The A’s Have It

Yao, Xianglan; Gordon, Elizabeth M.; Barochia, Amisha V.; Remaley, Alan T.; Levine, Stewart J.

doi:10.1016/j.chest.2016.05.035

Cited by 21 publications

(8 citation statements)

References 48 publications

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“…Apolipoprotein A-1 modulates lung health and contributes to protective pathways in lung biology, decreasing severity of respiratory diseases including asthma 80–82. This protein has been considered as a potential novel therapeutic agent for asthmatics 80,81,83. Congruent with our findings in the BALF of horses with severe asthma, BALF and serum samples from human asthmatics and murine models also demonstrate decreased levels of apolipoprotein A-1 82,84.…”

Section: Discussionsupporting

confidence: 78%

<p>Modeling the pasture-associated severe equine asthma bronchoalveolar lavage fluid proteome identifies molecular events mediating neutrophilic airway inflammation</p>

Bright

Dittmar

Nanduri

et al. 2019

VMRR

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Background: Pasture-associated severe equine asthma is a warm season, environmentally-induced respiratory disease characterized by reversible airway obstruction, persistent and non-specific airway hyper-responsiveness, and chronic neutrophilic airway inflammation. During seasonal exacerbation, signs vary from mild to life-threatening episodes of wheezing, coughing, and chronic debilitating labored breathing. Purpose: In human asthma, neutrophilic airway inflammation is associated with more severe and steroid-refractory asthma phenotypes, highlighting a need to decipher the mechanistic basis of this disease characteristic. We hypothesize that the collective biological activities of proteins in bronchoalveolar lavage fluid (BALF) of horses with pasture-associated severe asthma predict changes in neutrophil functions that contribute to airway neutrophilic inflammation. Methods: Using shotgun proteomics, we identified 1,003 unique proteins in cell-free BALF from six horses experiencing asthma exacerbation and six control herdmates. Contributions of each protein to ten neutrophil functions were modeled using manual biocuration to determine each protein’s net effect on the respective neutrophil functions. Results: A total of 417 proteins were unique to asthmatic horses, 472 proteins were unique to control horses (p<0.05), and 114 proteins were common in both groups. Proteins whose biological activities are responsible for increasing neutrophil migration, chemotaxis, cell spreading, transmigration, and infiltration, which would collectively bring neutrophils to airways, were over-represented in the BALF of asthmatic relative to control horses. By contrast, proteins whose biological activities support neutrophil activation, adhesion, phagocytosis, respiratory burst, and apoptosis, which would collectively shorten neutrophil lifespan, were under-represented in BALF of asthmatic relative to control horses. Interaction networks generated using Ingenuity ® Pathways Analysis further support the results of our biocuration. Conclusion: Congruent with our hypothesis, the collective biological functions represented in differentially expressed proteins of BALF from horses with pasture-associated severe asthma support neutrophilic airway inflammation. This illustrates the utility of systems modeling to organize functional genomics data in a manner that characterizes complex molecular events associated with clinically relevant disease.

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Section: Discussionsupporting

confidence: 78%

<p>Modeling the pasture-associated severe equine asthma bronchoalveolar lavage fluid proteome identifies molecular events mediating neutrophilic airway inflammation</p>

Bright

Dittmar

Nanduri

et al. 2019

VMRR

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“…Although lipid affinity is the basis of their cholesterol efflux activity, P12 more strongly induced cholesterol efflux than P9-P11 despite its weaker lipid affinity. This finding also suggested that other factors, such as ABCA1 dependence, affect the cholesterol efflux activity of AAMPs in addition to lipid affinity and amphipathicity (Yao, Gordon, Barochia, Remaley, & Levine, 2016).…”

Section: Discussionmentioning

confidence: 76%

A novel apoA‐I mimetic peptide suppresses atherosclerosis by promoting physiological HDL function in apoE^−/− mice

Gou

Wang

Zhong

et al. 2020

British J Pharmacology

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Background and Purpose Apolipoprotein A‐I (apoA‐I) mimetic peptides (AAMPs) are short peptides that can mimic the physiological effects of apoA‐I, including the suppression of atherosclerosis by reversely transporting peripheral cholesterol to the liver. As the hydrophobicity of apoA‐I is considered important for its lipid transport, novel AAMPs were designed and synthesized in this study by gradually increasing the hydrophobicity of the parent peptide, and their anti‐atherosclerotic effects were tested. Experimental Approach Seventeen new AAMPs (P1–P17) with incrementally increased hydrophobicity were designed and synthesized by replacing the amino acids 221–240 of apoA‐I (VLESFKVSFLSALEEYTKKL). Their effects on cholesterol efflux were evaluated. Their cytotoxicity and haemolytic activity were also measured. The in vitro mechanism of the action of the new peptides was explored. Adult apolipoprotein E−/− mice were used to evaluate the anti‐atherosclerotic activity of the best candidate, and the mechanistic basis of its anti‐atherosclerotic effects was explored. Key Results Seventeen new AAMPs (P1–P17) were synthesized, and their cholesterol efflux activity and cytotoxicity were closely related to their hydrophobicity. P12 (FLEKLKELLEHLKELLTKLL) was the best candidate and most strongly promoted cholesterol efflux among the non‐toxic peptides (P1–P12). With its phospholipid affinity, P12 facilitated cholesterol transport through the ATP‐binding cassette transporter A1. In vivo, P12 exhibited prominent anti‐atherosclerotic activity via coupling with HDL. Conclusion and Implications P12 featured adequate hydrophobicity, which ensured its efficient binding with cytomembrane phospholipids, cholesterol and HDL, and provided a basis for its ability to reversely transport cholesterol and treat atherosclerosis.

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“…ABCA1 expression is specific to eosinophil and neutrophil lineage and is needed for proper Apolipoprotein A-I (apoA-I) mediated reverse cholesterol transport that blocks granulocyte colony-stimulating factor (G-CSF) from initiating neutrophilic inflammation 89 . ApoA-I mimetic peptides can decrease both neutrophilic and eosinophilic airway inflammation suggesting that the apoA-I/ABCA1 pathway may have a protective effect on asthma 105 .…”

Section: Discussionmentioning

confidence: 99%

Derangement of cell cycle markers in peripheral blood mononuclear cells of asthmatic patients as a reliable biomarker for asthma control

Hachim

Elemam

Ramakrishnan

et al. 2021

Sci Rep

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In asthma, most of the identified biomarkers pertain to the Th2 phenotype and no known biomarkers have been verified for severe asthmatics. Therefore, identifying biomarkers using the integrative phenotype-genotype approach in severe asthma is needed. The study aims to identify novel biomarkers as genes or pathways representing the core drivers in asthma development, progression to the severe form, resistance to therapy, and tissue remodeling regardless of the sample cells or tissues examined. Comprehensive reanalysis of publicly available transcriptomic data that later was validated in vitro, and locally recruited patients were used to decipher the molecular basis of asthma. Our in-silicoanalysis revealed a total of 10 genes (GPRC5A, SFN, ABCA1, KRT8, TOP2A, SERPINE1, ANLN, MKI67, NEK2, and RRM2) related to cell cycle and proliferation to be deranged in the severe asthmatic bronchial epithelium and fibroblasts compared to their healthy counterparts. In vitro, RT qPCR results showed that (SERPINE1 and RRM2) were upregulated in severe asthmatic bronchial epithelium and fibroblasts, (SFN, ABCA1, TOP2A, SERPINE1, MKI67, and NEK2) were upregulated in asthmatic bronchial epithelium while (GPRC5A and KRT8) were upregulated only in asthmatic bronchial fibroblasts. Furthermore, MKI76, RRM2, and TOP2A were upregulated in Th2 high epithelium while GPRC5A, SFN, ABCA1 were upregulated in the blood of asthmatic patients. SFN, ABCA1 were higher, while MKI67 was lower in severe asthmatic with wheeze compared to nonasthmatics with wheezes. SERPINE1 and GPRC5A were downregulated in the blood of eosinophilic asthmatics, while RRM2 was upregulated in an acute attack of asthma. Validation of the gene expression in PBMC of locally recruited asthma patients showed that SERPINE1, GPRC5A, SFN, ABCA1, MKI67, and RRM2 were downregulated in severe uncontrolled asthma. We have identified a set of biologically crucial genes to the homeostasis of the lung and in asthma development and progression. This study can help us further understand the complex interplay between the transcriptomic data and the external factors which may deviate our understanding of asthma heterogeneity.

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The A’s Have It

Cited by 21 publications

References 48 publications

<p>Modeling the pasture-associated severe equine asthma bronchoalveolar lavage fluid proteome identifies molecular events mediating neutrophilic airway inflammation</p>

<p>Modeling the pasture-associated severe equine asthma bronchoalveolar lavage fluid proteome identifies molecular events mediating neutrophilic airway inflammation</p>

A novel apoA‐I mimetic peptide suppresses atherosclerosis by promoting physiological HDL function in apoE^−/− mice

Derangement of cell cycle markers in peripheral blood mononuclear cells of asthmatic patients as a reliable biomarker for asthma control

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The A’s Have It

Cited by 21 publications

References 48 publications

<p>Modeling the pasture-associated severe equine asthma bronchoalveolar lavage fluid proteome identifies molecular events mediating neutrophilic airway inflammation</p>

<p>Modeling the pasture-associated severe equine asthma bronchoalveolar lavage fluid proteome identifies molecular events mediating neutrophilic airway inflammation</p>

A novel apoA‐I mimetic peptide suppresses atherosclerosis by promoting physiological HDL function in apoE−/− mice

Derangement of cell cycle markers in peripheral blood mononuclear cells of asthmatic patients as a reliable biomarker for asthma control

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A novel apoA‐I mimetic peptide suppresses atherosclerosis by promoting physiological HDL function in apoE^−/− mice