Animal models of hospital-acquired pneumonia: current practices and future perspectives

Bielen, Kenny; Jongers, Bart ‘s; Malhotra-Kumar, Surbhi; Goossens, Herman; Kumar‐Singh, Samir

doi:10.21037/atm.2017.03.72

Cited by 36 publications

(32 citation statements)

References 118 publications

(114 reference statements)

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“…Moreover, peripheral or central administration of M1 and M2 cells have also been shown to have beneficial, deleterious or no effect, suggesting that the evolution and functions of different subsets of microglia and brain macrophages in post-stroke brain are more complex than initially thought [ 15 , 39 , 40 ]. In this study, ≈50% of animals by day 3–4 developed pneumonia [ 24 , 25 ]. These data suggest that spontaneous development of infection due to stroke-induced immunosuppression, also shown earlier [ 13 ], is a major confounding factor for macrophage polarization studies.…”

Section: Discussionmentioning

confidence: 98%

“…Studies were performed on mixed gender Wistar rats aged 8–12 weeks with mean weight of 271 ± 39 g. Animals had ad libitum access to food and water before and after surgery and were housed in groups until 2 days before surgery, when they were housed individually. Animals that were febrile and/or showed histological evidence of pneumonia, as described by us previously [ 24 , 25 ], were excluded from the study. Animals belonged to sham or experimental stroke group (n = 6 per group for each study time point) and healthy control group (n = 6).…”

Section: Methodsmentioning

confidence: 99%

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CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia

Boddaert¹,

Bielen²,

Jongers³

et al. 2018

PLoS ONE

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Classical or M1 activity of microglia/macrophages has been described in several neurodegenerative and brain inflammatory conditions and has also been linked to expansion of ischemic injury in post-stroke brain. While different pathways of M1 polarization have been suggested to occur in the post-stroke brain, the precise underlying mechanisms remain undefined. Using a transient middle cerebral artery occlusion (MCAO) rat model, we showed a progressive M2 to M1 polarization in the perilesional brain region with M1 cells becoming one of the dominant subsets by day 4 post-stroke. Comparing key receptors involved in M1 polarization (CD8, IFNγR, Clec4, FcγR, TLR3 and TLR4) and their signal transducers (Syk, Stat1, Irf3, and Traf6) at the day 4 time point, we showed a strong upregulation of CD8 along with SYK transducer in dissected perilesional brain tissue. We further showed that CD8 expression in the post-stroke brain was associated with activated (CD68+) macrophages and that progressive accumulation of CD8+CD68+ cells in the post-stroke brain coincided with increased iNOS (M1 marker) and reduced Arg1 (M2 marker) expression on these cells. In vitro ligand-based stimulation of the CD8 receptor caused increased iNOS expression and an enhanced capacity to phagocytose E. coli particles; and interestingly, CD8 stimulation was also able to repolarize IL4-treated M2 cells to an M1 phenotype. Our data suggest that increased CD8 signaling in the post-stroke brain is primarily associated with microglia/macrophages and can independently drive M1 polarization, and that modulation of CD8 signaling could be a potential target to limit secondary post-stroke brain damage.

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Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia

Boddaert¹,

Bielen²,

Jongers³

et al. 2018

PLoS ONE

Self Cite

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“…As controls, animals ( n = 8) received identical bacterial instillation without prior ventilation (P A group). Anesthesia was reversed using 300 μg/kg atipamezole and animals were monitored for clinical signs of pneumonia [7,45] until 24 h post-infection when they were euthanized, tissue collected, and analyzed.…”

Section: Methodsmentioning

confidence: 99%

Mechanical Ventilation Impairs IL-17 Cytokine Family Expression in Ventilator-Associated Pneumonia

Winter

Jongers

Bielen

et al. 2019

IJMS

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Mechanical ventilation (MV) is the primary risk factor for the development of ventilator-associated pneumonia (VAP). Besides inducing a pro-inflammatory T-helper (Th)-1 cytokine response, MV also induces an anti-inflammatory Th2 cytokine response, marked by increased IL-4 secretion and reduced bacterial phagocytic capacity of rodent lung macrophages. Since IL-4 is known to downregulate both Th1 and Th17 cytokines, the latter is important in mediating mucosal immunity and combating bacterial and fungal growth, we studied and showed here in a rat model of MV that Th17 cytokines (IL-17A, IL-17F, and IL-22) were significantly upregulated in the lung as a response to different MV strategies currently utilized in clinic. To study whether the increased IL-4 levels are associated with downregulation of the anti-bacterial Th17 cytokines, we subsequently challenged mechanically ventilated rats with an intratracheal inoculation of Pseudomonas aeruginosa (VAP model) and showed a dramatic downregulation of IL-17A, IL-17F, and IL-22, compared to animals receiving the same bacterial burden without MV. For the studied Th1 cytokines (IFNγ, TNFα, IL-6, and IL-1β), only IFNγ showed a significant decrease as a consequence of bacterial infection in mechanically ventilated rats. We further studied IL-17A, the most studied IL-17 family member, in intensive care unit (ICU) pneumonia patients and showed that VAP patients had significantly lower levels of IL-17A in the endotracheal aspirate compared to patients entering ICU with pre-existing pneumonia. These translational data, obtained both in animal models and in humans, suggest that a deficient anti-bacterial Th17 response in the lung during MV is associated with VAP development.

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“…(27) In addition, IL-6 also activates T lymphocytes with the formation of plasma cells and antibodies. (28,29) In high doses it modulates the expression of hepatocyte-specific genes, which encode proteins of the acute phase of inflammation and, thereby, provide the transformation of inflammation into a chronic form. (30,31) The administration of Kezacin in animals with bronchopneumonia, in comparison with untreated animals, was accompanied by a statistically significant increase in the levels of IL-1β (by 3.43 times), IL-2 (by 1.95 times), INF-γ (by 3.29 times), and MCP-1 (by 2.07 times) and a decrease in the levels of TNFα (by 1.85 times) and IL-6 (by 2.20 times) (Fig.1).…”

Section: Resultsmentioning

confidence: 99%

Cytokine Profile and Its Correction by Immunomodulators in Experimental Bronchopulmonary Inflammation in Rats

Darenskaya¹,

Mokrenko²,

Shabanov³

et al. 2019

IJBM

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The aim of this study was to assess the changes in the levels of the blood serum pro-and anti-inflammatory cytokines in rats with experimental bronchopneumonia and after administration of immunomodulators. Materials and Methods: Research was carried out on mature male Wistar rats (n=111), weighing 220-250g. The bronchopulmonary inflammation in the rats was modeled by administration of 0.1 ml of gum turpentine in the rats' trachea under etherization. All rats were divided into four groups: Group 1 included intact animals (n=18); Group 2 included animals having bronchopneumonia (n=19); Group 3 included animals having bronchopneumonia treated with Krezacin (n=15); Group 4 included animals having bronchopneumonia treated with Metaprot (n=16). Right after the operation and for the next 5 days, a solution of one of the test immunomodulators was injected (once a day) abdominally in the experimental animals: 25mg/kg of Krezacin or 25mg/kg of Metaprot. On Day 5 of the experiment, the animals were decapitated under anesthesia and blood samples were collected. The concentration of cytokines in the blood was determined by the flow immunofluorometry method with the device Bio-RadLaboratories (USA). Results: The administration of Krezacin in animals with bronchopneumonia, in comparison with untreated animals, was accompanied by a statistically significant increase in the levels of IL-1β (by 3.43 times), IL-2 (by 1.95 times), INF-γ (by 3.29 times), and MCP-1 (by 2.07 times) and a decrease in the levels of TNFα (by 1.85 times) and IL-6 (by 2.20 times). Administration of Krezacin increased anti-inflammatory cytokines considerably: IL-4 by 5.22 times and IL-10 by 2.41 times. Analysis of results after administration of Metaprot demonstrates an increase in the levels of IL-1β (by 2.57 times), IL-2 (by 2 times), INF-γ (by 3.21 times), and MCP-1 (by 1.98 times) and a decrease in the levels of TNFα (by 2.17 times) and IL-6 (by 2.5 times), compared to data on untreated animals. Anti-inflammatory cytokines also increased greatly: IL-4 by 5.3 times and IL-10 by 3.71 times. Conclusion: The results obtained show that investigated preparations reduce the severity and intensity of bronchopneumonia in rats. Krezacin and Metaprot demonstrate the properties of true immunomodulators, increasing protective properties of cytokines and providing the adaptive response of the body in severe bronchopulmonary pathology.

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Animal models of hospital-acquired pneumonia: current practices and future perspectives

Cited by 36 publications

References 118 publications

CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia

CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia

Mechanical Ventilation Impairs IL-17 Cytokine Family Expression in Ventilator-Associated Pneumonia

Cytokine Profile and Its Correction by Immunomodulators in Experimental Bronchopulmonary Inflammation in Rats

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