Aaron Vose, Anastasiya Birukova, Michaela Albright, Adam Schlobohm, Stavros Garantziotis, Purushothama Rao Tata, Christina Barkauskas, Robert Tighe
{"title":"Hyaluronan Directs Alveolar Type II Cell Response to Acute Ozone Exposure in Mice.","authors":"Aaron Vose, Anastasiya Birukova, Michaela Albright, Adam Schlobohm, Stavros Garantziotis, Purushothama Rao Tata, Christina Barkauskas, Robert Tighe","doi":"10.1165/rcmb.2024-0385OC","DOIUrl":"10.1165/rcmb.2024-0385OC","url":null,"abstract":"<p><p>Becoming more frequent because of climate change, ozone (O<sub>3</sub>) exposures can cause lung injury. Alveolar type 2 (AT2) cells and hyaluronan (HA), a matrix component, are critical to repairing lung injury and restoring homeostasis. Here, we define the impact of HA on AT2 cells after acute O<sub>3</sub> exposure. C57BL/6J mice were exposed to filtered air or O<sub>3</sub> (2 ppm) for 3 hours. HA was measured in BAL and lung tissue; HAS (HA synthase) 1, 2, and 3 and HYAL (hyaluronidase) 1, 2, and 3 mRNA were measured in lung tissue and BAL cells. At 48 to 72 hours after O<sub>3</sub> exposure, HA increased in BAL fluid by ELISA and lung tissue by immunohistochemistry, with new HA deposition localized to the alveolar ducts. This was associated with increased whole-lung HAS2 mRNA expression. Using an AT2 lineage reporter (<i>Sftpc-CreER;Rosa-Tm</i>) mouse strain, we noted that proliferating AT2 cells colocalized with O<sub>3</sub>-induced HA deposition in the alveolar duct region. In addition, AT2-to-AT1 cell differentiation after O<sub>3</sub> was noted. To determine whether O<sub>3</sub>-induced HA alters AT2 cell function, we inhibited HA-AT2 interaction with a synthetic inhibitor (Pep-1), which diminished AT2 proliferation. Mice treated with Pep-1 after O<sub>3</sub> exposure demonstrated increased BAL albumin concentration compared with filtered air exposure, suggesting that inhibition of HA-AT2 cell interactions resulted in persistent alveolar-capillary permeability and diminished resolution of O<sub>3</sub>-induced lung injury. Overall, the findings suggest that HA increases in the alveolar duct after acute O<sub>3</sub> exposure and that HA-AT2 cell interactions are required for resolution of acute O<sub>3</sub>-induced lung injury.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"109-119"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Sectm1a Depletion Promotes Neutrophil Recruitment during Pneumococcal Pneumonia.","authors":"Hiromu Tanaka, Hirofumi Kamata, Makoto Ishii, Takanori Asakura, Ho Namkoong, Kensuke Nakagawara, Atsuho Morita, Tatsuya Kusumoto, Shuhei Azekawa, Masanori Kaji, Genta Nagao, Naoki Fukunaga, Tomoyasu Nishimura, Keisuke Asakura, Naoki Hasegawa, Koichi Fukunaga","doi":"10.1165/rcmb.2024-0276OC","DOIUrl":"10.1165/rcmb.2024-0276OC","url":null,"abstract":"<p><p>Airway epithelial cells (AECs) play an essential role in the immune response during bacterial pneumonia. Secreted and transmembrane 1a (Sectm1a) is specifically expressed in AECs during early <i>Streptococcus pneumoniae</i> (SP) infection. However, its function remains largely unexplored. Here, we aimed to clarify the function of Sectm1a during serotype 3 pneumococcal pneumonia primarily using an <i>in vivo</i> mouse model. Our findings showed that Type I IFNs directly induced Sectm1a expression in AECs. Sectm1a depletion in an <i>in vivo</i> mouse model improved survival rate and enhanced the clearance of intrapulmonary bacterial burden at an early stage of SP infection. Correspondingly, Sectm1a depletion increased the count of intrapulmonary γδT cells, promoted IL-17A production by these cells, and enhanced intrapulmonary neutrophil responses against SP. Notably, IL-17A production in isolated lung γδT cells was directly suppressed by Sectm1a <i>ex vivo</i>. Furthermore, Sectm1a depletion altered the migration and activation markers of γδT cells <i>in vivo</i>, indicating that the AEC-derived Sectm1a is associated with the phenotypes of γδT cells. These findings suggest that Type I IFNs may play an important role through AEC-derived Sectm1a in this model, and Sectm1a signaling modulates excessive neutrophil inflammation and influences bacterial clearance by directly altering γδT cell functions during pneumococcal pneumonia. In summary, this study demonstrates that the Type I IFN-Sectm1a pathway could be a potential target to modify the acute response to bacterial pneumonia.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"60-72"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Martin H Kang, Sylvia P Thomas, Caralyn Westley, Thomas Blouin, Liqun Xu, Ying Kai Chan, Erin Lisk, Sarah E Allen, Arul Vadivel, Kennedy Nangle, Janani Ramamurthy, Yanlong Pei, Lunndon A Lewis, Jessica J Chiang, Martin J Romeo, Silvia Vaena, Elizabeth C O'Quinn, Henry D Schrecker, Casey G Langdon, Paul J Nietert, George M Church, Jeffrey A Whitsett, Sarah K Wootton, Bernard Thébaud
{"title":"Novel Immune Response Evasion Strategy to Redose Adeno-associated Viral Vectors and Prolong Survival in Surfactant Protein-B-Deficient Mice.","authors":"Martin H Kang, Sylvia P Thomas, Caralyn Westley, Thomas Blouin, Liqun Xu, Ying Kai Chan, Erin Lisk, Sarah E Allen, Arul Vadivel, Kennedy Nangle, Janani Ramamurthy, Yanlong Pei, Lunndon A Lewis, Jessica J Chiang, Martin J Romeo, Silvia Vaena, Elizabeth C O'Quinn, Henry D Schrecker, Casey G Langdon, Paul J Nietert, George M Church, Jeffrey A Whitsett, Sarah K Wootton, Bernard Thébaud","doi":"10.1165/rcmb.2024-0247OC","DOIUrl":"10.1165/rcmb.2024-0247OC","url":null,"abstract":"<p><p>Surfactant protein-B (SP-B) deficiency is a lethal neonatal respiratory disease with few therapeutic options. Gene therapy using adeno-associated viruses (AAVs) to deliver human <i>SFTPB</i> cDNA (AAV-hSPB) can improve survival in a mouse model of SP-B deficiency. However, the effect of this gene therapy wanes. Gene therapy efficacy could be prolonged if AAV vectors could be redosed, but readministering vectors is hindered by an immune response that includes TLR9 (Toll-like receptor 9) recognition of unmethylated CpG DNA motifs in the AAV genome. One strategy to mitigate TLR9 recognition of AAV is to incorporate decoy nucleotide sequences within the AAV genome. In this work we examined if an AAV containing these TLR9 inhibitory oligonucleotide sequences (AAV-hSPB<sub>TLR9i</sub>) could mitigate the immune response sufficiently to redose AAV in the lungs and prolong the survival of SP-B-deficient mice. Indeed, AAV-hSPB<sub>TLR9i</sub> could be redosed multiple times, which significantly improved survival in our mouse model. This was partially a result of long-term increased <i>SFTPB</i> RNA and SP-B protein expression. Conversely, redosing AAV-hSPB resulted in the rapid death of SP-B-deficient mice after the second AAV dose. TLR9 inhibition enabled readministration by avoiding the broad stimulation of genes belonging to multiple pathways in the host immune and inflammatory responses, including components of the IFN pathways. Thus, redosing of AAV vectors in the lungs using TLR9 inhibitory sequences is a promising strategy for prolonging gene therapy efficacy, with a proof of concept for AAV readministration in a clinically relevant mouse model of SP-B deficiency.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"120-134"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142976956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria L Ford, Anushka Ruwanpathirana, Rodney D Britt
{"title":"The Art(ery) of Contraction: Using Precision-Cut Lung Slices to Model Pulmonary Hypertension in Acute Respiratory Distress Syndrome.","authors":"Maria L Ford, Anushka Ruwanpathirana, Rodney D Britt","doi":"10.1165/rcmb.2024-0603ED","DOIUrl":"10.1165/rcmb.2024-0603ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"1-2"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An Old Dog Performing the Same Old Tricks: The Role of TGF-β Receptor in Tissue Factor Release and Extracellular Vesicle Formation.","authors":"R Chad Wade, Jessy S Deshane","doi":"10.1165/rcmb.2024-0627ED","DOIUrl":"10.1165/rcmb.2024-0627ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"9-11"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Novel Sarcoidosis Epitope Augments MHCII, CD80, and CD86 Expression and Promotes B-Cell Differentiation and IgG Production.","authors":"Jaya Talreja, Changya Peng, Kezhong Zhang, Lobelia Samavati","doi":"10.1165/rcmb.2024-0428OC","DOIUrl":"10.1165/rcmb.2024-0428OC","url":null,"abstract":"<p><p>Numerous chronic human disorders are associated with immune activation by an obscure antigen (or antigens). We identified ChainA, a novel sarcoidosis epitope, by immunoscreening of a novel T7 phage library and confirmed an abundance of ChainA IgG antibody in sarcoidosis. We tested whether the ChainA epitope elicits immune responses through B-cell activation, plasma cell differentiation, and antibody production. Peripheral blood mononuclear cells (PBMCs) from healthy control participants and patients with sarcoidosis were challenged by chemically synthesized ChainA epitope, and cellular activation markers of B cells, T cells, major histocompatibility complex (MHC) classes, plasma cell differentiation, and unfolded protein response (UPR) transcription factors were assessed. ChainA increased the expression of MHC Class II (MHCII) and CD80/CD86 costimulatory molecules. ChainA significantly augmented the transition of naive B cells to memory B cells and plasma cells in PBMCs from patients with sarcoidosis compared with those from healthy control participants. B cell differentiation to antibody-secreting plasma cells requires the activation of UPR, B lymphocyte-induced maturation protein 1 (or, Blimp-1), and X-box binding protein 1 (XBP-1). ChainA treatment upregulated the expression of Blimp-1 and the spliced form of XBP-1, a transcriptional activator of endoplasmic reticulum stress response. Furthermore, the transition of B cells to plasma cells in response to ChainA induced the production of anti-ChainA IgG. In parallel to human PBMCs, utilizing murine splenocytes, we validated our observations that ChainA challenge augments MHCII expression, robust UPR responses, and an increased production of IgG-specific antibody against ChainA. These results indicate that the ChainA epitope may be involved in the pathogenesis of sarcoidosis, as it activates MHCII, memory B cells, plasma cell differentiation, and the production of ChainA-specific IgG.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"135-146"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chimwemwe Mwase, Stephen A Schworer, Rodney C Gilmore, Faria Khan, Alane Blythe C Dy, Adam L Haber, Richard C Boucher, Scott H Randell, Nigel Mackman, Jin-Ah Park
{"title":"TGF-β Receptor-dependent Tissue Factor Release and Proteomic Profiling of Extracellular Vesicles from Mechanically Compressed Human Bronchial Epithelial Cells.","authors":"Chimwemwe Mwase, Stephen A Schworer, Rodney C Gilmore, Faria Khan, Alane Blythe C Dy, Adam L Haber, Richard C Boucher, Scott H Randell, Nigel Mackman, Jin-Ah Park","doi":"10.1165/rcmb.2024-0130OC","DOIUrl":"10.1165/rcmb.2024-0130OC","url":null,"abstract":"<p><p>In asthma, tissue factor (TF) concentrations are elevated in the lung. In our previous studies using mechanically compressed human bronchial epithelial (HBE) cells, which are a well-defined <i>in vitro</i> model of bronchoconstriction during asthma exacerbations, we detected TF within extracellular vesicles (EVs) released from compressed HBE cells. Here, to better characterize the potential role of this mechanism in asthma, we tested the extent to which the transcriptional regulation of epithelial cell-derived TF varied between donors with and without asthma. Using RNA <i>in situ</i> hybridization, we detected epithelial expression of <i>F3</i>, the TF protein-encoding gene, in human airways. Next, to determine the role of TGF-β receptor (TGF-βR) in the regulation of TF, we exposed well-differentiated HBE cells to mechanical compression in the presence or absence of a pharmacological inhibitor of TGF-βR. Furthermore, to identify the protein cargo of EVs released from HBE cells, we used tandem mass tag mass spectrometry. Our findings revealed significantly higher <i>F3</i> expression in the airways of patients with asthma compared with healthy control subjects. However, we observed no differences in <i>F3</i> expression or TF release between asthmatic and nonasthmatic HBE cells, both at baseline and after compression. Mechanistically, compression-induced <i>F3</i> expression in HBE cells depended on TGF-βR. Our proteomic analysis identified 22 differentially released proteins in EVs, with higher concentrations in compressed cells compared with controls. Gene Ontology analysis indicates that these proteins are involved in diverse biological processes, highlighting a potential role for epithelial cell-derived EVs during asthma exacerbations.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"88-95"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shannon Kay, Haseena Rajeevan, Moeun Son, Jason Kwah, Maria Ramirez, Yunqing Liu, Zuoheng Wang, Xiting Yan, Gustavo Nino, Clemente Britto, Geoffrey Chupp, Jose L Gomez
{"title":"Sex-biased Gene Expression Underlies Immune Dysfunction in Asthma.","authors":"Shannon Kay, Haseena Rajeevan, Moeun Son, Jason Kwah, Maria Ramirez, Yunqing Liu, Zuoheng Wang, Xiting Yan, Gustavo Nino, Clemente Britto, Geoffrey Chupp, Jose L Gomez","doi":"10.1165/rcmb.2024-0565OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0565OC","url":null,"abstract":"<p><p>Asthma prevalence and severity differs between males and females across the lifespan. Pre-pubescent males are more likely to experience asthma, but females are disproportionately affected after puberty with higher symptom burden and decreased type 2 inflammation. However, as human male and female genomes are almost identical, it is especially difficult to identify differentially expressed genes by sex to account for differences in disease susceptibility and manifestations without large sample sizes. Although several genes and genetic polymorphisms lead to sex-specific effects in asthma risk, the effects of sex-biased gene expression on clinical features within patients with asthma remain understudied. In this study, we characterized gene expression differences between females and males through meta-analysis of transcriptomes of blood samples from adult patients with and without asthma in a large gene expression database (n=3,639, 56% female). A separate, local validation cohort (n=132, 78% female) identified clinical correlations with expression levels of sex-biased expressed genes. We identified 61 genes differentially expressed by sex in circulating immune cells that are unique to adult subjects with asthma and correlate with important clinical features of asthma. These genes are implicated in lymphocyte proliferation and differentiation, as well as innate and adaptive immune allergic responses in the lung. In addition, similar transcriptional meta-analyses of pediatric asthma demonstrated age-specific gene expression effects. In summary, our findings support a sex-specific inflammatory architecture in asthma that is associated with differential gene expression in the blood and is age-specific.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pink1/Parkin Mediated Mitophagy - Friend or Foe in Hypoxia-induced Pulmonary Vascular Remodeling?","authors":"Oleg Pak, Natascha Sommer","doi":"10.1165/rcmb.2025-0272ED","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0272ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}