Persistent Pathology in Influenza-Infected Mouse Lungs

Kanegai, Cindy M; Xi, Ying; Donne, Matthew; Gotts, Jeffrey E.; Driver, Ian; Amidzic, Gorica; Lechner, Andrew J.; Jones, Kirk D.; Vaughan, Andrew E.; Chapman, Harold A.; Rock, Jason R.

doi:10.1165/rcmb.2015-0387le

Cited by 69 publications

(99 citation statements)

References 10 publications

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“…These pod-derived structures are also likely to be consistent with the pathological finding known as 'bronchiolization' in which new cystic airway structures are produced in lung disease. These disease-associated 'neo-bronchioles' are characteristically lined by a ciliated respiratory epithelium, as was the case in the corresponding murine experiments (Kanegai et al, 2016). Interestingly, following infection with a less virulent H3N2 influenza strain, X31, no pods were observed (Kanegai et al, 2016).…”

Section: Transdifferentiation and Transdetermination Of Airway Cellsmentioning

confidence: 77%

“…In this case, the relevant LNEPs were marked by a Krt5-CreER driver, but lacked obvious KRT5 protein, thus making them 'lineage negative'. Strikingly, the authors proposed that LNEP-derived pods gave rise to a 'failed regenerative' process following H1N1 influenza infection (Kanegai et al, 2016;Vaughan et al, 2015). Indeed, the authors showed that these pods formed 'cysts' that persist long term (200 days) and generated structures that appear similar to the honeycomb lesions that characterize fibrotic human lungs (Fig.…”

Section: Transdifferentiation and Transdetermination Of Airway Cellsmentioning

confidence: 99%

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Plasticity in the lung: making and breaking cell identity

2017

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In contrast to a prior emphasis on the finality of cell fate decisions in developmental systems, cellular plasticity is now emerging as a general theme in the biology of multiple adult organ systems. In the lung, lineage tracing has been used to identify distinct epithelial stem and progenitor cell populations. These cells, together with their differentiated progeny, maintain a stable identity during steady state conditions, but can display remarkable lineage plasticity following injury. This Review summarizes our current understanding of the different cell lineages of the adult mammalian lung and their responses to injury. In the lung, which is constantly exposed to infection and aerosolized toxins, epithelial plasticity might be more of a rule than an exception, and it is likely that different injuries elicit different facultative responses.

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Section: Transdifferentiation and Transdetermination Of Airway Cellsmentioning

confidence: 77%

Section: Transdifferentiation and Transdetermination Of Airway Cellsmentioning

confidence: 99%

Plasticity in the lung: making and breaking cell identity

2017

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“…29 Recently, it was shown that these Krt5 pods are not observed during lung injury induced by less virulent X31 influenza in mice, suggesting that the severity of lung injury may dictate the cellular repair process. 31 It is possible that the persistent ER stress observed herein may modulate the ability of the progenitor cells to differentiate and to form alveolar structure.…”

Section: Discussionmentioning

confidence: 93%

Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery from Influenza Infection

Pociask

Robinson

Chen

et al. 2017

The American Journal of Pathology

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Seasonal and pandemic influenza is a cause of morbidity and mortality worldwide. Most people infected with influenza virus display mild-to-moderate disease phenotypes and recover within a few weeks. Influenza is known to cause persistent alveolitis in animal models; however, little is known about the molecular pathways involved in this phenotype. We challenged C57BL/6 mice with influenza A/PR/8/34 and examined lung pathologic processes and inflammation, as well as transcriptomic and epigenetic changes at 21 to 60 days after infection. Influenza induced persistent parenchymal lung inflammation, alveolar epithelial metaplasia, and epithelial endoplasmic reticulum stress that were evident after the clearance of virus and resolution of morbidity. Influenza infection induced robust changes in the lung transcriptome, including a significant impact on inflammatory and extracellular matrix protein expression. Despite the robust changes in lung gene expression, preceding influenza (21 days) did not exacerbate secondary Staphylococcus aureus infection. Finally, we examined the impact of influenza on miRNA expression in the lung and found an increase in miR-155. miR-155 knockout mice recovered from influenza infection faster than controls and had decreased lung inflammation and endoplasmic reticulum stress. These data illuminate the dynamic molecular changes in the lung in the weeks after influenza infection and characterize the repair process, identifying a novel role for miR-155. (Am J Pathol 2017, 187: 851e863; http://dx

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“…In animal models of limited injury, the lung mobilizes several cellular sources including basal cells, club cells, and alveolar type 2 (AT2 or AEC2) cells to repair the local damage 1 . However, when faced with extensive injury caused by sublethal influenza infection and, to a lesser extent, bleomycin exposure, the lung resorts to a unique distal stem/progenitor cell population that expands rapidly to form KRT5 cell clusters in the damaged alveolar region 2, 3, 5–7 . This injury response is remarkable and has generated substantial interest for several reasons.…”

mentioning

confidence: 99%

“…Third, unlike conventional epithelial cells, such activated cells are highly mobile. Finally, although capable of differentiation into functional alveolar cells, the KRT5 cells remain mostly as an undifferentiated dysplastic epithelium in vivo 7 . For these reasons, origin, activation, expansion, and differentiation of this stem/progenitor cell population have remained unclear and are now tackled in this study.…”

mentioning

confidence: 99%