Lung defenses against Pseudomonas aeruginosa in C5-deficient mice with different genetic backgrounds

Cerquetti, M C; Sordelli, D O; Bellanti, Joseph A.; Hooke, Anne Morris

doi:10.1128/iai.52.3.853-857.1986

Cited by 34 publications

(15 citation statements)

References 25 publications

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“…The deleterious effects of the C5 deficiency on the mortality rate, on the bacterial clearance, and on the magnitude of neutrophil influx have been reported in congenic B10.D2 strains following infection with P. aeruginosa (6,17). However, the effect of C5 on the host response may be modulated by the mouse genetic background.…”

Section: Discussionmentioning

confidence: 99%

“…Mice have been used to study the genetic factors regulating the natural resistance to P. aeruginosa in peritoneal and corneal infections (3,4,23,26). Other studies have dealt with aerosol or intratracheal infection of mice with free P. aeruginosa (6,11,17,33,34,36). A chronic mouse model of pulmonary infection with P. aeruginosa entrapped in beads has also been developed (38) and used thereafter to study protection conferred by immunization (25).…”

mentioning

confidence: 99%

“…We have modified this latter mouse model (38) to study the endobronchial inflammation induced by P. aeruginosa infection in different inbred strains of mice. Entrapment of P. aeruginosa in agar beads allows an increase in the interaction time between the host and the pathogen (12), since planktonic bacteria are rapidly cleared from the lungs (by 4 h) following infection of an immunocompetent host (6,11,34). This model may also allow the determination of the genetic regulation of the mechanism(s) underlying the early host response to P. aeruginosa infection.…”

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confidence: 99%

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Endobronchial inflammation following Pseudomonas aeruginosa infection in resistant and susceptible strains of mice

1995

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The early endobronchial inflammation induced by Pseudomonas aeruginosa infection varies in resistant and susceptible strains of mice. Mice of the DBA/2 strain are severely afflicted by the infection, with a high bacterial burden accumulating rapidly following inoculation and a high mortality rate occurring. Mice of the BALB/c strain are resistant to infection and clear the bacteria within 3 to 7 days. Infection of (BALB/c ؋ DBA/2)F 1 hybrid mice showed that the resistance to lung P. aeruginosa infection is inherited as a dominant trait. Mice of the A/J and C57BL/6 strains were found to have an intermediate phenotype to Pseudomonas aeruginosa infection when compared with BALB/c and DBA/2 strains. The decrease in the bacterial load seen early after infection coincided with a steady and strong recruitment of inflammatory cells to the bronchoalveolar spaces of mice of the resistant BALB/c strain. On the other hand, the recruitment of inflammatory cells to the lungs of mice of the susceptible DBA/2 strain was deficient, resulting in the failure to control bacterial multiplication. Chemotactic factors, proinflammatory cytokines, and the number and function of recruited inflammatory cells may play major roles in the determination of the genetic resistance to lung infection with P. aeruginosa in a normal immunocompetent host.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Endobronchial inflammation following Pseudomonas aeruginosa infection in resistant and susceptible strains of mice

1995

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“…Mice that are genetically deficient in complement C5 exhibit increased susceptibility to bacterial infections, for example Pseudomonas (Cerquetti et al ., 1986) and Listeria (Lawrence and Schell, 1978), and fungal infections, for example candida (Mullick et al ., 2006).…”

Section: Complement Factormentioning

confidence: 99%

Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: soluble targets

Martin

Bugelski

2012

British J Pharmacology

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Monoclonal antibodies (mAbs) and fusion proteins directed towards soluble targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 14 currently approved mAbs and fusion proteins targeted to soluble targets. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency 'Scientific Discussions' and United States Food and Drug Administration 'Pharmacology/Toxicology Reviews' and package inserts (United States Prescribing Information). Data on the following approved biopharmaceuticals were included: adalimumab, anakinra, bevacizumab, canakinumab, certolizumab pegol, denosumab, eculizumab, etanercept, golimumab, infliximab, omalizumab, ranibizumab, rilonacept and ustekinumab. Some related biopharmaceuticals in late-stage development were also included for comparison. Good concordance with human pharmacodynamics was found for both non-human primates (NHPs) receiving the human biopharmaceutical and mice receiving rodent homologues (surrogates). In contrast, there was limited concordance for human adverse effects in genetically deficient mice, mice receiving surrogates or NHPs receiving the human pharmaceutical. In summary, the results of this survey show that although both mice and NHPs have good predictive value for human pharmacodynamics, neither species have good predictive value for human adverse effects. No evidence that NHPs have superior predictive value was found. AbbreviationsCFR, Code of Federal Regulations; DTH, delayed-type hypersensitivity; EMA, European Medicines Agency; FDA, Food and Drug Administration; GLP, good laboratory practices; ICH, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; mAb, monoclonal antibody; NHP, non-human primate; OECD, Organisation for Economic Co-operation and Development; RANK-L, receptor activator of NF-kB ligand; TDAR, T-cell-dependent antibody response; USPI, United States Prescribing Information IntroductionThe non-clinical safety evaluation of medicinal products intended for human use is generally tested in two mammalian species, a rodent and a non-rodent [International Conference on Harmonization (ICH) guideline M3 (R2) (2009), for small-molecular-weight pharmaceuticals and ICH S6 (R1) (1997, Addendum 2011), for large-molecule biopharmaceuticals]. The purpose of these studies is to identify potential target organs for toxicity and to establish a dose at which no adverse effects are observed. A comparison between the maximum tolerated dose and the no observed adverse effect level provides the safety margin for the product. Toxicities may be characterized as 'on-target', that is, directly related to the pharmacology of the product, or may be considered 'offtarget', that is, not directly related to the pharmacology BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 806 British Journal of Pharmacology (2012) Guengerich, 2011). Examples of 'of...

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“…The phenotype is also the function of other genes; i.e. the response to Pseudomonas varied among different strains of C5-deficient mice (82).…”

Section: Host Defensesmentioning

confidence: 99%

Complement: a critical test of its biological importance

Schmidt

Colten

2000

Immunological Reviews

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The biological activities of the more than 30 proteins that comprise the complement system have been elucidated in parallel lines of investigation that resulted in the purification of the proteins and studies of their function in vitro. Twenty years ago, the first complement cDNA clones were generated. Subsequently the structure and chromosomal localization of the complement genes and the primary sequences of their gene products were revealed. For some, even their higher order structure was solved. This work, coupled with studies of complement gene expression, biosynthesis, post-synthetic processing and secretion, contributed to an analysis of the relatively rare naturally occurring genetic deficiencies of complement proteins discovered fortuitously in humans sand experimental animals. Not until the past 5 years, with the application of methods for manipulating genes in vivo (targeted deletion and overexpression), has it been possible to definitively assign specific functions to complement proteins and to assess their importance in the intact organism. These relatively recent studies have confirmed the in vitro work or revealed unexpected roles for complement effector and regulatory proteins in host defenses, specific immunity, immunopathology, metabolism and reproductive biology This work is reviewed and the implications for understanding human diseases and the design of novel pharmaceutical agents are discussed. The promise of this line of investigation is certain but the context imposed by gender, developmental stage, other genes and environment must be taken into account before the practical implications of this deeper understanding of complement biology are fully realized.

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Lung defenses against Pseudomonas aeruginosa in C5-deficient mice with different genetic backgrounds

Cited by 34 publications

References 25 publications

Endobronchial inflammation following Pseudomonas aeruginosa infection in resistant and susceptible strains of mice

Endobronchial inflammation following Pseudomonas aeruginosa infection in resistant and susceptible strains of mice

Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: soluble targets

Complement: a critical test of its biological importance

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