Publications

Airway diseases often feature persistent neutrophilic inflammation and infection. In cystic fibrosis bronchitis, for example, Pseudomonas aeruginosa is isolated frequently. Previously, this laboratory revealed that neutrophils become major sources of histamine in mice with tracheobronchitis caused by the wall-less bacterium Mycoplasma pulmonis. To test the hypothesis that more-broadly pathogenic P. aeruginosa (which expresses cell wall-associated LPS and novel toxins) has similar effects, we incubated naïve mouse neutrophils with two strains of P. aeruginosa. Strain PAO1 greatly increased neutrophil histamine content and secretion, whereas strain PA103 depressed histamine production by killing neutrophils. The histamine-stimulating capacity of PAO1, but not PA103-mediated toxicity, persisted in heat-killed organisms. In PAO1-infected mice, lung and neutrophil histamine content increased. However, PAO1 did not alter production by mast cells (classical histamine reservoirs), which also resisted PA103 toxicity. To explore mechanisms of neutrophil-selective induction, we measured changes in mRNA encoding histidine decarboxylase (rate-limiting for histamine synthesis), probed involvement of endotoxin-TLR pathways in Myd88-deficient neutrophils, and examined contributions of pyocyanin and exotoxins. Results revealed that PAO1 increased histamine production by up-regulating histidine decarboxylase mRNA via pathways largely independent of TLR, pyocyanin, and type III secretion system exotoxins. PAO1 also increased histidine decarboxylase mRNA in neutrophils purified from infected lung. Stimulation required direct contact with neutrophils and was blocked by phagocytosis inhibitor cytochalasin D. In summary, Pseudomonas-augmented histamine production by neutrophils is strain-dependent in vitro and likely mediated by up-regulation of histidine decarboxylase. These findings raise the possibility that Pseudomonas-stimulated neutrophils can enhance airway inflammation by producing histamine.

BACKGROUND

Short telomere length (TL) is an independent predictor of mortality in patients with coronary heart disease (CHD). However, the relationship between physical fitness and TL has not been explored in these patients.

METHODS

In a cross sectional study of 944 outpatients with stable CHD, we performed exercise treadmill testing, assessed self-reported physical activity, and measured leukocyte TL using a quantitative PCR assay. We used generalized linear models to calculate mean TL (T/S ratio), and logistic regression models to compare the proportion of patients with short TL (defined as the lowest quartile), among participants with low, medium and high physical fitness, based on metabolic equivalent tasks achieved (METs).

RESULTS

229 participants had low physical fitness (<5 METS), 334 had moderate physical fitness (5-7 METS), and 381 had high physical fitness (>7 METS). Mean ± T/S ratio ranged from 0.86±0.21 (5349±3781 base pairs) in those with low physical fitness to 0.95±0.23 (5566±3829 base pairs) in those with high physical fitness (p<.001). This association remained strong after adjustment for numerous patient characteristics, including measures of cardiac disease severity and physical inactivity (p = 0.005). Compared with participants with high physical fitness, those with low physical fitness had 2-fold greater odds of having TL in the lowest quartile (OR 2.39, 95% CI 1.60-3.55; p<.001). This association was similar after multivariable adjustment (OR 1.94, 95%CI, 1.18-3.20; p = 0.009). Self-reported physical inactivity was associated with shorter TL in unadjusted analyses, but not after multivariable adjustment.

CONCLUSIONS

We found that worse objectively-assessed physical fitness is associated with shorter leukocyte telomere length in patients with CHD. The clinical implications of this association deserve further study.

BACKGROUND

Information is scant assessing outcomes in lung transplantation (LT) in advanced occupational lung diseases (OLD).

AIMS

To analyse survival after LT for OLD.

METHODS

Using data from the US Organ Procurement and Transplantation Network Registry (OPTN-R), we identified subjects aged ≥ 18 years transplanted for OLD from 2005 to 2010. OPTN-R selected referents of corresponding age, sex and body mass index (BMI) who underwent LT for other diagnoses were also identified. Post-LT survival time was estimated with Cox proportional hazard models. Baseline age, BMI, forced expiratory volume in 1 s, creatinine, lung allocation score, donor age, donor lung ischaemic time and transplant type (single versus bilateral) were included as covariates. Time-dependent covariates were used to model differences in relative risk over time.

RESULTS

Thirty-seven males underwent LT for silicosis (n = 19) or other OLD (n = 18) during the analytic period (0.5% of all LTs). For non-silicotic OLD, 6-month and 1- and 3-year survival estimates were 66, 55 and 55%, compared with the silicotic group (86, 86 and 76%) and referent group (89, 84 and 67%). During the first year post-transplant, those with OLD (silicosis and others combined) manifested an overall 2-fold increased mortality risk [hazard ratio (HR) 2.3, 95% CI 1.3-4.4; P < 0.05] compared to referents. In stratified analysis, this increased risk of death was restricted to those with non-silicotic OLD (HR 3.1, 95% CI 1.5-6.6; P < 0.01). Poorer survival was limited to the first year post-LT.

CONCLUSIONS

Subjects undergoing LT for OLD other than silicosis may be at increased risk of death in the first year post-transplantation.