Murine models of acute and chronic lung infection with cystic fibrosis pathogens

Bragonzi, Alessandra

doi:10.1016/j.ijmm.2010.08.012

Cited by 108 publications

(124 citation statements)

References 84 publications

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…In this regard, chronic models of inflammation in XCGD mice, similarly to cystic fibrosis, may provide information useful for the design of clinical studies, including preparatory regimens to dampen inflammation at HSC collection or transplantation. 45 Finally, our data further validate the use of regulated vectors based on transcriptional or post-transcriptional regulators that allow the adequate expression of a functional transgene while preventing ectopic expression in undifferentiated HSCs. 23 Taken together, our results provide a useful and manageable model that mimics the hallmarks of human disease and demonstrates robust preclinical evidence of efficacy and supports the progression to the clinical settings of gene therapy with regulated lentiviral vectors.…”

Section: Discussionsupporting

confidence: 60%

Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response

Farinelli

Hernández

Rossi³

et al. 2016

Molecular Therapy

Self Cite

View full text Add to dashboard Cite

Chronic granulomatous disease (CGD) is a primary immunodeficiency due to a deficiency in one of the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. CGD patients are characterized by an increased susceptibility to bacterial and fungal infections, and to granuloma formation due to the excessive inflammatory responses. Several gene therapy approaches with lentiviral vectors have been proposed but there is a lack of in vivo data on the ability to control infections and inflammation. We set up a mouse model of acute infection that closely mimic the airway infection in CGD patients. It involved an intratracheal injection of a methicillin-sensitive reference strain of S. aureus. Gene therapy, with hematopoietic stem cells transduced with regulated lentiviral vectors, restored the functional activity of NADPH oxidase complex (with 20-98% of dihydrorhodamine positive granulocytes and monocytes) and saved mice from death caused by S. aureus, significantly reducing the bacterial load and lung damage, similarly to WT mice even at low vector copy number. When challenged, gene therapytreated XCGD mice showed correction of proinflammatory cytokines and chemokine imbalance at levels that were comparable to WT. Examined together, our results support the clinical development of gene therapy protocols using lentiviral vectors for the protection against infections and inflammation.

show abstract

Section: Discussionsupporting

confidence: 60%

Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response

Farinelli

Hernández

Rossi³

et al. 2016

Molecular Therapy

Self Cite

View full text Add to dashboard Cite

show abstract

“…The rat model of biofilm lung infection proposed by Johansen and Høiby (39) was used with minor modifications. The model is reported in the literature to produce a pulmonary infection that is stable for more than a month, and this chronic lung infection mimics what is found in human chronic lung infections, for example, infections in patients with cystic fibrosis (16,17,(39)(40)(41). Briefly, P. aeruginosa cells were immobilized in spherical alginate beads to mimic the biofilm matrix effect and to prevent clearance from the lung after bacterial inoculation into the animals.…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

Torres

Helfer

Bernardes

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 Ϯ 12.1 g · h/ml and 13.3 Ϯ 3.5 g · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor ϭ 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CL lung ) was added to the model for these animals (CL lung ϭ 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.

show abstract

“…Although CF murine models generally do not mimic the severe CF lung disease observed in humans (18), Cftr tm1UNC mice backcrossed on a C57BL/6 background exhibit increased pulmonary inflammatory response and increased susceptibility to lung infections with CF-related bacterial and viral pathogens, including respiratory syncytial virus (RSV) (19). We found that the numbers, maturation, activation, and T cell-stimulatory capacity were altered in CF lung DCs at baseline and after infection with RSV.…”

mentioning

confidence: 89%

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

Krause

Limberis

et al. 2013

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Dysfunction of the cystic fibrosis transmembrane regulator (CFTR) leads to chronic inflammation and infection of the respiratory tract. The role of CFTR for cells of the pulmonary immune system is only partly understood. The present study analyzes the phenotype and immune stimulatory capacity of lung dendritic cells (DCs) from CFTR knockout (CF) mice. Total numbers of conventional DCs, plasmacytoid DCs, and CD103-positive DCs were lower in CF mice compared with wild-type (WT) control mice, as was the expression of major histocompatibility complex class II molecules (MHCII), CD40, and CD86. After pulmonary infection with respiratory syncytial virus, DC numbers increased in WT mice but not in CF mice, and the T cellstimulatory capacity of CF DCs was impaired. The culture of CF lung DCs with bronchoalveolar lavage fluid (BALF) from WT mice increased the expression of MHCII, CD40, and CD86. The supplementation of CF BALF with sphingosine-1-phosphate (S1P), a mediator of immune cell migration and activation that is decreased in CF BALF, rescued the reduced expression of MHCII and CD40 in WT lung DCs and human blood DCs. These findings suggest that DCs are impaired in the CF lung, and that altered S1P affects lung DC function. These findings provide a novel link between defective CFTR and pulmonary innate immune dysfunction in CF.

show abstract

Murine models of acute and chronic lung infection with cystic fibrosis pathogens

Cited by 108 publications

References 84 publications

Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response

Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

Contact Info

Product

Resources

About