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Phenotyping Mouse Pulmonary Function In Vivo with the Lung Diffusing Capacity
Published on: January 6, 2015
Iron overload is associated with increased susceptibility to pulmonary Pythium insidiosum infection in mice
Donglin Zhu1, Ling Yan2, Jian Sun3
1Department of Clinical Laboratory, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Background:
Pythium insidiosum is a fungus-like oomycete capable of causing disease with high mortality rates. Although pulmonary Pythium insidiosum infections are rare, they are associated with an extremely high fatality rate. The mechanisms underlying Pythium insidiosum infection remain unclear and may be associated with immune dysregulation or iron overload. Existing animal models do not adequately replicate the pathophysiological process of pulmonary invasive infection by Pythium insidiosum in humans. Therefore, this study aims to establish a murine model of pulmonary Pythium insidiosum infection and to investigate the role of the Th1/Th2 immune balance in the progression of pulmonary infection.
Methods:
BALB/c mice were divided into the following groups: control group, iron dextran (ID) group, cyclophosphamide (CTX) group, lipopolysaccharide (LPS) group, and groups affected by various factor combinations (e.g., LPS + CTX group, ID + CTX group, ID + LPS group). Mice were inoculated intratracheally with Pythium insidiosum hyphae after pretreatment. Body weight, clinical symptoms, inflammatory cell counts in venous blood and bronchoalveolar lavage fluid (BALF), pulmonary histopathological damage, pathogen burden, as well as serum levels of ferritin (FER), Th1 cytokines (IL-2, IL-12p70, IFN-γ, TNF-α) and Th2 cytokines (IL-4, IL-5, IL-13, IL-10) were assessed in each group.
Results:
Among all groups, LPS + CTX and ID + CTX groups exhibited severe infection symptoms, significant weight loss, and the highest clinical symptom scores (all P < 0.001). The ID + CTX group showed more pronounced increases in hematoxylin eosin (HE)-stained lung injury scores and Grocott's Methenamine Silver (GMS)-stained hyphal burden scores (all P < 0.001). Compared with the control group, the ID + CTX group demonstrated decreased venous blood leukocyte (WBC), neutrophil (NEUT), and lymphocyte (LYMPH) counts, elevated FER levels, and significantly reduced LYMPH counts in BALF (all P < 0.01). Cytokine analysis revealed that Th1 cytokine (IFN-γ, TNF-α) levels were significantly suppressed in the ID + CTX group after preconditioning (both P < 0.001). Following infection, Th1 responses remained relatively suppressed, while Th2 responses showed an upward trend that did not reach statistical significance (all P > 0.05), more consistent with a relative Th2 shift resulting from Th1 suppression.
Conclusion:
This study established a murine model of pulmonary Pythium insidiosum infection for the first time through intratracheal hyphae inoculation following ID + CTX preconditioning. The findings suggest that iron overload is associated with Th1 immune response suppression and relative Th2 shift, which may be related to increased susceptibility and pathological damage in pulmonary Pythium insidiosum infection. However, further functional experiments are needed to validate causal relationships.
Insights
This study developed a new mouse model for pulmonary Pythium insidiosum infection. Iron overload was linked to suppressed Th1 immunity and increased susceptibility, suggesting a role in severe lung disease.
Area of Science:
- Immunology
- Infectious Diseases
- Pathology
Background:
- Pythium insidiosum causes high-mortality infections, particularly in the lungs, with unclear mechanisms.
- Existing animal models fail to fully replicate human pulmonary Pythium insidiosum infections.
- Immune dysregulation and iron overload are suspected factors in disease pathogenesis.
Purpose of the Study:
- Establish a novel murine model for pulmonary Pythium insidiosum infection.
- Investigate the role of the Th1/Th2 immune balance in infection progression.
- Explore the impact of iron overload and immune modulators on infection severity.
Main Methods:
- BALB/c mice were preconditioned with iron dextran (ID) and/or cyclophosphamide (CTX) and lipopolysaccharide (LPS).
- Mice were inoculated intratracheally with Pythium insidiosum hyphae.
- Evaluated clinical symptoms, inflammatory markers, histopathology, pathogen burden, and Th1/Th2 cytokine profiles.
Main Results:
- The ID+CTX group showed severe infection, significant weight loss, and increased lung injury and pathogen burden.
- This group exhibited decreased leukocytes, elevated ferritin, and reduced Th1 cytokines (IFN-γ, TNF-α).
- A trend towards Th2 response shift was observed, correlating with Th1 suppression.
Conclusions:
- A new murine model for pulmonary Pythium insidiosum infection was successfully established using ID+CTX preconditioning.
- Iron overload appears to suppress Th1 immunity, leading to a relative Th2 shift and increased susceptibility.
- Findings suggest iron overload contributes to severe pulmonary Pythium insidiosum infection, warranting further investigation.
