Progression of pulmonary disease after disappearance of Pseudomonas in cystic fibrosis.

Tosi, Michael F.; Stern, R C; Davis, Pamela B.

doi:10.1164/ajrccm.152.1.7599818

Cited by 14 publications

(10 citation statements)

References 4 publications

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“…Different models do, however, present components of the phenotype (9,10). For example, Kent et al (11) produced a congenic Cftr tm1UNC mouse strain in C57BL/6J (B6) background and showed the lung disease measured in these mice to include clinical attributes such as a perpetual neutrophil influx (12)(13)(14), patchy inflammation (15), mucus accumulation, and interstitial fibrosis in the lower airways (1). Altered macrophage function (16) and increased numbers of neutrophils in the bronchoalveolar lavage of Cftr tm1Eur mice (17) and subepithelial accumulation of lymphocytes in nasal tissue of Cftr tm1UNC and Cftr TgHm1G551D mice have also been reported (18).…”

Section: †mentioning

confidence: 99%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

The Journal of Immunology

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We previously observed the lungs of naive BALB/cJ Cftrtm1UNC mice to have greater numbers of lymphocytes, by immunohistochemical staining, than did BALB wild type littermates or C57BL/6J Cftrtm1UNC mice. In the present study, we initially investigated whether this mutation in Cftr alters the adaptive immunity phenotype by measuring the lymphocyte populations in the lungs and spleens by FACS and by evaluating CD3-stimulated cytokine secretion, proliferation, and apoptosis responses. Next, we assessed a potential influence of this lymphocyte phenotype on lung function through airway resistance measures. Finally, we mapped the phenotype of pulmonary lymphocyte counts in BALB × C57BL/6J F2 Cftrtm1UNC mice and reviewed positional candidate genes. By FACS analysis, both the lungs and spleens of BALB Cftrtm1UNC mice had more CD3+ (both CD4+ and CD8+) cells than did littermates or C57BL/6J Cftrtm1UNC mice. Cftrtm1UNC and littermate mice of either strain did not differ in anti-CD3–stimulated apoptosis or proliferation levels. Lymphocytes from BALB Cftrtm1UNC mice produced more IL-4 and IL-5 and reduced levels of IFN-γ than did littermates, whereas lymphocytes from C57BL/6J Cftrtm1UNC mice demonstrated increased Il-17 secretion. BALB Cftrtm1UNC mice presented an enhanced airway hyperresponsiveness to methacholine challenge compared with littermates and C57BL/6J Cftrtm1UNC mice. A chromosome 7 locus was identified to be linked to lymphocyte numbers, and genetic evaluation of the interval suggests Itgal and Il4ra as candidate genes for this trait. We conclude that the pulmonary phenotype of BALB Cftrtm1UNC mice includes airway hyperresponsiveness and increased lymphocyte numbers, with the latter trait being influenced by a chromosome 7 locus.

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Section: †mentioning

confidence: 99%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

The Journal of Immunology

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“…It has been demonstrated that clinical progression of lung disease with deterioration of forced expiratory volume in one second (FEV1) occurred despite the disappearance of P. aeruginosa from sputum specimens, suggesting that lung disease can also progress with other bacteria [28]. Additionally, epidemiological data show that infection with P. aeruginosa is confounded with the degree of pulmonary impairment which already exists [29] and that P. aeruginosa, although associated with some decrease in FEV1, does not cause sudden deterioration in CF patients [30].…”

Section: Diagnosis Of Pseudomonas Aeruginosa Lung Infectionmentioning

confidence: 99%

Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus

Döring¹,

Conway²,

Heijerman³

et al. 2000

Eur Respir J

557

478

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Cystic fibrosis (CF) is the most common lethal hereditary disorder with autosomal recessive heredity in caucasians. The majority of CF patients suffer from chronic respiratory infection with the opportunistic bacterial pathogen Pseudomonas aeruginosa. No consensus among clinicians has been reached so far concerning antibiotic treatment against P. aeruginosa in CF patients.Consensus answers to 24 important questions in this context, based on current evidence, are presented, given by a panel of 34 European experts. Questions addressed and answered are: The diagnosis of P. aeruginosa lung colonization in CF; The impact of P. aeruginosa on the clinical state of CF patients; The assessment of P. aeruginosa susceptibility against antibiotics and the importance of these results for the clinician; The use of monotherapy versus combination therapy; The development of microbial resistance; The achievement of optimal airway concentrations; The effects of subinhibitory concentrations of antibiotics on P. aeruginosa; Statements on the pharmacokinetics of antibiotics in CF patients; Recommendations for doses and dosing intervals and length of treatment regimens; and Toxic side effects due to repeated antibiotic therapy was addressed.The expert panel answered further questions on the use of fluoroquinolones in children with CF, on the administration of nebulized antibiotics and whether prevention of P. aeruginosa lung colonization is possible in CF using antibiotic therapy.Problems of antibiotic therapy at home and in the hospital were addressed, a consensus statement on regular maintenance treatment, or treatment on demand, was given and different routes of administration of antibiotics were recommended for different clinical situations.Finally, the factors which determine the choice of the antibiotic, the dosage, and the duration of the treatment in cystic fibrosis patients were addressed and the design of future antibiotic studies in the context of Pseudomonas aeruginosa lung infection in cystic fibrosis patients were recommended. Eur Respir J 2000; 16: 749±767.

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“…Furthermore, there are suggestions that more advanced lung disease becomes self-sustained with clinical sequelae (serial infections, excessive inflammation, bronchiectasis) ravaging the airway system until inevitable death from respiratory failure. Even eradication of Pseudomonas aeruginosa infection cannot prevent a further progression of the disease [64]. To distinguish this later phase of self-perpetuating disease from the initial CFTR-controlled one, it has recently been proposed to refer to it as CF lung disease as opposed to CF disease [65, 66].…”

Section: How Do Cftr Mutations Contribute To Clinical Variation In Cf?mentioning

confidence: 99%

Genotype and Phenotype in Cystic Fibrosis

2000

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Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene which encodes a protein expressed in the apical membrane of exocrine epithelial cells. CFTR functions principally as a cAMP-induced chloride channel and appears capable of regulating other ion channels. Besides the most common mutation, ΔF508, accounting for about 70% of CF chromosomes worldwide, more than 850 mutant alleles have been reported to the CF Genetic Analysis Consortium. These mutations affect CFTR through a variety of molecular mechanisms which can produce little or no functional CFTR at the apical membrane. This genotypic variation provides a rationale for phenotypic effects of the specific mutations. The extent to which various CFTR alleles contribute to clinical variation in CF is evaluated by genotype-phenotype studies. These demonstrated that the degree of correlation between CFTR genotype and CF phenotype varies between its clinical components and is highest for the pancreatic status and lowest for pulmonary disease. The poor correlation between CFTR genotype and severity of lung disease strongly suggests an influence of environmental and secondary genetic factors (CF modifiers). Several candidate genes related to innate and adaptive immune response have been implicated as pulmonary CF modifiers. In addition, the presence of a genetic CF modifier for meconium ileus has been demonstrated on human chromosome 19q13.2. The phenotypic spectrum associated with mutations in the CFTR gene extends beyond the classically defined CF. Besides patients with atypical CF, there are large numbers of so-called monosymptomatic diseases such as various forms of obstructive azoospermia, idiopathic pancreatitis or disseminated bronchiectasis associated with CFTR mutations uncharacteristic for CF. The composition, frequency and type of CFTR mutations/variants parallel the spectrum of CFTR-associated phenotypes, from classic CF to mild monosymptomatic presentations. Expansion of the spectrum of disease associated with the CFTR mutant genes creates a need for revision of the diagnostic criteria for CF and a dilemma for setting nosologic boundaries between CF and other diseases with CFTR etiology.

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Progression of pulmonary disease after disappearance of Pseudomonas in cystic fibrosis.

Cited by 14 publications

References 4 publications

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus

Genotype and Phenotype in Cystic Fibrosis

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