Pulmonology
Abstract
Authors
Jianfei Ji, Wenjing You, Xiaoli Sun, Peng Zhao
Abstract
Despite advances in treatment approaches for lung cancer, the morbidity and survival of lung cancer patients with malignant pleural effusions (MPE) remain poor. This is in part due to gaps in understanding the role of immune cells in the pleural fluid microenvironment. We performed single cell analysis with flow cytometry validation of CD45+ cells in eight malignant and five benign pleural fluid (BPE) specimens to identify changes in the transcriptomic landscape of immune cells across disease states. We found upregulation of pro-inflammatory signaling pathways, including interferon and TNF signaling, in T cells, B cells, and macrophages in benign compared to malignant pleural effusions. Pro-inflammatory HLA-DR+ macrophages were associated with good survival outcomes while pro-tumorigenic HLA-DR- macrophages with upregulation of angiogenesis, TGFβ, and fibronectin signaling were associated with poor survival outcomes in patients with MPE. We also validated these findings with macrophage cell surface expression markers using flow cytometry in 14 MPE and 7 BPE specimens. Finally, we performed multiplex cytokine analysis which showed enrichment of the type 3 inflammatory cytokine, IL17A, in MPE as a putative mechanism for macrophage reprogramming. These data provide a rich resource for interrogating the immune cell types and states present across the spectrum of pleural disease. They offer not only prognostic value for patient outcomes at the time of pleural fluid collection, but also insights into novel immunotherapy targets.
Authors
Aaditya Khatri, Huimin Wang, Zhicheng Ji, Prekshaben Patel, Smita K. Nair, Javid P. Mohammed, Beth H. Shaz, Andrew B. Nixon, Scott M. Palmer, Kamran Mahmood
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and respiratory failure. While T cells are elevated in IPF lungs, their contributions to fibrosis beyond inflammation remain poorly understood. Here, we performed multiplex imaging and single-cell RNA and protein profiling on about 90,000 CD3+ T cells from control and fibrotic lungs, revealing 11 distinct subsets of CD4+ and CD8+ T cells, including a rare CD56+ regulatory T cell. In addition to increased T cell numbers in severely fibrotic lungs compared with non-diseased controls, we observed CD4+ and CD8+ T cells localized near epithelial cells and in niches of abnormal epithelium. CXCR4/MIF signaling emerged as a central axis mediating T cell–epithelial interactions, while epidermal growth factor receptor (EGFR) and TGF-β pathways dominated in multiple T cell subsets. Our findings support the concept that T cells in IPF adopt nonclassical activation patterns that are driven by epithelial interactions within the fibrotic microenvironment. These studies provide a foundation for exploring alternative therapeutic strategies in IPF lungs by modulating T cell behavior and communication networks.
Authors
Ana P.M. Serezani, Julia M.R. Bazzano, Bruno D. Pascoalino, Ludmilla da Silva, Abigail J. Dietrich, Chase J. Taylor, Taylor Sherrill, Annika Vannan, Carla L. Calvi, Paula I. Gonzalez-Ericsson, Erin M. Wilfong, Matthew Bacchetta, Ciara M. Shaver, Lorraine B. Ware, Margaret L. Salisbury, Luc Van Kaer, Nicholas E. Banovich, Jonathan A. Kropski, Timothy S. Blackwell
Abstract
The cholinergic antiinflammatory pathway attenuates lung inflammation via the α7 nicotinic acetylcholine receptor (α7 nAChR) on immune cells. However, the role of α7 nAChR on lung megakaryocytes (Mks) in allergic airway inflammation remains unknown. In this study, allergen-challenged mouse models were used with conditional Mk-specific Chrna7 knockout, pharmacological activation (GTS-21), and Mk reconstitution. IL-33 expression and p38 MAPK signaling were assessed. We found that allergen challenge upregulated α7 nAChR specifically in lung Mks. Mk-specific Chrna7 deletion significantly alleviated allergic airway inflammation, whereas GTS-21 exacerbated inflammation via an Mk-dependent mechanism. Reconstitution with α7 nAChR+ Mks restored airway inflammatory responses. Mechanistically, α7 nAChR activation promoted Mk IL-33 synthesis and secretion through p38 MAPK signaling. Taken together, our results show that α7 nAChR on lung Mks plays a proinflammatory role in allergic airway inflammation, challenging its classical antiinflammatory paradigm and revealing pathogenic mechanisms.
Authors
Hang Wu, Rujia Tao, Shitao Xie, Yao Zhou, Jin-Fu Xu, Zhenwei Xia, Xiao Su
Abstract
Authors
Lori Asarian, Jianlong Jia, Dmytro Sirokha, Lara Paulini, Daniela Dietel, Mircea Gabriel Stoleriu, Marion Frankenberger, Ali Önder Yildirim, Katharina S. Götze, Juergen Behr, Gary M. Hunninghake, Isis E. Fernandez
Abstract
Authors
Allen Duong, Sajad Moshkelgosha, Tereza Martinu, Stephen Juvet
Abstract
Authors
Kadambari Vijaykumar, Liang Ma, Kevin Chen, Liping Tang, Nikoleta Pavelkova, Elex Harris, Kajal Jadhav, Qian Li, Mohamed Hanafy, Hinnerk Schulz-Hildebrandt, Guillermo J. Tearney, Finn Hawkins, Darrell N. Kotton, Steven M. Rowe
Abstract
CFTR in the lung epithelium contributes to the secretion of a surface liquid layer that is essential to lung homeostasis and defense. The understanding of how liquid is secreted in the lung is derived largely from studies of the airway epithelium. Comparatively little is known about liquid secretion mechanisms in the alveolar epithelium, including its cellular source. To define which cell type drives alveolar liquid secretion, we generated transgenic mice that expressed a Cftr null allele in alveolar type 1 (AT1) cells, type 2 (AT2) cells, or both, then viewed liquid secretion in live alveoli using confocal microscopy of isolated, perfused lungs. Our findings show liquid secretion was blocked in alveoli of all three transgenic mice, indicating that both AT1 and AT2 cells contribute to alveolar liquid secretion. Cftr null expression in AT1 cells also blocked the secretion-mediated clearance of small particle and bacterial clusters from alveolar walls, indicating that AT1 cell CFTR contributes to alveolar defense. Together, these findings show alveolar liquid secretion depends on both AT1 and AT2 cell CFTR, and that CFTR in AT1 cells – a cell type not traditionally considered in liquid secretion mechanisms or CFTR-related lung diseases – contributes to lung liquid dynamics and host defense.
Authors
Sayahi Suthakaran, Sonya Homami, Deebly Chavez, Stephanie Tang, Sarah K.L. Moore, Chaya Sussman, Jimmy Zhang, Clemente J. Britto, Alice Prince, Alison J. May, Jaymin J. Kathiriya, Jaime L. Hook
Abstract
The mechanisms by which e-cigarette vaping (EV) affects lung health remain unclear. Clinical data from clusters of EV-associated lung injury indicate that EV damages distal lung parenchyma and increases vulnerability to second-hit injury, including respiratory viral infections. Using human lung endothelial and epithelial cells and precision-cut lung slices, we investigated the mechanisms underlying distal lung cell injury and repair triggered by brief (24-hour) EV exposure. Using RNA sequencing of lung tissue from Golden Syrian hamsters, we evaluated the persistence of lung stress responses (10 days after 5 days of EV exposure and determined the impact of EV on host defense against influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. EV disrupted the barrier function of human distal lung cells through JNK stress-response signaling, triggered autophagy with impaired autophagolysosomal degradation, suppressed mTOR signaling and cell proliferation, and culminated in apoptosis. Analysis of transcriptional responses in EV-exposed hamster lungs revealed persistent activation of pathways involving JNK signaling, autophagy, barrier dysfunction, tissue remodeling, and impaired Th1 immunity. EV pre-exposure increased the viral burden of SARS-CoV-2, downregulated antiviral genes (Ifit1, Isg15, Nfkbia), and altered Stat1 and Irf7 immune signaling, while amplifying oxidative stress and IL-12 signaling. These findings show that short-term EV exposure triggered stress-induced distal lung cell injury with persistent changes in antiviral immunity and molecular pathways associated with tissue remodeling. When sustained, as with habitual EV use, these alterations may increase susceptibility to respiratory viral infections and contribute to the development of chronic lung disease.
Authors
Tanner C. Rivera, Kelly S. Schweitzer, Christina F. Cornell, Jordan M. Nall, Nicholas Egersdorf, Courtney Moeder, Riley A. Cooney, Eszter K. Vladar, Steve D. Groshong, Gregory P. Downey, James P. Bridges, Richard Bowen, Hong Wei Chu, Irina Petrache
Abstract
Authors
Yudai Miyashita, Taisuke Kaiho, Yuriko Yagi, Taichi Nagano, Xin Wu, Yuanqing Yan, Haiying Sun, Carl Atkinson, GR Scott Budinger, Ankit Bharat, Chitaru Kurihara
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