Pulmonary function in patients with pandemic H1N1

Koppe, Soraia; Túlio, Alexandra Ignes Bruni; Villegas, Isabela Lúcia Pelloso; Motter, Arlete Ana

doi:10.1590/1980-5918.029.004.ao17

Cited by 5 publications

(2 citation statements)

References 21 publications

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“…Functional Characterization of Post-injury Keratinization/Dysplasia-''Band-Aid'' or Permanent Maladaptation? Because intrapulmonary p63 + progenitor cells and their progeny occupy alveolar space where AT2/AT1 restoration and functional regeneration might otherwise occur, and given that differentiation of these cells into AT2/AT1s is infrequent in most cases (Kanegai et al, 2016;Vaughan et al, 2015), it must be considered whether p63 + progenitors and their derivatives are potential contributors to the long-term compromise of pulmonary function seen in some human survivors of severe pulmonary injury (Koppe et al, 2016;Liu et al, 2015). The development of chronic inflammation (Keeler et al, 2018;Rane et al, 2019) and bronchiolized epithelium within previously gasexchanging areas of the lung almost certainly have deleterious effects on long-term lung health.…”

Section: Reviewmentioning

confidence: 99%

Basal-like Progenitor Cells: A Review of Dysplastic Alveolar Regeneration and Remodeling in Lung Repair

2020

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Despite the central importance of the respiratory system, the exact mechanisms governing lung repair after severe injury remain unclear. The notion that alveolar type 2 cells (AT2s) self-renew and differentiate into alveolar type 1 cells (AT1s) does not fully encompass scenarios where these progenitors are severely affected by disease, e.g., H1N1 influenza or SARS-CoV-2 (COVID-19). Intrapulmonary p63 + progenitor cells, a rare cell type in mice but potentially encompassing more numerous classic basal cells in humans, are activated in such severe injury settings, proliferating and migrating into the injured alveolar parenchyma, providing a short-term “emergency” benefit. While the fate of these cells is controversial, most studies indicate that they represent a maladaptive repair pathway with a fate restriction toward airway cell types, rarely differentiating into AT2 or AT1 cells. Here, we discuss the role of intrapulmonary basal-like p63 + cells in alveolar regeneration and suggest a unified model to guide future studies.

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Section: Reviewmentioning

confidence: 99%

Basal-like Progenitor Cells: A Review of Dysplastic Alveolar Regeneration and Remodeling in Lung Repair

2020

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“…This maladaptive repair by intrapulmonary p63 + progenitors is similar to alveolar bronchiolization seen in humans with interstitial lung disease (ILD) (Seibold et al, 2013; Smirnova et al, 2016; Vaughan et al, 2015), acute respiratory distress syndrome (ARDS) and DAD (Taylor et al, 2018), and COVID-19 (Fernanda de Mello Costa et al, 2020; Melms et al, 2021; Zhao et al, 2020), in which dysplastic bronchiolization forms ectopically in the alveoli. The loss of alveolar epithelial populations and the failure of ectopic bronchiolized tissue to resolve over time suggest that while it probably aids in barrier restoration in the short term, this dysplastic repair response is ultimately maladaptive, likely contributing to the long-term compromise of pulmonary function seen in some survivors of severe pulmonary injury (Koppe et al, 2016; Liu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

ΔNp63 drives dysplastic alveolar remodeling and restricts epithelial plasticity upon severe lung injury

Weiner

Zhao

Zayas

et al. 2022

Preprint

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Unlike many mammalian vital organs, the lung exhibits a robust, multifaceted regenerative response to severe injuries such as influenza infection, which primarily targets epithelial cells in the airways and alveoli. Quiescent lung-resident epithelial progenitors proliferate, migrate, and differentiate following lung injury, participating in two distinct reparative pathways: functionally beneficial regeneration and dysplastic tissue remodeling. Intrapulmonary airway-resident basal-like p63+ progenitors are one such progenitor cell type that migrates from the airways to form ectopic bronchiolar tissue in the alveoli, generating honeycomb-like cysts that fail to resolve after injury. Though this phenomenon is now well described, the cell-autonomous signals that drive dysplastic alveolar remodeling remain uncertain, a question made especially salient by observations that p63+ progenitors also expand dramatically upon diffuse alveolar damage in humans resulting from a variety of insults including SARS-CoV-2-induced ARDS. Here we show that the master basal cell transcription factor ΔNp63 is required for the immense migratory capacity of intrapulmonary p63+ progenitors and consequently for the dysplastic repair pathway manifest by these cells. We further demonstrate that ΔNp63 restricts the fate plasticity of intrapulmonary p63+ progenitors by regulating their epigenetic landscape, and that loss of ΔNp63 alters the deposition of active and repressive histone modifications at key differentiation gene loci, allowing ΔNp63KO progenitors to proceed towards airway or alveolar differentiation depending on their surrounding environment. These insights into the regulatory mechanisms of dysplastic repair and intrapulmonary p63+ progenitor fate choice highlight potential therapeutic targets to promote more effective alveolar regeneration following severe lung injuries.

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Mesenchyme-free expansion and transplantation of adult alveolar progenitor cells: steps toward cell-based regenerative therapies

et al. 2019

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Alveolar type-2 (AT2) cells are necessary for the lung’s regenerative response to epithelial insults such as influenza. However, current methods to expand these cells rely on mesenchymal co-culture, complicating the possibility of transplantation following acute injury. Here we developed several mesenchyme-free culture conditions that promote growth of murine AT2 organoids. Transplanting dissociated AT2 organoids into influenza-infected mice demonstrated that organoids engraft and either proliferate as AT2 cells or unexpectedly adopt a basal cell-like fate associated with maladaptive regeneration. Alternatively, transplanted primary AT2 cells also robustly engraft, maintaining their AT2 lineage while replenishing the alveolar type-1 (AT1) cell population in the epithelium. Importantly, pulse oximetry revealed significant increase in blood-oxygen saturation in primary AT2 recipients, indicating that transplanted cells also confer increased pulmonary function after influenza. We further demonstrated that both acid installation and bleomycin injury models are also amenable to AT2 transplantation. These studies provide additional methods to study AT2 progenitor potential, while serving as proof-of-principle for adoptive transfer of alveolar progenitors in potential therapeutic applications.

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Pulmonary function in patients with pandemic H1N1

Cited by 5 publications

References 21 publications

Basal-like Progenitor Cells: A Review of Dysplastic Alveolar Regeneration and Remodeling in Lung Repair

Basal-like Progenitor Cells: A Review of Dysplastic Alveolar Regeneration and Remodeling in Lung Repair

ΔNp63 drives dysplastic alveolar remodeling and restricts epithelial plasticity upon severe lung injury

Mesenchyme-free expansion and transplantation of adult alveolar progenitor cells: steps toward cell-based regenerative therapies

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