Carrie L Kempf, Jin H Song, Saad Sammani, Tadeo Bermudez, Vivian Reyes Hernon, Lin Tang, Hua Cai, Sara M Camp, Carly A Johnson, Mohamed S Basiouny, Leslie A Bloomquist, Jacqueline S Rioux, Carl W White, Livia A Veress, Joe G N Garcia
Objective: Human and preclinical studies of sulfur mustard (SM)-induced acute and chronic lung injuries highlight the role of unremitting inflammation. We assessed the utility of targeting the novel DAMP and TLR4 ligand, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), utilizing a humanized mAb (ALT-100) in rat models of SM exposure.
Methods: Acute (SM 4.2 mg/kg, 24 hrs), subacute (SM 0.8 mg/kg, day 7), subacute (SM 2.1 mg/kg, day 14), and chronic (SM 1.2 mg/kg, day 29) SM models were utilized.
Results: Each SM model exhibited significant increases in eNAMPT expression (lung homogenates) and increased levels of phosphorylated NFkB and NOX4. Lung fibrosis (Trichrome staining) was observed in both sub-acute and chronic SM models in conjunction with elevated smooth muscle actin (SMA), TGFβ, and IL-1β expression. SM-exposed rats receiving ALT-100 (1 or 4 mg/kg, weekly) exhibited increased survival, highly significant reductions in histologic/biochemical evidence of lung inflammation and fibrosis (Trichrome staining, decreased pNFkB, SMA, TGFβ, NOX4), decreased airways strictures, and decreased plasma cytokine levels (eNAMPT, IL-6, IL-1β. TNFα).
Conclusion: The highly druggable, eNAMPT/TLR4 signaling pathway is a key contributor to SM-induced ROS production, inflammatory lung injury and fibrosis. The ALT-100 mAb is a potential medical countermeasure to address the unmet need to reduce SM-associated lung pathobiology/mortality.
目的：对硫芥子气（SM）诱导的急性和慢性肺损伤进行的人体和临床前研究强调了持续炎症的作用。我们评估了利用人源化 mAb（ALT-100）靶向新型 DAMP 和 TLR4 配体 eNAMPT（细胞外烟酰胺磷酸核糖基转移酶）在大鼠 SM 暴露模型中的效用：方法：利用急性（SM 4.2 毫克/千克，24 小时）、亚急性（SM 0.8 毫克/千克，第 7 天）、亚急性（SM 2.1 毫克/千克，第 14 天）和慢性（SM 1.2 毫克/千克，第 29 天）SM 模型：结果：每种 SM 模型的 eNAMPT 表达（肺匀浆）都明显增加，磷酸化 NFkB 和 NOX4 的水平也有所提高。在亚急性和慢性 SM 模型中均可观察到肺纤维化（三色染色），同时平滑肌肌动蛋白（SMA）、TGFβ 和 IL-1β 的表达也升高。接受 ALT-100（1 或 4 毫克/千克，每周一次）治疗的 SM 暴露大鼠存活率提高，肺部炎症和纤维化的组织学/生化证据（Trichrome 染色、pNFkB、SMA、TGFβ、NOX4 减少）显著减少，气道狭窄减少，血浆细胞因子水平（ENAMPT、IL-6、IL-1β、TNFα）降低：结论：高度可药用的 eNAMPT/TLR4 信号通路是 SM 诱导的 ROS 生成、肺部炎症损伤和纤维化的关键因素。ALT-100 mAb 是一种潜在的医疗对策，可满足减少 SM 相关肺部病理生物学/死亡率的未满足需求。
{"title":"TLR4 Ligation by eNAMPT, a Novel DAMP, is Essential to Sulfur Mustard- Induced Inflammatory Lung Injury and Fibrosis.","authors":"Carrie L Kempf, Jin H Song, Saad Sammani, Tadeo Bermudez, Vivian Reyes Hernon, Lin Tang, Hua Cai, Sara M Camp, Carly A Johnson, Mohamed S Basiouny, Leslie A Bloomquist, Jacqueline S Rioux, Carl W White, Livia A Veress, Joe G N Garcia","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Objective: </strong>Human and preclinical studies of sulfur mustard (SM)-induced acute and chronic lung injuries highlight the role of unremitting inflammation. We assessed the utility of targeting the novel DAMP and TLR4 ligand, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), utilizing a humanized mAb (ALT-100) in rat models of SM exposure.</p><p><strong>Methods: </strong>Acute (SM 4.2 mg/kg, 24 hrs), subacute (SM 0.8 mg/kg, day 7), subacute (SM 2.1 mg/kg, day 14), and chronic (SM 1.2 mg/kg, day 29) SM models were utilized.</p><p><strong>Results: </strong>Each SM model exhibited significant increases in eNAMPT expression (lung homogenates) and increased levels of phosphorylated NFkB and NOX4. Lung fibrosis (Trichrome staining) was observed in both sub-acute and chronic SM models in conjunction with elevated smooth muscle actin (SMA), TGFβ, and IL-1β expression. SM-exposed rats receiving ALT-100 (1 or 4 mg/kg, weekly) exhibited increased survival, highly significant reductions in histologic/biochemical evidence of lung inflammation and fibrosis (Trichrome staining, decreased pNFkB, SMA, TGFβ, NOX4), decreased airways strictures, and decreased plasma cytokine levels (eNAMPT, IL-6, IL-1β. TNFα).</p><p><strong>Conclusion: </strong>The highly druggable, eNAMPT/TLR4 signaling pathway is a key contributor to SM-induced ROS production, inflammatory lung injury and fibrosis. The ALT-100 mAb is a potential medical countermeasure to address the unmet need to reduce SM-associated lung pathobiology/mortality.</p>","PeriodicalId":72981,"journal":{"name":"European journal of respiratory medicine","volume":"6 1","pages":"389-397"},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139934502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nancy G Casanova, Sara M Camp, Manuel L Gonzalez-Garay, Ken Batai, Lori Garman, Courtney G Montgomery, Nathan Ellis, Rick Kittles, Christian Bime, Amy P Hsu, Steven Holland, Yves A Lussier, Jason Karnes, Nadera Sweiss, Lisa A Maier, Laura Koth, David R Moller, Naftali Kaminski, Joe G N Garcia
Background: A limited pool of SNPs are linked to the development and severity of sarcoidosis, a systemic granulomatous inflammatory disease. By integrating genome-wide association studies (GWAS) data and expression quantitative trait loci (eQTL) single nuclear polymorphisms (SNPs), we aimed to identify novel sarcoidosis SNPs potentially influencing the development of complicated sarcoidosis.
Methods: A GWAS (Affymetrix 6.0) involving 209 African-American (AA) and 193 European-American (EA, 75 and 51 complicated cases respectively) and publicly-available GWAS controls (GAIN) was utilized. Annotation of multi-tissue eQTL SNPs present on the GWAS created a pool of ~46,000 eQTL SNPs examined for association with sarcoidosis risk and severity (Logistic Model, Plink). The most significant EA/AA eQTL SNPs were genotyped in a sarcoidosis validation cohort (n=1034) and cross-validated in two independent GWAS cohorts.
Results: No single GWAS SNP achieved significance (p<1x10-8), however, analysis of the eQTL/GWAS SNP pool yielded 621 eQTL SNPs (p<10-4) associated with 730 genes that highlighted innate immunity, MHC Class II, and allograft rejection pathways with multiple SNPs validated in an independent sarcoidosis cohort (105 SNPs analyzed) (NOTCH4, IL27RA, BTNL2, ANXA11, HLA-DRB1). These studies confirm significant association of eQTL/GWAS SNPs in EAs and AAs with sarcoidosis risk and severity (complicated sarcoidosis) involving HLA region and innate immunity.
Conclusion: Despite the challenge of deciphering the genetic basis for sarcoidosis risk/severity, these results suggest that integrated eQTL/GWAS approaches may identify novel variants/genes and support the contribution of dysregulated innate immune responses to sarcoidosis severity.
背景：肉样瘤病是一种全身性肉芽肿性炎症性疾病，与肉样瘤病的发病和严重程度有关的 SNPs 数量有限。通过整合全基因组关联研究（GWAS）数据和表达定量性状位点（eQTL）单核多态性（SNPs），我们旨在确定可能影响复杂性肉样瘤病发展的新型肉样瘤病SNPs：我们利用了一项涉及 209 例非洲裔美国人（AA）和 193 例欧洲裔美国人（EA，分别为 75 例和 51 例复杂病例）的 GWAS（Affymetrix 6.0）以及公开的 GWAS 对照（GAIN）。对出现在 GWAS 上的多组织 eQTL SNP 进行注释后，建立了一个约有 46,000 个 eQTL SNP 的基因库，研究其与肉样瘤病风险和严重程度的关系（逻辑模型，Plink）。最重要的 EA/AA eQTL SNP 在肉样瘤病验证队列（n=1034）中进行了基因分型，并在两个独立的 GWAS 队列中进行了交叉验证：结果：没有一个 GWAS SNP 达到显著性（p结论：尽管破译肉样瘤病风险/严重程度的遗传基础是一项挑战，但这些结果表明，综合 eQTL/GWAS 方法可能会发现新的变体/基因，并支持先天性免疫反应失调对肉样瘤病严重程度的贡献。
{"title":"Examination of eQTL Polymorphisms Associated with Increased Risk of Progressive Complicated Sarcoidosis in European and African Descent Subjects.","authors":"Nancy G Casanova, Sara M Camp, Manuel L Gonzalez-Garay, Ken Batai, Lori Garman, Courtney G Montgomery, Nathan Ellis, Rick Kittles, Christian Bime, Amy P Hsu, Steven Holland, Yves A Lussier, Jason Karnes, Nadera Sweiss, Lisa A Maier, Laura Koth, David R Moller, Naftali Kaminski, Joe G N Garcia","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background: </strong>A limited pool of SNPs are linked to the development and severity of sarcoidosis, a systemic granulomatous inflammatory disease. By integrating genome-wide association studies (GWAS) data and expression quantitative trait loci (eQTL) single nuclear polymorphisms (SNPs), we aimed to identify novel sarcoidosis SNPs potentially influencing the development of complicated sarcoidosis.</p><p><strong>Methods: </strong>A GWAS (Affymetrix 6.0) involving 209 African-American (AA) and 193 European-American (EA, 75 and 51 complicated cases respectively) and publicly-available GWAS controls (GAIN) was utilized. Annotation of multi-tissue eQTL SNPs present on the GWAS created a pool of ~46,000 eQTL SNPs examined for association with sarcoidosis risk and severity (Logistic Model, Plink). The most significant EA/AA eQTL SNPs were genotyped in a sarcoidosis validation cohort (n=1034) and cross-validated in two independent GWAS cohorts.</p><p><strong>Results: </strong>No single GWAS SNP achieved significance (p<1x10-8), however, analysis of the eQTL/GWAS SNP pool yielded 621 eQTL SNPs (p<10-4) associated with 730 genes that highlighted innate immunity, MHC Class II, and allograft rejection pathways with multiple SNPs validated in an independent sarcoidosis cohort (105 SNPs analyzed) (NOTCH4, IL27RA, BTNL2, ANXA11, HLA-DRB1). These studies confirm significant association of eQTL/GWAS SNPs in EAs and AAs with sarcoidosis risk and severity (complicated sarcoidosis) involving HLA region and innate immunity.</p><p><strong>Conclusion: </strong>Despite the challenge of deciphering the genetic basis for sarcoidosis risk/severity, these results suggest that integrated eQTL/GWAS approaches may identify novel variants/genes and support the contribution of dysregulated innate immune responses to sarcoidosis severity.</p>","PeriodicalId":72981,"journal":{"name":"European journal of respiratory medicine","volume":"5 1","pages":"359-371"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139934501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mortality in Hospitalized Covid19 Patients during First Wave in a Tertiary Hospital in Northern Patagonia","authors":"","doi":"10.31488/ejrm.128","DOIUrl":"https://doi.org/10.31488/ejrm.128","url":null,"abstract":"","PeriodicalId":72981,"journal":{"name":"European journal of respiratory medicine","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82402119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neo-Adjuvant Therapies in Lung Cancer – Past Present and Future Directions","authors":"","doi":"10.31488/ejrm.131","DOIUrl":"https://doi.org/10.31488/ejrm.131","url":null,"abstract":"","PeriodicalId":72981,"journal":{"name":"European journal of respiratory medicine","volume":"151 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75411832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Prospective, Non-Controlled Pilot Study to Evaluate the Efficacy and Safety of Cefditoren Pivoxil in COVID-19 Patients with Mild to Moderate Pneumonia","authors":"","doi":"10.31488/ejrm.123","DOIUrl":"https://doi.org/10.31488/ejrm.123","url":null,"abstract":"","PeriodicalId":72981,"journal":{"name":"European journal of respiratory medicine","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77787342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Management of Covid-19 based on Risk Features","authors":"","doi":"10.31488/ejrm.127","DOIUrl":"https://doi.org/10.31488/ejrm.127","url":null,"abstract":"","PeriodicalId":72981,"journal":{"name":"European journal of respiratory medicine","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81943672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Efficacy and Safety of Levofloxacin in Outpatient Treatment of Exacerbations of COPD and Bronchiectasis","authors":"","doi":"10.31488/ejrm.125","DOIUrl":"https://doi.org/10.31488/ejrm.125","url":null,"abstract":"","PeriodicalId":72981,"journal":{"name":"European journal of respiratory medicine","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75481131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Vaccine Delivery by Precipitation (VDBP) Lessons from Poison Ivy for Protein Antigens in General and Specifically for SARS Co-V2","authors":"","doi":"10.31488/ejrm.130","DOIUrl":"https://doi.org/10.31488/ejrm.130","url":null,"abstract":"","PeriodicalId":72981,"journal":{"name":"European journal of respiratory medicine","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87405223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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