Pulmonology
Abstract
Authors
Nadir Yehya, Jacob E. Till, Nishi Srivastava, Donglan Zhang, Jason D. Christie, Erica L. Carpenter, Nilam S. Mangalmurti, Wanding Zhou
Abstract
Talc pleurodesis is highly effective for preventing recurrence of pneumothorax and pleural effusion, but can be complicated by dissemination, acute lung injury, lead exposure, and foreign body-induced chronic inflammation and pain. Our objective is to develop a safe, biodegradable, contaminant-free particle for pleurodesis. We used mouse models of pneumothorax and malignant pleural effusion to compare the efficacy and safety of pleurodesis with talc and hydroxyapatite microspheres (HAM). Intrapleural instillation of microspheres induced pleural adhesions, fibrosis and symphysis as effectively as talc, and resulted in more durable protection from experimental pneumothorax. HAM and talc both induced an osteoclastogenic, inflammatory and fibrotic response in pleural lavage cells. Intrapleural HAM was resorbed by osteoclast action over 3 months, whereas talc was not cleared. Deletion of the osteoclast effector, CTSK, diminished pleural adhesion formation and fibrosis by talc and HAM, and inhibition of osteoclastogenesis with anti-RANKL antibody delayed HAM clearance. We found no difference in activity level, feeding behavior or lung compliance between particles, but talc induced more persistent pleural inflammation. We conclude that HAM resulted in an osteoclastogenic and fibrogenic pleural response that induced pleurodesis that was more durable than talc with a superior safety profile due in part to osteoclast-mediated particle clearance.
Authors
Yusuke Tanaka, Yuki Takahashi, Yuma Shindo, Lori B. Pitstick, Steven L. Teitelbaum, Wei Zou, Xiangning Wang, Jason Woods, Kathryn A. Wikenheiser-Brokamp, Francis X. McCormack
Abstract
Bronchopulmonary dysplasia (BPD), a prevalent and chronic lung disease affecting premature newborns, results in vascular rarefaction and alveolar simplification. Although the vasculature has been recognized as a main player in this disease, the recently found capillary heterogeneity and cellular dynamics of endothelial subpopulations in BPD remain unclear. Here, we show Cap2 cells are damaged during neonatal hyperoxic injury, leading to their replacement by Cap1 cells which, in turn, significantly decline. Single cell RNA-seq identifies the activation of numerous p53 target genes in endothelial cells (ECs), including Cdkn1a (p21). While global deletion of p53 results in worsened vasculature, endothelial-specific deletion of p53 reverses the vascular phenotype and improves alveolar simplification during hyperoxia. This recovery is associated with the emergence of a transitional EC state, enriched for oxidative stress response genes and growth factors. Notably, this transitional EC gene signature is conserved in an aberrant capillary population identified in human BPD with pulmonary hypertension, underscoring the biological and clinical relevance of our findings. These results reveal a key role for p53 in maintaining endothelial lineage fidelity during pulmonary capillary repair following hyperoxic injury and highlight the critical contribution of the endothelium to BPD pathogenesis.
Authors
Lisandra Vila Ellis, Jonathan D. Bywaters, Amanda Ceas, Yun Liu, Jennifer M.S. Sucre, Jichao Chen
Abstract
High endothelial venules (HEVs) are important structures in lymph nodes (LNs) that mediate lymphocyte homing, and their dedifferentiation is a necessary step before LN metastasis. Whether vascular endothelial growth factor–related (VEGF-related) signaling, which plays an important role in LN metastasis, is involved in the dedifferentiation of HEVs remains unclear. Here, we confirmed increased expression of VEGFA, VEGFC, and VEGFD; HEV dedifferentiation; and impaired lymphocyte homing function in tumor-draining LNs (TDLNs). Furthermore, we demonstrated that tumor-secreted VEGFA induced lymphangiogenesis in TDLNs to promote premetastatic niche (PMN) formation; VEGFC promoted HEV proliferation but did not affect its lymphocyte homing function. Notably, we showed that VEGFD induced the dedifferentiation of HEVs by binding to VEGFR2 on the endothelial surface of HEVs and further impaired the lymphocyte homing function of TDLNs. Overall, we revealed that tumor-secreted VEGFD interacted with VEGFR2, induced HEV dedifferentiation, and reduced lymphocyte homing, providing potential insights for the prevention and treatment of LN metastasis.
Authors
Weichang Yang, Juan Wu, Shanshan Cai, Hongquan Xing, Jiajia Xiang, Xinyi Zhang, Xiaoyan Su, Xiaoqun Ye
Abstract
Hematopoietic stem cell transplantation (HCT) is a potentially life-saving therapy but can lead to lung injury due to chemoradiation toxicity, infection, and immune dysregulation. We previously showed that bronchoalveolar lavage (BAL) transcriptomes representing pulmonary inflammation and cellular injury can phenotype post-HCT lung injury and predict mortality. To test whether peripheral blood might be a suitable surrogate for BAL, we compared 210 paired BAL and blood transcriptomes obtained from 166 pediatric HCT patients at 27 hospitals. BAL and blood RNA abundance showed minimal correlation at the level of individual genes, gene set enrichment scores, imputed cell fractions, and T- and B-cell receptor clonotypes. Instead, we identified significant site-specific transcriptional programs. In BAL, pathways related to immunity, hypoxia, and epithelial mesenchymal transition were tightly co-expressed and linked to mortality. In contrast, in blood, expression of endothelial injury, DNA repair, and cellular metabolism pathways was associated with mortality. Integration of paired BAL and blood transcriptomes dichotomized patients into two groups with significantly different rates of hypoxia and clinical outcomes within 1 week of BAL. These findings reveal a compartmentalized injury response, where BAL and blood transcriptomes provide distinct but complementary insights into local and systemic mechanisms of post-HCT lung injury.
Authors
Emma M. Pearce, Erica Evans, Madeline Y. Mayday, Gustavo Reyes, Miriam R. Simon, Jacob Blum, Hanna Kim, Jessica Mu, Peter J. Shaw, Courtney M. Rowan, Jeffery J. Auletta, Paul L. Martin, Caitlin Hurley, Erin M. Kreml, Muna Qayed, Hisham Abdel-Azim, Amy K. Keating, Geoffrey D.E. Cuvelier, Janet R. Hume, James S. Killinger, Kamar Godder, Rabi Hanna, Christine N. Duncan, Troy C. Quigg, Paul Castillo, Nahal R. Lalefar, Julie C. Fitzgerald, Kris M. Mahadeo, Prakash Satwani, Theodore B. Moore, Benjamin Hanisch, Aly Abdel-Mageed, Dereck B. Davis, Michelle P. Hudspeth, Greg A. Yanik, Michael A. Pulsipher, Christopher C. Dvorak, Joseph L. DeRisi, Matt S. Zinter
Abstract
Asthma is characterized by exacerbated response to triggers such as allergen. While pulmonary neuroendocrine cells (PNECs), a rare population of airway epithelial cells, are essential for amplifying allergen-induced asthma response, how PNECs are regulated to achieve this role remains poorly understood. Here we show that in the adult mouse airway, inactivation of achaete-scute-like protein 1 gene in PNECs led to loss of these cells. Intriguingly, exposure of these mutants to house dust mites (HDM), a common allergen, led to reappearance of PNECs. Similarly, exposure of wild-type mice to HDM led to PNEC hyperplasia, a result of proliferation of existing PNECs and transdifferentiation from club cells. Single-cell RNA-Seq experiments revealed PNEC heterogeneity, including the emergence of an allergen-induced PNEC subtype. Notch signaling was downregulated in HDM-treated airway, and treatment with Notch agonist prevented PNEC hyperplasia. These findings together suggest that HDM-induced PNEC hyperplasia may contribute to exacerbated asthma response.
Authors
Estelle Kim, Brian K. Wells, Hannah Indralingam, Yujuan Su, Jamie Verheyden, Xin Sun
Abstract
Idiopathic pulmonary fibrosis (IPF) is a severe diffuse progressive fibrosing interstitial disease leading to respiratory failure and death in the absence of organ transplantation. Substantial evidence has confirmed the pivotal role of fibroblasts in the progression of IPF, yet effective therapeutic options are scarce. Single-cell transcriptomics profiling revealed that among the diverse fibroblast subsets, FAP1+ alveolar fibroblasts (AFs) are pivotal for the progression of IPF. On the basis of these findings, we developed FAP1-targeting chimeric antigen receptor cytotoxic effector regulatory T (CAR-cTregs) cells, which leverage the targeted killing advantage of the currently trending CAR-based immunotherapy for tumors and incorporate the immunosuppressive functions of Tregs to mitigate the inflammation caused by both the disease itself and CAR-T-cell infusion. Accordingly, CAR-cTregs were constructed to effectively eliminate FAP1+ fibroblasts in vitro. This cytotoxic effect can be abrogated by inhibitors of the granzyme-perforin pathway. In the bleomycin-induced PF model, CAR-cTregs were found to reverse fibrosis characterized by diminished recruitment of fibrocytes and improved remodeling of epithelial cells. Together, our results demonstrate that CAR-cTregs can serve as a promising therapeutic option for IPF and provide a novel strategy for treating multiple chronic inflammatory diseases by inducing both cytotoxicity and immunosuppression.
Authors
Yun-Han Jiang, Meng Zhou, Meng-Di Cheng, Sai Chen, Ying-Qiang Guo
Abstract
MICB is a ligand for NKG2D. We have shown NK cells are central to lung transplant acute lung injury (ALI) via NKG2D activation, and increased MICB in bronchoalveolar lavage predicts ALI severity. Separately, we found a MICB polymorphism (MICBG406A) is associated with decreased ALI risk. We hypothesized this polymorphism would protect against severe SARS-CoV-2 respiratory disease. We analyzed 1,036 patients hospitalized with SARS-CoV-2 infection from the IMPACC cohort. Associations between MICBG406A and outcomes were determined by linear regression or Cox Proportional Hazards models. We also measured immune profiles of peripheral blood, upper and lower airway. We identified 560 major allele homozygous patients, and 426 and 50 with one or two copies of the variant allele. MICBG406A conferred reduced odds of severe COVID-19 (OR = 0.73, CI = 0.58–0.93, P = 0.04). MICBG406A homozygous participants demonstrated 34% reduced cumulative odds for mechanical ventilation or death (CI = 0.51–0.85, P = 0.005) and 43% reduced risk for mortality (CI = 0.35–0.77, P = 0.001). Patients with MICBG406A variant alleles had reduced soluble inflammatory mediators and differential regulation of multiple immune pathways. These findings demonstrate a novel association between increasing MICBG406A variant allele copies and reduced COVID-19 severity, independent of SARS-CoV-2 viral burden and humoral immunity, suggesting the NKG2D-ligand pathway as an intervention target.
Authors
Harry Pickering, Narges Alipanah-Lechner, Ernie Chen, Dylan Duchen, Holden T. Maecker, Seunghee Kim-Schulze, Ruth R. Montgomery, Chris Cotsapas, Hanno Steen, Florian Krammer, Charles R. Langelier, Ofer Levy, Lindsey R. Baden, Esther Melamed, Lauren I.R. Ehrlich, Grace A. McComsey, Rafick P. Sekaly, Charles B. Cairns, Elias K. Haddad, Albert C. Shaw, David A. Hafler, David B. Corry, Farrah Kheradmand, Mark A. Atkinson, Scott C. Brakenridge, Nelson I. Agudelo Higuita, Jordan P. Metcalf, Catherine L. Hough, William B. Messer, Bali Pulendran, Kari C. Nadeau, Mark M. Davis, Ana Fernandez-Sesma, Viviana Simon, Monica Kraft, Christian Bime, David J. Erle, Joanna Schaenman, Al Ozonoff, Bjoern Peters, Steven H. Kleinstein, Alison D. Augustine, Joann Diray-Arce, Patrice M. Becker, Nadine Rouphael, Matthew C. Altman, Steven E. Bosinger, Walter L. Eckalbar, IMPACC Network, Carolyn S. Calfee, Oscar A. Aguilar, Elaine F. Reed, John R. Greenland, Daniel R. Calabrese
Abstract
Pulmonary fibrosis (PF) is a life-threatening disease that requires effective and well-tolerated therapeutic modalities. Previously, the distinct pathogenic roles of cannabinoid receptor 1 (CB1R) and inducible nitric oxide synthase (iNOS) in the lungs and their joint therapeutic targeting were highlighted in PF. However, the cell-specific role of CB1R in PF has not been explored. Here, we demonstrate that CB1R in alveolar macrophages (AMs) mediates the release of anandamide into the alveoli, which promotes PF by inducing profibrotic macrophages that are accessible to locally delivered antifibrotic therapy. A multitargeted therapy may improve therapeutic efficacy in PF. Pulmonary delivery of 0.5 mg/kg/day MRI-1867 (zevaquenabant), a peripherally acting hybrid CB1R/iNOS inhibitor, is as effective as systemic delivery of 10 mg/kg/day, and also matches the efficacy of nintedanib in mitigating bleomycin-induced PF. A systems pharmacology approach reveals that zevaquenabant and nintedanib treatments reverse pathologic changes in both distinct and shared PF-related pathways, which are conserved in human and mouse. Moreover, zevaquenabant treatment also attenuated fibrosis and profibrotic mediators in human precision-cut lung slices. These findings establish CB1R-expressing AMs as a therapeutic target and support local delivery of dual CB1R/iNOS inhibitor zevaquenabant by inhalation as an effective, well-tolerated, and safer strategy for PF.
Authors
Abhishek Basu, Muhammad Arif, Kaelin M. Wolf, Madeline Behee, Natalie L. Johnson, Lenny Pommerolle, Ricardo H. Pineda, John Sembrat, Charles N. Zawatsky, Szabolcs Dvorácskó, Nathan J. Coffey, Joshua K. Park, Seray B. Karagoz, Grzegorz Godlewski, Tony Jourdan, Judith Harvey-White, Melanie Königshoff, Malliga R. Iyer, Resat Cinar
Abstract
Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously demonstrated that expression of an AT2 cell exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here, using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 self-renewal and accumulation of transitional epithelial cells. We identify deficient AMP-kinase signaling as a critical component of AT2 cell dysfunction and demonstrate that targeting this druggable signaling hub can rescue the aberrant AT2 cell metabolic phenotype and mitigate lung fibrosis in vivo.
Authors
Luis R. Rodríguez, Konstantinos-Dionysios Alysandratos, Jeremy Katzen, Aditi Murthy, Willy Roque Barboza, Yaniv Tomer, Sarah Bui, Rebeca Acín-Pérez, Anton Petcherski, Kasey Minakin, Paige Carson, Swati Iyer, Katrina Chavez, Charlotte H. Cooper, Apoorva Babu, Aaron I. Weiner, Andrew E. Vaughan, Zoltan Arany, Orian S. Shirihai, Darrell N. Kotton, Michael F. Beers
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