involving ADAM33 that has implications for the development of AHR in early life. Further studies are needed to elucidate the mechanisms whereby ADAM33 mediates this.