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• W4322753617 abstract "Respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can trigger chronic lung disease that persists and even progresses after expected clearance of infectious virus. To gain an understanding of this process, the current study examined a series of consecutive fatal cases of coronavirus disease 2019 (COVID-19) that came to autopsy at 27 to 51 days after hospital admission. In each patient, a stereotyped bronchiolar-alveolar pattern of lung remodeling was identified with basal epithelial cell hyperplasia, immune activation, and mucinous differentiation. Remodeling regions featured macrophage infiltration and apoptosis and a marked depletion of alveolar type 1 and 2 epithelial cells. This pattern closely resembled findings from an experimental model of post-viral lung disease that requires basal-epithelial stem cell growth, immune activation, and differentiation. Together, these results provide evidence of basal epithelial cell reprogramming in long-term COVID-19 and thereby yield a pathway for explaining and correcting lung dysfunction in this type of disease. Respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can trigger chronic lung disease that persists and even progresses after expected clearance of infectious virus. To gain an understanding of this process, the current study examined a series of consecutive fatal cases of coronavirus disease 2019 (COVID-19) that came to autopsy at 27 to 51 days after hospital admission. In each patient, a stereotyped bronchiolar-alveolar pattern of lung remodeling was identified with basal epithelial cell hyperplasia, immune activation, and mucinous differentiation. Remodeling regions featured macrophage infiltration and apoptosis and a marked depletion of alveolar type 1 and 2 epithelial cells. This pattern closely resembled findings from an experimental model of post-viral lung disease that requires basal-epithelial stem cell growth, immune activation, and differentiation. Together, these results provide evidence of basal epithelial cell reprogramming in long-term COVID-19 and thereby yield a pathway for explaining and correcting lung dysfunction in this type of disease. The coronavirus disease 2019 (COVID-19) pandemic spotlights the need to better understand both acute and chronic disease triggered by severe respiratory viral infection. The acute phase of disease with severe pneumonia and lung injury dominated the early management and study of the crisis.1Osuchowski M. Winkler M. Skirecki T. Cajander S. Shankar-Hari M. Lachmann G. Monneret G. Venet F. Buer M. Brunkhorst F. Weis S. Garcia-Salido A. Kox M. Cavaillon J.-M. Uhle F. Weigand M. Blohe S. Wiersinga W. Almansa R. de la Fuente A. Martin-LOeches I. Meisel C. Spinetti T. Schefold J. Cilloniz C. Torres A. Giamarellos-Bourboulis E. Ferrer R. Girardis M. Cossarizza A. Netea M. van der Poll T. Bermejo-Martin J. Rubia I. The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity.Lancet Respir Med. 2021; 9: 622-642Google Scholar However, even then, it appeared likely that progressive and often long-term disease was also a significant cause of morbidity and mortality. Indeed, a high percentage of patients with COVID-19 survived the acute infectious illness only to experience the major degree of organ dysfunction over a more prolonged time course during and after the initial hospitalization.2del Rio C. Collins L.F. Malani P. Long-term health consequences of COVID-19.JAMA. 2020; 324: 1723-1724Google Scholar,3Al-Aly Z. Xie Y. Bowe B. High-dimensional characterization of post-acute sequelae of COVID-19.Nature. 2021; 594: 259-264Google Scholar This outcome was consistent with previous observations that other types of respiratory viruses can also trigger a pathway to long-term immune-mediated disease.4Holtzman M.J. Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens.J Clin Invest. 2012; 122: 2741-2748Google Scholar Thus, viral initiation, exacerbation, and progression of chronic lung disease can be found in clinical observations and corresponding experimental models of asthma, chronic obstructive pulmonary disease, and related inflammatory disease phenotypes.4Holtzman M.J. Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens.J Clin Invest. 2012; 122: 2741-2748Google Scholar Together, these observations increase the likelihood that the host response to the virus can be reprogrammed from protection to an abnormal remodeling response in susceptible individuals. Whether and how this alternative pathway might also be linked to progressive and/or long-term COVID-19 still need to be defined. To address this issue, lung tissue samples from autopsies of patients with COVID-19 were studied to obtain cell and molecular insights in the context of previous observations.4Holtzman M.J. Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens.J Clin Invest. 2012; 122: 2741-2748Google Scholar The analysis focused on a consecutive series of patients with COVID-19 who died long after onset of illness (27 to 51 days after hospital admission) to provide a snapshot of long-term post-viral lung disease. In fact, this opportunity for analysis of lung tissue was largely unprecedented in human studies of this disease process. In that context, the study found consistent and striking basal-epithelial cell hyperplasia that extended beyond the usual airway location and instead moved into the distal airspaces of the lung. As introduced above, this remodeling process was captured long after the start of the initial illness but in close association with morbidity and mortality from the disease. Moreover, this same pattern of progression was predominant in experimental models of viral infection using natural pathogens for mice, such as Sendai virus,5Kim E.Y. Battaile J.T. Patel A.C. You Y. Agapov E. Grayson M.H. Benoit L.A. Byers D.E. Alevy Y. Tucker J. Swanson S. Tidwell R. Tyner J.W. Morton J.D. Castro M. Polineni D. Patterson G.A. Schwendener R.A. Allard J.D. Peltz G. Holtzman M.J. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease.Nat Med. 2008; 14: 633-640Google Scholar, 6Byers D.E. Alexander-Brett J. Patel A.C. Agapov E. Dang-Vu G. Jin X. Wu K. You Y. Alevy Y.G. Girard J.-P. Stappenbeck T.S. Patterson G.A. Pierce R.A. Brody S.L. Holtzman M.J. Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease.J Clin Invest. 2013; 123: 3967-3982Google Scholar, 7Wu K. Kamimoto K. Zhang Y. Yang K. Keeler S.P. Gerovac B.J. Agapov E.V. Austin S.P. Yantis J. Gissy K.A. Byers D.E. Alexander-Brett J. Hoffmann C.M. Wallace M. Hughes M.E. Morris S.A. Holtzman M.J. Basal-epithelial stem cells cross an alarmin checkpoint for post-viral lung disease.J Clin Invest. 2021; 131: e149336Google Scholar and for humans, such as influenza A virus and respiratory enterovirus-D68.8Keeler S.P. Agapov E.V. Hinojosa M.E. Letvin A.N. Wu K. Holtzman M.J. Influenza a virus infection causes chronic lung disease linked to sites of active viral RNA remnants.J Immunol. 2018; 201: 2354-2368Google Scholar,9Zhang Y. Mao D. Keeler S.P. Wang X. Wu K. Gerovac B.J. Shornick L.P. Agapov E. Holtzman M.J. Respiratory enterovirus (like parainfluenza virus) can cause chronic lung disease if protection by airway epithelial STAT1 is lost.J Immunol. 2019; 202: 2332-2347Google Scholar Those studies ultimately identified a subset of basal-epithelial stem cells (basal-ESCs) that are critical for homeostasis but also reprogrammable to become an essential driver of lung remodeling signatures.7Wu K. Kamimoto K. Zhang Y. Yang K. Keeler S.P. Gerovac B.J. Agapov E.V. Austin S.P. Yantis J. Gissy K.A. Byers D.E. Alexander-Brett J. Hoffmann C.M. Wallace M. Hughes M.E. Morris S.A. Holtzman M.J. Basal-epithelial stem cells cross an alarmin checkpoint for post-viral lung disease.J Clin Invest. 2021; 131: e149336Google Scholar Herein, the study identified similar circuitry for lung remodeling in post-viral patients with COVID-19 with the possibility that the same components can be targeted to address long-term COVID-19 in the lung and perhaps other tissue sites. Human lung tissue was obtained from a series of consecutive autopsies performed from April to August 2020 at Barnes-Jewish Hospital (St. Louis, MO). As nondisease controls, human lung samples were obtained from an Advanced Lung Disease Tissue Registry that contains whole lung explants harvested but not used for lung transplantation, as described previously,10Deslee G. Woods J. Moore C. Conradi S. Gierada D. Atkinson J. Battaile J. Liu L. Patterson A. Adair-Kirk T. Holtzman M. Pierce R. Oxidative damage to nucleic acids in severe emphysema.Chest. 2009; 135: 965-974Google Scholar,11Byers D.E. Wu K. Dang-Vu G. Jin X. Agapov E. Zhang X. Battaile J.T. Schechtman K.B. Yusen R. Pierce R.A. Holtzman M.J. Triggering receptor expressed on myeloid cells-2 (TREM-2) expression tracks with M2-like macrophage activity and disease severity in COPD.Chest. 2018; 153: 77-86Google Scholar and from a tissue procurement service (IIAM, Edison, NJ). A summary of clinical characteristics is provided in Supplemental Table S1. All human studies were conducted with protocols approved by the Washington University (St. Louis, MO) Institutional Review Board. Tissues were fixed with 10% formalin, embedded in paraffin, cut into sections (5 μm thick), and adhered to charged slides. Sections were deparaffinized in Fisherbrand CitroSolv (Fisher Scientific, Hampton, NH; number 04-355-121), hydrated, and treated with heat-activated antigen unmasking solution (Vector Laboratories, Inc., Newark, CA; number H-3301-250 or H-3300-250). Tissue processing and then hematoxylin-eosin, periodic acid–Schiff–hematoxylin, and Gomori trichrome staining were performed, as described previously.6Byers D.E. Alexander-Brett J. Patel A.C. Agapov E. Dang-Vu G. Jin X. Wu K. You Y. Alevy Y.G. Girard J.-P. Stappenbeck T.S. Patterson G.A. Pierce R.A. Brody S.L. Holtzman M.J. Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease.J Clin Invest. 2013; 123: 3967-3982Google Scholar,8Keeler S.P. Agapov E.V. Hinojosa M.E. Letvin A.N. Wu K. Holtzman M.J. Influenza a virus infection causes chronic lung disease linked to sites of active viral RNA remnants.J Immunol. 2018; 201: 2354-2368Google Scholar Immunostaining was performed using the following primary antibodies: rabbit anti–angiotensin-converting enzyme 2 (ACE-2) polyclonal antibody (pAb) (ab65863; Abcam, Cambridge, UK), mouse anti–ACE-2 monoclonal antibody (mAb) (clone 171606; R&D Systems, Minneapolis, MN), rabbit anti–keratin 5 (anti-KRT5) pAb (ab53121; Abcam) and mAb (clone EP1601Y; ab52635; Abcam), rabbit anti–aquaporin 3 (anti-AQP3) pAb (ab125219; Abcam), mouse anti-CD68 mAb (clone Kp-1; Sigma-Aldrich, St. Louis, MO), rabbit anti-CD163 mAb (clone D6U1J; Cell Signaling, Danvers, MA), rabbit anti-CD31 mAb (clone EPR17259; Abcam), rabbit anti–collagen IV mAb (clone EPR20966; Abcam), mouse anti–secretoglobin 1A1 (anti-SCGB1A1) mAb (clone E-11; Santa Cruz Biotechnology, Dallas, TX), mouse anti–acetylated tubulin (clone 6-11B-1; Sigma-Aldrich), mouse anti–mucin 5AC (anti-MUC5AC) mAb (clone 45M1; ThermoFisher Scientific, Waltham, MA; and Santa Cruz Biotechnology), mouse anti–HT2-280 pAb (TB-27AHT2-280; Terrace Biotech, San Francisco, CA), rabbit anti–surfactant protein C pAb (ab90716; Abcam), rabbit anti-podoplanin mAb (clone EPR7072; Abcam), rabbit anti–mucin 5B (anti-MUC5B) pAb (ab87276; Abcam), rabbit anti–Ki-67 mAb (clone D2H10; Cell Signaling), rabbit active (cleaved) caspase-3 mAb (clone 5 A1E; Cell Signaling), and mouse anti-CXCL17 mAb (clone 422204; R&D Systems). Antibody binding was detected with Alexa Fluor 488 or 594 conjugated secondary antibodies (ThermoFisher Scientific; numbers A-21206, A-21207, A-21202, and A-21203) matched to primary antibodies. All sections were counterstained with DAPI and were imaged using a DM5000 B microscope (Leica, Wetzlar, Germany) for conventional imaging. Staining was quantified in whole lung sections using a NanoZoomer S60 slide scanner (Hamamatsu, Shizuoka, Japan) and ImageJ software version 1.53v (NIH, Bethesda, MD; https://imagej.net/ij/index.html, last accessed January 7, 2023), as described previously.7Wu K. Kamimoto K. Zhang Y. Yang K. Keeler S.P. Gerovac B.J. Agapov E.V. Austin S.P. Yantis J. Gissy K.A. Byers D.E. Alexander-Brett J. Hoffmann C.M. Wallace M. Hughes M.E. Morris S.A. Holtzman M.J. Basal-epithelial stem cells cross an alarmin checkpoint for post-viral lung disease.J Clin Invest. 2021; 131: e149336Google Scholar For the present experiments, an entire lung section was scanned and analyzed for each patient or subject (n = 5 per group) to assess lung remodeling region phenotype. All data are presented as means ± SEM and are representative of five patients with COVID-19 or five subjects without the disease. Unpaired t-test as well as mixed-model repeated measures analysis of variance with Tukey correction for multiple comparisons were used to assess statistical significance between means. In all cases, significance threshold was set at P < 0.05. The number of patients and subjects for each experimental condition is defined in the figure legends. To understand clinical observations of long-term disease after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, a protocol was developed to obtain and analyze the lung tissue samples from a consecutive set of hospitalized patients who underwent autopsy for COVID-19 as a primary cause of death. This group of five patients was highly relevant to long-term post-viral disease because they died at 27 to 51 days after initial presentation for care and positive testing for SARS-CoV-2 infection (Supplemental Table S1). Examination of hematoxylin-eosin staining of lung biopsy sections from all patients showed histopathologic changes of organizing diffuse alveolar damage (Figure 1A). In addition, this staining revealed a stereotyped pattern of airway epithelial cell hyperplasia that extended into distal airspaces that were filled with cellular and mucinous material (Figure 1A). Periodic acid–Schiff–hematoxylin staining confirmed these findings, including accumulation of mucus in these same locations (Figure 1A). Gomori trichrome staining indicated that these same bronchiolar-alveolar lung remodeling regions were also sites for collagen accumulation consistent with a fibrotic reaction (Figure 1A). Immunostaining with basal epithelial cell markers KRT5 and AQP37Wu K. Kamimoto K. Zhang Y. Yang K. Keeler S.P. Gerovac B.J. Agapov E.V. Austin S.P. Yantis J. Gissy K.A. Byers D.E. Alexander-Brett J. Hoffmann C.M. Wallace M. Hughes M.E. Morris S.A. Holtzman M.J. Basal-epithelial stem cells cross an alarmin checkpoint for post-viral lung disease.J Clin Invest. 2021; 131: e149336Google Scholar more specifically identified the presence of basal-epithelial cell clusters extending into former alveolar spaces (Figure 1B). Quantitative levels of KRT5+ and AQP3+ staining were each significantly increased in patients with COVID-19 compared with subjects without disease (Figure 1, C and D). These remodeling sites (matched for size and morphology) also showed increased staining for monocyte-macrophage surface receptors CD68 and CD163 compared with nondisease controls (Figure 1, E and F). Accumulation of CD68+ macrophages was most prominent in remodeled airspaces defined by collagen IV+ basement membrane and CD31+ vascular borders (Figure 1G). These results served as an index of basal-epithelial cell hyperplasia-metaplasia and monocyte-macrophage infiltration to mark the extent of lung remodeling regions in patients with COVID-19. The spatial distribution and morphology of alveolar type 2 (AT2) and type 1 (AT1) cells during late-stage disease were examined to define the observed damage to the alveolar epithelium. As expected, immunostaining showed that KRT5+ basal cells were restricted to airway mucosal sites, and HT2-280+ surfactant protein C+ AT2 cells and podoplanin+ AT1 cells were confined to alveolar sites in nondisease control subjects (Figure 2, A and B ). In contrast, KRT5+ cells were abundant, whereas HT2-280+, surfactant protein C+, and podoplanin+ cells were nearly absent, in the lung remodeling regions of patients with COVID-19 (Figure 2, A and B). Expression of the SARS-CoV-2 receptor ACE-2 was localized to KRT5+ basal epithelial cells in airway mucosa and remodeling regions, with rare expression on α-tubulin+ ciliated cells and no significant expression on HT2-280+ AT2 cells, SCGB1A1+ club cells, or CD68+ macrophages (data not shown) (Figure 2C). These findings suggested viral capacity for primary infection of basal epithelial cells in proximal airway and distal lung remodeling sites. As a further readout of post-viral lung remodeling, mucinous differentiation, as defined by expression of the predominant lung gel-forming mucins MUC5AC and MUC5B, was characterized. Nondisease control subjects had the usual pattern of mixed MUC5AC+ and MUC5B+ staining in airway mucosal epithelium, predominant MUC5B+ staining in submucosal glands, and no detectable MUC5AC+ or MUC5B+ staining in alveolar epithelium (Figure 3A). As noted previously,6Byers D.E. Alexander-Brett J. Patel A.C. Agapov E. Dang-Vu G. Jin X. Wu K. You Y. Alevy Y.G. Girard J.-P. Stappenbeck T.S. Patterson G.A. Pierce R.A. Brody S.L. Holtzman M.J. Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease.J Clin Invest. 2013; 123: 3967-3982Google Scholar nondisease control subjects (who were on mechanical ventilation, similar to patients) exhibited variable amounts of airway mucus staining, but none of the controls showed lung remodeling regions as found in patients with COVID-19. In contrast, mixed MUC5AC+ and MUC5B+ staining that was generally colocalized to mucous cells in lung remodeling regions was observed for each of the patients with COVID-19 (Figure 3B). Quantitation of mucin staining showed a significant increase in MUC5AC+ and MUC5B+ staining at these sites compared with comparable bronchiolar-alveolar sites in nondisease controls (Figure 3C). The study also aimed to better define the net increases in monocytes-macrophages as an index of epithelial and immune cell activation. A slight but significant increase in Ki-67+ cells in patients with COVID-19 was observed as a sign of cell proliferation, but this growth signal was not seen in the HT2-280+ AT2 cell or CD68+ macrophage population in patients with COVID-19 or nondisease controls (data not shown) (Figure 4, A and B ). In contrast, a marked increase in active caspase-3+ cells as a marker of programmed cell death (apoptosis) was observed in patients with COVID-19 compared with that in controls (Figure 4, C and D). Moreover, the active caspase-3 signal was not localized to the decreased population of HT2-280+ AT2 cells but instead was colocalized primarily to the increased population of CD68+ lung macrophages (Figure 4, E and F). This combination of results suggested that macrophage accumulation resulted from chemokine-dependent migration into the remodeling sites. In that regard, a marked increase was observed in chemokine CXCL17+ cells that colocalized at least in part to KRT5+ basal epithelial cells in remodeling regions in patients with COVID-19 (Figure 4, G and H). Cytoplasmic staining for CXCL17 was consistent with localization to the secretory pathway. Together, these findings were consistent with monocyte-macrophage accumulation based on tissue infiltration despite an increased level of programmed cell death even at this late stage of post-viral lung disease. This recruitment was associated with immune activation of basal epithelial cells for production of macrophage chemokine CXCL17. This study analyzed a series of autopsies from patients with COVID-19 with late-stage lung disease at least 27 to 51 days after initial viral infection. The results reveal a bronchiolar-alveolar lung remodeling process that is characterized by the following: i) basal epithelial cell hyperplasia and metaplasia with extension into former alveolar spaces; ii) colocalized depletion of alveolar types of epithelial cells normally found in these spaces; iii) epithelial stem–progenitor cell differentiation to mucous cells with mucins characteristic of mucosal and submucosal locations; and iv) basal epithelial cell production of chemokine CXCL17 associated with lung monocyte-macrophage infiltration. This study presents these findings in the context of human clinical studies and comparable animal models. Data on post-viral lung remodeling in humans are limited. The COVID-19 pandemic generated an unprecedented opportunity to define this process in vivo. Initial data from patients with COVID-19 documented the early phase of diffuse alveolar damage typical of lung injury and acute respiratory distress syndrome.12Barton L.M. Duval E.J. Stroberg E. Ghosh S. Mukhopadhyay S. COVID-19 autopsies, Oklahoma, USA.Am J Clin Pathol. 2020; 153: 725-733Google Scholar, 13Martines R.B. Ritter J.M. Matkovic E. Gary J. Bollweg B.C. Bullock H. Goldsmith C.S. Silva-Flannery L. Seixas J.N. Reagan-Steiner S. Uyeki T.M. Denison A. Bhatnagar J. Shieh W.-J. Zaki S.R. Group C.-P.W. Pathology and pathogenesis of SARS-CoV-2 associated with fatal coronavirus disease, United States.Emerg Infect Dis. 2020; 26: 2005-2015Google Scholar, 14Hariri L.P. North C.M. Shih A.R. Israel R.A. Maly J.H. Villalba J.A. Vinarsky V. Rubin J. Okin D.A. Sclafani A. Alladina J.W. Griffith J.W. Gillette M.A. Raz Y. Richards C.J. Wong A.K. Ly A. Hung Y.P. Chivulkula R.R. Petri C.R. Calhoun T.F. Brenner L.N. Hibbert K.A. Medoff B.D. Hardin C.C. Stone J.R. Mino-Kenudson M. Lung histopathology in coronavirus disease 2019 as compared with severe acute respiratory syndrome and H1N1 influenza.Chest. 2021; 159: 73-84Google Scholar Thereafter, basal-epithelial cell repair,15Fang Y. Liu H. Huang H. Li H. Saqi A. Qiang L. Que J. Distinct stem/progenitor cells proliferate to regenerate the trachea, intrapulmonary airways and alveoli in COVID-19 patients.Cell Res. 2020; 30: 705-707Google Scholar,16Delorey T.M. Ziegler C.G.K. Heimberg G. Normand R. Yang Y. Segerstolpe A. Abbonddanza D. Fleming S.J. Subramanian A. Montoro D.T. Jagadeesh K.A. Dey K.D. Sen P. Slyper M. Pita-Juarez Y.H. Phillips D. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets.Nature. 2021; 595: 107-113Google Scholar AT2 cell loss,17Gerard L. Lecocq M. Bouzin C. Hoton D. Schmit G. Pereira J.P. Montiel V. Plante-Bordeneuve T. Laterre P.-F. Pilette C. Increased angiotensin-converting enzyme 2 and loss of alveolar type II cells in COVID-19-related acute respiratory distress syndrome.Am J Respir Crit Care Med. 2021; 204: 1024-1034Google Scholar macrophage accumulation,18Dorward D.A. Russell C.D. Um I.H. Elshani M. Armstrong S.D. Penrice-Randal R. Millar T. Lerpiniere C.E.B. Tagliavini G. Hartley C.S. Randle N.P. Gachanja N.N. Potey P.M.D. Dong X.W. Anderson A.M. Campbell V.L. Duguid A.J. Qsous W.A. BouHaidar R. Baillie J.K. Dhaliwal K. Wallace W.A. Bellamy C.O.C. Prost S. Smith C. Hiscox J.A. Harrison D.J. Lucas C.D. Tissue-specific immunopathology in fatal COVID-19.Am J Respir Crit Care Med. 2021; 203: 192-201Google Scholar,19Wang C. Xie J. Zhao L. Fei X. Zhang H. Tan Y. Nie X. Zhou L. Liu Z. Ren Y. Yuan L. Zhang Y. Zhang J. Liang L. Chen X. Liu X. Wang P. Han X. Weng X. Chen Y. Yu T. Zhang X. Cai J. Chen R. Shi Z.-L. Bian X.-W. Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients.EBioMedicine. 2020; 57: 102833Google Scholar predominant MUC5AC+ mucus production,20Yin W. Cao W. Zhou G. Wang L. Sun J. Zhu A. YWang Z. Zhou Y. Liu X. Li Y. Zhong N. Zhao J. Liu L. Ran P. Analysis of pathological changes in the epithelium in COVID-19 patient airways.ERJ Open Res. 2021; 7 (00690-2020)Google Scholar and selective MUC5B+ microcysts21Kato T. Asakura T. Edwards C.E. Dang H. Mikami Y. Okuda K. Chen G. Sun L. Gilmore R.C. Hawkins P. De la Cruz G. Cooley M.R. Bailey A.B. Hewitt S.M. Chertow D.S. NIH COVID-19 Autopsy Consortium Borczuk A.C. Salvatore S. Martinez F.J. Thorne L.B. Askin F.B. Ehre C. Randell S.H. O'Neal W.K. Baric R.S. Boucher R.C. Prevalence and mechanisms of mucus accumulation in COVID-19 lung disease.Am J Respir Crit Care Med. 2022; 206: 1336-1352Google Scholar were reported at subsequent stages of disease in lungs of patients with COVID-19. The present series of entirely long-term cases was further characterized by the consistent development of lung remodeling regions with KRT5+-AQP3+ basal-epithelial cell hyperplasia-metaplasia, combined AT1 and AT2 cell dropout, mixed MUC5AC+ and MUC5B+ mucus production, and CD68+CD163+ monocyte-macrophage accumulation, despite accelerated caspase-3+ apoptotic turnover. Together, the data provide histologic, cellular, and molecular definition of the switch from acute lung injury to chronic bronchiolization that was suggested in descriptive reports of autopsies after presumed viral infection22Taylor M.S. Chivukula R.R. Myers L.C. Jeck W.R. Waghray A. Tata P.R. Selig M.K. O'Donnell W.J. Farver C.F. Thompson B.T. Rajagopal J. Kradin R.L. A conserved distal lung regenerative pathway in acute lung injury.Am J Pathol. 2018; 188: 1149-1160Google Scholar and basal cell growth derived from single-cell RNA-sequencing analysis of COVID-19 samples.16Delorey T.M. Ziegler C.G.K. Heimberg G. Normand R. Yang Y. Segerstolpe A. Abbonddanza D. Fleming S.J. Subramanian A. Montoro D.T. Jagadeesh K.A. Dey K.D. Sen P. Slyper M. Pita-Juarez Y.H. Phillips D. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets.Nature. 2021; 595: 107-113Google Scholar,23Chua R.L. Lukassen S. Trump S. Hennig B.P. Wendisch D. Pott F. et al.COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis.Nat Biotechnol. 2020; 38: 970-979Google Scholar, 24Zhao Z. Zhao Y. Zhou Y. Wang X. Zhang T. Zuo W. Single-cell analysis identified lung progenitor cells in COVID-19 patients.Cell Proliferation. 2020; 53: e12931Google Scholar, 25Salahudeen A.A. Choi S.S. Rustagi A. Zhu J. van Unen V. de la O S.M. Flynn R.A. Margalef-Catala M. Santos A.J.M. Ju J. Batish A. Usui T. Zheng G.X.Y. Edwards C.E. Wagar L.E. Luca V. Anchang B. Nagendran M. Nguyen K. Hart D.J. Terry J.M. Belgrader P. Ziraldo S.B. Mikkelsen T.S. Harbury P.B. Glenn J.S. Garcia K.C. Davis M.M. Baric R.S. Sabatti C. Amieva M.R. Blish C.A. Desai T.J. Kuo C.J. Progenitor identification and SARS-CoV-2 infection in human distal lung organoids.Nature. 2020; 588: 670-675Google Scholar, 26Melms J. Biermann J. Huang H. Wang Y. Nair A. Tagore S. et al.A molecular single-cell lung atlas of lethal COVID-19.Nature. 2021; 595: 114-119Google Scholar, 27Wendisch D. Dietrich O. Mari T. von Stillfried S. Ibarra I. Mittermaier M. et al.SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis.Cell. 2021; 184: 6243-6261Google Scholar The present finding of viral receptor ACE-2 on basal epithelial cells suggests that this cell population might be a direct target for reprogramming toward long-term growth, immune activation, and mucinous differentiation. These new findings also enable comparison of the present data to animal models to better define the pathogenesis of post-viral lung disease. At present, experimental models of SARS-CoV-2 infection do not yet provide a model of long-term lung disease with high fidelity to the human phenotype noted above. This discrepancy is likely a reflection of the inability to duplicate the usual pattern of severe respiratory infection. In that regard, the usual inhaled mechanism of spread (extending from upper airway to alveolar sites) and the consequent severity of infection can be achieved with the natural Sendai virus pathogen in mice. This type of infection thereby yields a remarkably similar pattern of acute infectious illness and, in turn, manifests the key signatures of post-viral lung remodeling disease found in COVID-19.7Wu K. Kamimoto K. Zhang Y. Yang K. Keeler S.P. Gerovac B.J. Agapov E.V. Austin S.P. Yantis J. Gissy K.A. Byers D.E. Alexander-Brett J. Hoffmann C.M. Wallace M. Hughes M.E. Morris S.A. Holtzman M.J. Basal-epithelial stem cells cross an alarmin checkpoint for post-viral lung disease.J Clin Invest. 2021; 131: e149336Google Scholar,9Zhang Y. Mao D. Keeler S.P. Wang X. Wu K. Gerovac B.J. Shornick L.P. Agapov E. Holtzman M.J. Respiratory enterovirus (like parainfluenza virus) can cause chronic lung disease if protection by airway epithelial STAT1 is lost.J Immunol. 2019; 202: 2332-2347Google Scholar,28Wu K. Byers D.E. Jin X. Agapov E. Alexander-Brett J. Patel A.C. Cella M. Gilfilan S. Colonna M. Kober D.L. Brett T.J. Holtzman M.J. TREM-2 promotes macrophage survival and lung disease after respiratory viral infection.J Exp Med. 2015; 212: 681-697Google Scholar This experimental model also reveals a basal-ESC subset that jumps the usual bronchiolar-alveolar boundary and grows into distal airspaces as a new site for differentiation and immune activation that is required for long-term dysfunction.7Wu K. Kamimoto K. Zhang Y. Yang K. Keeler S.P. Gerovac B.J. Agapov E.V. Austin S.P. Yantis J. Gissy K.A. Byers D.E. Alexander-Brett J. Hoffmann C.M. Wallace M. Hughes M.E. Morris S.A. Holtzman M.J. Basal-epithelial stem cells cross an alarmin checkpoint for post-viral lung disease.J Clin Invest. 2021; 131: e149336Google Scholar Single-cell analysis marks this cell subset and its descendant lineage with macrophage chemokine Cxcl17 expression in mice7Wu K. Kamimoto K. Zhang Y. Yang K. Keeler S.P. Gerovac B.J. Agapov E.V. Austin S.P. Yantis J. G" @default.
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