Controlled inhalation improves central and peripheral deposition in cystic fibrosis patients with moderate lung disease.

AIM: With progressive impairment of lung function, deposition of inhaled drug in the lungs becomes progressively more central, limiting its effectiveness. This pilot study explored the possibility that long slow inhalations might improve delivery of aerosol to the lung periphery in cystic fibrosis patients with moderate lung disease. METHODS: Five subjects aged 12-18 years (mean FEV1 72%; range 63-80%) inhaled a radiolabelled aerosol from a jet nebuliser on two occasions. Two inhalation techniques were compared: breathing tidally from a standard continuous output nebuliser and using long slow inhalations from the AKITA® JET system. RESULTS: Long slow breaths resulted in much lower oropharyngeal deposition with higher lung doses. Importantly, the peripheral lung increased proportionately. The increased lung dose is attributable to more of the larger inhaled droplets passing into the lower airways. This would be expected to increase the central deposition unless significantly more of the smaller droplets were able to penetrate deeper into the lungs. The data support improved delivery of drug to the distal lung when compared with tidal breathing. CONCLUSION: These pilot data suggest that this approach may prove to be clinically relevant in improving the efficacy of inhaled medication in those with moderate-severe lung disease.

Inhaled antibiotics: dry or wet?

Dry powder inhalers (DPIs) delivering antibiotics for the suppressive treatment of Pseudomonas aeruginosa in cystic fibrosis patients were developed recently and are now increasingly replacing time-consuming nebuliser therapy. Noninferiority studies have shown that the efficacy of inhaled tobramycin delivered by DPI was similar to that of wet nebulisation. However, there are many differences between inhaled antibiotic therapy delivered by DPI and by nebuliser. The question is whether and to what extent inhalation technique and other patient-related factors affect the efficacy of antibiotics delivered by DPI compared with nebulisers. Health professionals should be aware of the differences between dry and wet aerosols, and of patient-related factors that can influence efficacy, in order to personalise treatment, to give appropriate instructions to patients and to better understand the response to the treatment after switching. In this review, key issues of aerosol therapy are discussed in relation to inhaled antibiotic therapy with the aim of optimising the use of both nebulised and DPI antibiotics by patients. An example of these issues is the relationship between airway generation, structural lung changes and local concentrations of the inhaled antibiotics. The pros and cons of dry and wet modes of delivery for inhaled antibiotics are discussed.

The concentration of iron in real-world geogenic PM10 is associated with increased inflammation and deficits in lung function in mice.

BACKGROUND: There are many communities around the world that are exposed to high levels of particulate matter <10 µm (PM10) of geogenic (earth derived) origin. Mineral dusts in the occupational setting are associated with poor lung health, however very little is known about the impact of heterogeneous community derived particles. We have preliminary evidence to suggest that the concentration of iron (Fe) may be associated with the lung inflammatory response to geogenic PM10. We aimed to determine which physico-chemical characteristics of community sampled geogenic PM10 are associated with adverse lung responses. METHODS: We collected geogenic PM10 from four towns in the arid regions of Western Australia. Adult female BALB/c mice were exposed to 100 µg of particles and assessed for inflammatory and lung function responses 6 hours, 24 hours and 7 days post-exposure. We assessed the physico-chemical characteristics of the particles and correlated these with lung outcomes in the mice using principal components analysis and multivariate linear regression. RESULTS: Geogenic particles induced an acute inflammatory response that peaked 6 hours post-exposure and a deficit in lung mechanics 7 days post-exposure. This deficit in lung mechanics was positively associated with the concentration of Fe and particle size variability and inversely associated with the concentration of Si. CONCLUSIONS: The lung response to geogenic PM10 is complex and highly dependent on the physico-chemical characteristics of the particles. In particular, the concentration of Fe in the particles may be a key indicator of the potential population health consequences for inhaling geogenic PM10.

The role of GSTP1 polymorphisms and tobacco smoke exposure in children with acute asthma.

BACKGROUND: The glutathione S-transferase enzymes (GSTs) play an important role in the detoxification of environmental tobacco smoke (ETS), which contributes to airway inflammation, a key component of asthma. Genetic variation in GST genes may influence individuals' ability to detoxify environmental pollutants. OBJECTIVE: To examine the role of polymorphisms in GSTP1 (Ile105Val and Ala114Val), alone and in combination with ETS exposure, on atopy and asthma severity. METHODS: GSTP1 Ile105Val and Ala114Val were genotyped and ETS exposure was assessed by parental questionnaire, which was validated by urinary cotinine measurements. Associations between ETS exposure, GSTP1 polymorphisms, and their interaction on atopy and asthma severity were investigated. RESULTS: For the functional GSTP1 105 SNP, those with the Ile/Ile genotype had odds for atopy of 2.77 (p = .054) when assessed by genotype alone, which increased to 9.02 (p = .050) when ETS was included, relative to individuals with other genotypes. Likewise, compared to children with other GSTP1 114 genotypes, those with Ala/Ala genotype had a 5.47-fold (p = .002) increased risk of atopy (p = .020) when assessed by genotype alone, increasing to 9.17-fold when ETS was included. The 105 Ile/Ile individuals all had the AA (105 Ile/Ile and 114 Ala/Ala) haplotype group; therefore, the odds for atopy were the same. Individuals without any *C haplotype (105 Val and 114 Val allele) who were exposed to ETS had a 9.17-fold increased risk of atopy when compared with individuals with at least one *C haplotype and not exposed to ETS (p = .020). CONCLUSION: There were significant interactions between GSTP1 SNPs, atopy, and ETS exposure in this cohort.

In utero smoke exposure and role of maternal and infant glutathione s-transferase genes on airway responsiveness and lung function in infancy.

RATIONALE: Xenobiotics in the maternal circulation are capable of crossing the placental barrier so a reduction in the mother and fetus's detoxification ability due to genetic variation in the glutathione S-transferases (GSTs) could expose the fetus to higher levels of toxins. OBJECTIVES: To investigate the interactive effects of maternal smoking during pregnancy with maternal and infant GST genotypes on airway responsiveness (AR) and lung function in infancy. METHODS: GSTT1, GSTP1 and GSTM1 were genotyped in infants and mothers, in utero smoke exposure was evaluated by questionnaire, AR was assessed by histamine challenge and Vmax(FRC) was measured using the rapid thoracoabdominal compression technique. We investigated the interactive effects of maternal smoking during pregnancy with maternal and infant GST genes on AR and lung function at 1, 6, and 12 months and longitudinally throughout the first year. MEASUREMENTS AND MAIN RESULTS: Infant and/or maternal GSTT1 nonnull was associated with reduced AR at 12 months and throughout the first year and increased Vmax(FRC) at 6 months. Maternal GSTP1 Val/Val or Ile/Val was associated with increased Vmax(FRC) at 6 months. In infants exposed to in utero smoke, infant and/or maternal GSTT1 nonnull was associated with reduced AR at 1 month and throughout the first year and increased Vmax(FRC) throughout the first year. Maternal GSTP1 Val/Val or Ile/Val was associated with increased Vmax(FRC) at 6 months. CONCLUSIONS: GST genes may be especially important during fetal development as they may modify, through proficient detoxification, the effects of in utero maternal smoke exposure on AR and lung function in infants.

Association of maternal smoking with increased infant oxidative stress at 3 months of age.

BACKGROUND: Cigarette smoke is a major source of free radicals and oxidative stress. With a significant proportion of women still smoking during pregnancy, this common and avoidable exposure has the potential to influence infant oxidative status, which is implicated in the increased propensity for airway inflammation and asthma. The aim of this study was to examine the effects of maternal smoking on markers of infant oxidative stress. METHODS: The level of oxidative stress (using urinary F2-isoprostanes as a marker of lipid peroxidation) was compared in infants of smokers (n = 33) and non-smokers (n = 54) at 3 months of age. These groups were balanced for maternal atopy and socioeconomic status. Infant urinary cotinine levels were also measured as an indicator of early postnatal cigarette smoke exposure. RESULTS: Maternal smoking was associated with significantly higher infant cotinine levels, despite the fact that most smoking mothers (83.8%) claimed not to smoke near their baby. Maternal smoking was associated with significantly higher markers of oxidative stress (F2-isoprostane) at 3 months of age. There was also a positive correlation between urinary F2-isoprostanes and infant urinary cotinine levels. CONCLUSIONS: Although this study does not separate the prenatal and postnatal effects of smoking, these findings indicate that environmental tobacco smoke in the early postnatal period adversely affects pro-oxidative/antioxidative status within weeks of life in very early infancy.

The effects of maternal smoking on early mucosal immunity and sensitization at 12 months of age.

With the dramatic rise in asthma and respiratory disease, there is an urgent need to determine the effects of common environmental exposures on early immune development. In this study, we examined the effects of maternal smoking as a major adverse exposure in early life, on mucosal immune function and allergen sensitization in the first year of life. A cohort of 60 smokers and 62 non-smokers was recruited in pregnancy, and followed prospectively at 3 and 12 months of age for saliva collection [for immunoglobulin (Ig) A measurements], urine collection (for cotinine levels) and clinical assessments (for allergy and infection history). Allergen skin-prick tests were also performed at 12 months of age. Specific IgA to common colonizing bacteria was measured on saliva samples, including pneumococcal polysaccharide (PS) serotype 14 and non-typeable Haemophilus influenza (NTHI) outer membrane protein 6 (OMP6). Eighty-two mothers and their infants completed the 12-month follow-up period--56 in the maternal non-smoking group and 26 in the maternal smoking group. Maternal smoking was associated with significantly higher total infant salivary IgA at 12 months of age (p = 0.026), and more chronic upper respiratory tract symptoms (p = 0.012). However, there were no differences in the level of specific IgA antibodies to common colonizing bacteria (pneumococcal PS serotype 14 and NTHI OMP6). In general, the IgA levels at 12 months were higher in children who had more chest infections in the first year (Kendall's tau b, 0.282; p = 0.003). There was also a trend of lower respiratory tract symptoms (wheeze) (p = 0.142) in infants of smokers. There were no effects of maternal smoking on the rates of allergen sensitization, atopic dermatitis and food allergy at 12 months of age. In conclusion, maternal smoking did not inhibit the production of anti-microbial IgA, suggesting that other factors are responsible for the increased susceptibility to infection in these infants. The increased mucosal inflammation in these children was not associated with effects on early allergy propensity.