Abstract
Background
IL-33, which is known to induce type 2 immune responses via group 2 innate lymphoid cells, has been reported to contribute to neutrophilic airway inflammation in chronic obstructive pulmonary disease. However, its role in the pathogenesis of emphysema remains unclear.
Methods
We determined the role of interleukin (IL)-33 in the development of emphysema using porcine pancreas elastase (PPE) and cigarette smoke extract (CSE) in mice. First, IL-33−/− mice and wild-type (WT) mice were given PPE intratracheally. The numbers of inflammatory cells, and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates, were analyzed; quantitative morphometry of lung sections was also performed. Second, mice received CSE by intratracheal instillation. Quantitative morphometry of lung sections was then performed again.
Results
Intratracheal instillation of PPE induced emphysematous changes and increased IL-33 levels in the lungs. Compared to WT mice, IL-33−/− mice showed significantly greater PPE-induced emphysematous changes. No differences were observed between IL-33−/− and WT mice in the numbers of macrophages or neutrophils in BAL fluid. The levels of hepatocyte growth factor were lower in the BAL fluid of PPE-treated IL-33−/− mice than WT mice. IL-33−/− mice also showed significantly greater emphysematous changes in the lungs, compared to WT mice, following intratracheal instillation of CSE.
Conclusion
These observations suggest that loss of IL-33 promotes the development of emphysema and may be potentially harmful to patients with COPD.
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Background
Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that is not fully reversible, leading to respiratory insufficiency and functional disability [1, 36, 37]. In the present study, however, VEGF levels in the lungs were not different between IL-33−/− and WT mice following instillation of PPE or CS; therefore, VEGF may not have been affected in our emphysema models.
This study had some limitations. First, although IL-33-/- mice displayed enhanced emphysematous changes, this only occurred when IL-33 was completely deficient. Treatment with anti-ST2 receptor antibody did not enhance emphysema development, suggesting that partial IL-33 blockade is not sufficient to induce emphysema. Whether blockade of the IL-33-ST2 axis is harmful or beneficial for COPD in the clinical setting remains unclear. Second, treatment with IL-33 did not significantly suppress emphysema development. However, modifications to the dose and timing of IL-33 administration may produce different outcomes. Thus, the effects of IL-33 supplementation for COPD remain unclear. Third, we have not assessed the CS-induced emphysema model, which more closely mimics human emphysema. We have shown that a congenital IL-33 defect might enhance elastase- and CSE-induced emphysema. Collectively, our results indicate that clinical manipulations of the IL-33-ST2 axis may have varying effects on lung structure.
Conclusions
We demonstrated that the loss of IL-33 may enhance the development of emphysema. Our data suggested that although IL-33 may affect CS-induced airway inflammation, complete loss of IL-33 may enhance emphysema and potentially be harmful in patients with COPD.
Abbreviations
- ANOVA:
-
One-way analysis of variance
- BAL:
-
Bronchoalveolar lavage
- COPD:
-
Chronic obstructive pulmonary disease
- CS:
-
Cigarette smoke
- CSE:
-
Cigarette smoke extract
- Cst:
-
Static lung compliance
- CXCL5:
-
C-X-C motif ligand 5
- ELISA:
-
Enzyme-linked immunosorbent assay
- H&E:
-
Hematoxylin and eosin
- HGF:
-
Hepatocyte growth factor
- IL:
-
Interleukin
- ILC2:
-
Group 2 innate lymphoid cell
- KC:
-
Keratinocyte chemoattractant
- Lm:
-
Mean linear intercept
- MCP-1:
-
Chemoattractant protein-1
- MIP-2:
-
Macrophage inflammatory protein-2
- NK:
-
Natural killer
- MMP-9:
-
Matrix metalloproteinase-9
- PBS:
-
Phosphate-buffered saline
- PPE:
-
Porcine pancreas elastase
- TIMP-1:
-
Tissue inhibitor of metalloproteinase-1
- TNF-α:
-
Tumor necrosis factor-alpha
- VEGF:
-
Vascular endothelial growth factor
- WT:
-
Wild-type
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Acknowledgements
The authors gratefully thank Eri Ando, Suzuka Yukimaru, and Mao Yabuuchi for their technical assistance.
Funding
The work reported here was supported in part by Novartis Pharma Research Grants 2019 (to N. Miyahara).
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Conceived and designed the research: NM, DM. Performed the experiments: DM, NM, AT, UF, NO, SS. Analyzed the data: DM, NM, AT, UF, NO, KK, NM. Interpreted the results of the experiments: DM, AK, YK, MY, MH, TS, SA, KK, YM, NM. Prepared the figures: DM, NO, AT, NM. Drafted the manuscript: DM, AT, NM. Approved the final version of the manuscript: DM, AT, NO, UF, SS, JI, AK, YK, MY, MH, TS, SA, KK, YM, NM. All authors read and approved the final manuscript.
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This study was approved by the Institutional Animal Care and Use Committee of Okayama University Medical School. Approved number is OKU-2014526.
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Additional file 1.
Treatment with anti-ST2 antibody in PPE-instilled mice. The mice received intraperitoneal injection of anti-ST2 antibody or IgG antibody on days -1, 1, 2, 4, 7, and 10 following instillation of PBS or PPE. BAL and lung morphometric measurements were performed on day 21 as described in the Materials and Methods. (A) Cell composition in BAL fluid. (B) Lm values. Data are shown as the mean ± SEM (n = 8 in each group). PBS/IgG: PBS-instilled mice treated with IgG. PPE/IgG: PPE-instilled mice treated with IgG. PPE/anti-ST2: PPE-instilled mice treated with anti-ST2 antibody. *P < 0.05 compared to PBS/PBS; There were no significant differences between PPE/IgG and PPE/anti-ST2.
Additional file 2.
Morphometric assessment of emphysema induced by intraperitoneal administration of cigarette smoke extract (CSE). The experimental protocol.
Additional file 3.
(B) Representative images of H&E-stained lung tissue (magnification: ×200).
Additional file 4.
(C) Lm values. WT PBS: WT mice treated with PBS. IL-33-/- PBS: IL-33-/- mice treated with PBS. WT CSE: WT mice treated with CSE. IL-33-/- CSE: IL-33-/- mice treated with CSE. The results for each group are shown as the mean ± SEM; n = 6–9 in each group. *P < 0.05 compared to WT PBS; **P < 0.05 compared to IL-33−/− PBS; #P < 0.05 compared to WT PPE.
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Morichika, D., Taniguchi, A., Oda, N. et al. Loss of IL-33 enhances elastase-induced and cigarette smoke extract-induced emphysema in mice. Respir Res 22, 150 (2021). https://doi.org/10.1186/s12931-021-01705-z
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DOI: https://doi.org/10.1186/s12931-021-01705-z