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. 2022 Nov 12;11(11):1334.
doi: 10.3390/pathogens11111334.

Long-Term Pulmonary Dysfunction by Hyperoxia Exposure during Severe Viral Lower Respiratory Tract Infection in Mice

Thijs A Lilien  1   2 , Miša Gunjak  2   3   4 , Despoina Myti  2   3   4 , Francisco Casado  2   3   4 , Job B M van Woensel  1 , Rory E Morty  2   4 , Reinout A Bem  1
Affiliations

Long-Term Pulmonary Dysfunction by Hyperoxia Exposure during Severe Viral Lower Respiratory Tract Infection in Mice

Thijs A Lilien et al. Pathogens. .

Abstract

Viral-induced lower respiratory tract infection (LRTI), mainly by respiratory syncytial virus (RSV), causes a major health burden among young children and has been associated with long-term respiratory dysfunction. Children with severe viral LRTI are frequently treated with oxygen therapy, hypothetically posing an additional risk factor for pulmonary sequelae. The main goal of this study was to determine the effect of concurrent hyperoxia exposure during the acute phase of viral LRTI on long-term pulmonary outcome. As an experimental model for severe RSV LRTI in infants, C57Bl/6J mice received an intranasal inoculation with the pneumonia virus of mice J3666 strain at post-natal day 7, and were subsequently exposed to hyperoxia (85% O2) or normoxia (21% O2) from post-natal day 10 to 17 during the acute phase of disease. Long-term outcomes, including lung function and structural development, were assessed 3 weeks post-inoculation at post-natal day 28. Compared to normoxic conditions, hyperoxia exposure in PVM-inoculated mice induced a transient growth arrest without subsequent catchup growth, as well as a long-term increase in airway resistance. This hyperoxia-induced pulmonary dysfunction was not associated with developmental changes to the airway or lung structure. These findings suggest that hyperoxia exposure during viral LRTI at young age may aggravate subsequent long-term pulmonary sequelae. Further research is needed to investigate the specific mechanisms underlying this alteration to pulmonary function.

Keywords: airway resistance; bronchiolitis; hyperoxia; oxygen; pneumovirus; respiratory syncytial viruses; respiratory tract infection.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Daily total body weight of mice per group: RPMI non-infected controls and PVM-infected mice with either normoxia exposure (NOX: 21% O2) or hyperoxia exposure (HYX: 85% O2). Grey area represents the duration of hyperoxia exposure. Mean weight with 95% CI are shown. NOX-RPMI (N = 30), HYX-RPMI (N = 28), NOX-PVM (N = 28), HYX-PVM (N = 31). a, p < 0.05 HYX-PVM vs. NOX-RPMI; b, p < 0.05 HYX-PVM vs. NOX-RPMI, HYX-RPMI; c, p < 0.05 HYX-PVM vs. all conditions.
Figure 2
Figure 2
Parameters based on single frequency FOT: (a) Compliance (Crs); (b) Elastance (Ers); and (c) Resistance (Rrs) of the respiratory system per group. RPMI non-infected controls and PVM-infected mice with either normoxia exposure (NOX: 21% O2) or hyperoxia exposure (HYX: 85% O2). Mean with 95% CI are shown. NOX-RPMI (N = 9), HYX-RPMI (N = 6), NOX-PVM (N = 6), HYX-PVM (N = 9). *, p < 0.05.
Figure 3
Figure 3
Parameters based on broadband frequency FOT: (a) Airway resistance (Rn); (b) Tissue damping (G); and (c) Tissue elastance (H) per group. RPMI non-infected controls and PVM-infected mice with either normoxia exposure (NOX: 21% O2) or hyperoxia exposure (HYX: 85% O2). Mean with 95% CI are shown. NOX-RPMI (N = 9), HYX-RPMI (N = 6), NOX-PVM (N = 6), HYX-PVM (N = 9). **, p < 0.01; ***, p < 0.001.
Figure 4
Figure 4
Real impedance based on broadband frequency FOT per group: RPMI non-infected controls and PVM-infected mice with either normoxia exposure (NOX: 21% O2) or hyperoxia exposure (HYX: 85% O2). Mean with 95% CI are shown. NOX-RPMI (N = 9), HYX-RPMI (N = 6), NOX-PVM (N = 6), HYX-PVM (N = 9). # p < 0.05 HYX-PVM vs. NOX-RPMI and HYX-RPMI, * p < 0.05 HYX-PVM vs. all conditions.
Figure 5
Figure 5
Representative pictures of design-based stereology per group: RPMI non-infected controls and PVM-infected mice with either normoxia exposure (NOX: 21% O2) or hyperoxia exposure (HYX: 85% O2). N = 5 for all conditions. (A,C,E,G): 100× magnification; (B,D,F,H): 400× magnification. Scale bar represents 200 µm.
Figure 6
Figure 6
Representative pictures of H&E staining per group: RPMI non-infected controls and PVM-infected mice with either normoxia exposure (NOX: 21% O2) or hyperoxia exposure (HYX: 85% O2). N = 5 for all conditions. (A,C,E,G): 100× magnification; (B,D,F,H): 400× magnification. Scale bar represents 200 µm.
Figure 7
Figure 7
Representative pictures of (A,C,E,G): MT staining for collagen (blue) and (B,D,F,H): immunohistochemistry staining for α-SMA (brown) per group: RPMI non-infected controls and PVM-infected mice with either normoxia exposure (NOX: 21% O2) or hyperoxia exposure (HYX: 85% O2). N = 5 for all conditions. All pictures are at 400 × magnification. Scale bar represents 200 µm.
See this image and copyright information in PMC

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