- Title
- Alveolar epithelial cells of lung fibrosis patients are susceptible to severe virus-induced injury
- Creator
- Read, Jane; Reid, Andrew T.; Schuliga, Michael; Thomson, Claire; Plit, Marshall; Mejia, Ross; Knight, Darryl A.; Lize, Muriel; Kasmi, Karim E.; Grainge, Christopher; Stahl, Heiko
- Relation
- Clinical Science Vol. 138, Issue 8, p. 537-554
- Publisher Link
- http://dx.doi.org/10.1042/CS20240220
- Publisher
- Portland Press Ltd
- Resource Type
- journal article
- Date
- 2024
- Description
- Patients with pulmonary fibrosis (PF) often experience exacerbations of their disease, characterised by a rapid, severe deterioration in lung function that is associated with high mortality. Whilst the pathobiology of such exacerbations is poorly understood, virus infection is a trigger. This study investigated virus-induced injury responses of alveolar and bronchial epithelial cells (AECs and BECs respectively) from patients with PF and age-matched controls (Ctrls). Air liquid interface (ALI) cultures of AECs, comprising type I and II pneumocytes or BECs were inoculated with influenza A virus (H1N1) at 0.1 multiplicity of infection (MOI). Levels of interleukin-6 (IL-6), IL-36γ and IL-1β were elevated in cultures of AECs from PF patients (PF-AECs, n=8-11), being markedly higher than Ctrl-AECs (n=5-6), 48 h post inoculation (pi) (P<0.05); despite no difference in H1N1 RNA copy numbers 24 h pi. Furthermore, the virus-induced inflammatory responses of PF-AECs were greater than BECs (from either PF patients or controls), even though viral loads in the BECs were overall 2 to 3-fold higher than AECs. Baseline levels of the senescence and DNA damage markers, nuclear p21, p16 and H2AXγ were also significantly higher in PF-AECs than Ctrl-AECs and further elevated post-infection. Senescence induction using etoposide augmented virus-induced injuries in AECs (but not viral load), whereas selected senotherapeutics (rapamycin and mitoTEMPO) were protective. This study provides evidence that senescence increases the susceptibility of AECs from PF patients to severe virus-induced injury and suggests targeting senescence may provide an alternative option to prevent or treat the exacerbations that worsen the underlying disease.
- Subject
- alveolar epithelium; influenza; pulmonary fibrosis; senescence; senotherapeutic; virus
- Identifier
- http://hdl.handle.net/1959.13/1502865
- Identifier
- uon:55279
- Identifier
- ISSN:0143-5221
- Language
- eng
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