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Updated: Aug 7, 2025
In vivo Measurement of the Mouse Pulmonary Endothelial Surface Layer
Published on: February 22, 2013
Vascular Endothelial Growth Factor A Contributes to Increased Mammalian Respiratory Epithelial Permeability Induced
Lin Lin1, Jie Yang1, Dajun Zhang1
1State Key Laboratory of Agricultural Microbiology, The Cooperative Innovation Center for Sustainable Pig Production, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
Abstract:
Pasteurella multocida infection can cause significant zoonotic respiratory problems in both humans and animals, but little is known about the mechanisms used by P. multocida to invade and cross the mammalian respiratory barrier. In this study, we investigated the influence of P. multocida infection on the dysfunction of the respiratory epithelial barrier. In vivo tests in mouse infection models demonstrated that P. multocida infection significantly increased epithelial permeability and increased the expression of vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) in murine tracheae and lungs. In murine lung epithelial cell (MLE-12) models, P. multocida infection decreased the expression of tight junctions (ZO-1) and adherens junctions (β-catenin and E-cadherin) proteins but induced the activation of hypoxia-inducible factor 1α (HIF-1α) and VEGFA signaling. When the expression of HIF-1α is suppressed, the induction of VEGFA and ZO-1 expression by P. multocida infection is decreased. We also found that intervention of HIF-1α and VEGFA signaling affected infection outcomes caused by respiratory bacteria in mouse models. Most importantly, we demonstrate that P. multocida infection increases the permeability of human respiratory epithelial cells and that this process is associated with the activation of HIF-1α and VEGFA signaling and likely contributes to the pathogenesis of P. multocida infection in humans. IMPORTANCE The mammalian respiratory epithelium forms the first line of defense against infections with P. multocida, an important zoonotic respiratory pathogen. In this study, we found that P. multocida infection increased respiratory epithelial permeability and promoted the induction of the HIF-1α-VEGFA axis in both mouse and murine cell models. Similar findings were also demonstrated in human respiratory epithelial cells. The results from this study provide important knowledge about the pathogenesis of P. multocida causing infections in both animals and humans.
Insights
Pasteurella multocida infection disrupts the respiratory barrier by increasing permeability and activating the HIF-1α-VEGFA pathway in both animal and human cells, contributing to zoonotic respiratory disease. This study reveals key pathogenic mechanisms.
Area of Science:
- Microbiology
- Pathogenesis
- Zoonotic Diseases
Background:
- Pasteurella multocida is a zoonotic pathogen causing respiratory issues in humans and animals.
- Mechanisms of P. multocida invasion and crossing of the mammalian respiratory barrier are poorly understood.
- The respiratory epithelial barrier is crucial for defense against P. multocida.
Purpose of the Study:
- To investigate how P. multocida infection affects respiratory epithelial barrier function.
- To elucidate the molecular mechanisms underlying P. multocida-induced respiratory barrier dysfunction.
- To determine the role of the HIF-1α-VEGFA signaling pathway in P. multocida pathogenesis.
Main Methods:
- In vivo mouse infection models to assess epithelial permeability and gene expression.
- In vitro murine lung epithelial cell (MLE-12) models to study protein expression and signaling pathways.
- Investigated the impact of suppressing HIF-1α expression.
- Tested interventions targeting HIF-1α and VEGFA signaling.
- Utilized human respiratory epithelial cells to validate findings.
Main Results:
- P. multocida infection significantly increased epithelial permeability in mice.
- Increased expression of VEGFA and eNOS observed in infected murine tracheae and lungs.
- Decreased expression of tight junction (ZO-1) and adherens junction (β-catenin, E-cadherin) proteins in MLE-12 cells.
- Induced activation of HIF-1α and VEGFA signaling in MLE-12 cells.
- Suppression of HIF-1α reduced VEGFA and ZO-1 induction by P. multocida.
- P. multocida infection increased permeability of human respiratory epithelial cells via HIF-1α and VEGFA activation.
Conclusions:
- P. multocida infection compromises the respiratory epithelial barrier integrity.
- The HIF-1α-VEGFA signaling axis is a key mediator of P. multocida-induced barrier dysfunction.
- These findings are relevant to both animal and human P. multocida infections.
- Understanding these mechanisms is crucial for developing therapeutic strategies against P. multocida.
