Local inflammation is known to contribute to respiratory disease and lung function, however the role of low-grade systemic inflammatory processes in lung function is less clear. To shed light on this issue, researchers from Spain, Italy, Germany and Finland have collaborated to investigate the association between inflammatory markers in the peripheral blood and respiratory function. The study, published in the European Respiratory Journal, also considered polymorphisms in genes coding for inflammatory markers.
Three inflammatory markers were measured in peripheral blood; C-reactive protein (CRP), IL-6 and fibrinogen. Every 4 weeks for 20 weeks, six repeated measurements of these indicators were taken from 134 postmyocardial infarction patients. Measures of respiratory function (forced expiratory volume in 1 s [FEV1], forced vital capacity [FVC] and forced expiratory flow between 25 and 75% of FVC [FEF25–75]) were determined by spirometry testing at baseline. Genotyping of 36 single nucleotide polymorphisms was performed in genes coding for the inflammatory markers.
IL-6 and CRP levels were negatively associated with the respiratory parameters. Individuals with polymorphism rs1205 and haplotype 2 of the CRP gene (rare variants) had better lung function as determined by FEV1 and FEF25–75. Individuals with polymorphism rs1205 and haplotype 2 were also less likely to have high CRP levels in the peripheral blood. These correlations were independent of smoking and factors connected with the severity of the cardiac condition. Respiratory function was found to be independent of serum levels of fibrinogen and its coding gene polymorphism. The lead author, Jordi Sunyer, comments that this may be because most of the patients were taking statins, which are known to reduce fibrinogen levels.
The authors conclude that the “results are very suggestive that heritability of lung function is at least partly controlled by the CRP gene. Applying a Mendelian randomization approach, the study supports a causal association between low-grade general inflammation and airway diseases.”
The results from this study may prompt further research into the possibility that systemic inflammation precedes a decline in respiratory function and may therefore be useful in early diagnoses.
Source: Sunyer J, Pistelli R, Plana E et al. Systemic inflammation, genetic susceptibility and lung function. Eur. Respir. J. 32(1), 92–97 (2008).
Inhaled liposomal ciprofloxacin success in the treatment of cystic fibrosis
Drug: Inhaled liposomal ciprofloxacin
Manufacturer: Aradigm Corporation, CA, USA
Indication: Daily inhalation reduces Pseudomonas bacterial density
Aradigm Corporation has announced promising results from a Phase II study into the efficacy and safety of its once-daily inhaled liposomal ciprofloxacin, conducted at leading cystic fibrosis centers in Australia and New Zealand.
The efficacy of the drug was determined by the change from baseline in the sputum Pseudomonas aeruginosa colony-forming units (CFUs). Over the 14-day treatment period, Pseudomonas CFUs decreased by an average of 1.43 log (p < 0.0001) in the 21 patients who completed the study. Furthermore, Pseudomonas bacterial density in the lung was still reduced by 1.02 log CFUs from the baseline 1 week after the study terminated, without additional antibiotic use. In addition to reducing bacterial concentration in the lung, the antibiotic improved respiratory function. The FEV1 mean increase was 6.86% from baseline after 14 days of treatment (p = 0.04).
Importantly, there were no serious adverse events reported during the study. Head of the study, John Wilson, explains why the antibiotic has the potential to be a success, “Reduction of the burden of treatment with more conveniently administered products would be most welcomed by the cystic fibrosis community. It was therefore important in this study that, in addition to the successful clinical efficacy and safety outcomes, the patients found the once daily dosing regimen very convenient. This is a very attractive feature of the new product candidate.”
Ciprofloxacin is commonly prescribed to treat lung infections because it has a broad-spectrum antibacterial action. Aradigm’s once-daily novel inhaled formulation of ciprofloxacin delivered in liposomes is to be used for chronic maintenance therapy as it is expected to achieve higher antibiotic concentration at the site of infection and relatively low systemic antibiotic concentrations to minimize side effects.
Source: Aradigm www.aradigm.com
Enzyme mediates movement of neutrophils in acute respiratory distress syndrome
Researchers from Chicago (IL, USA) have investigated the role of muscle myosin light-chain kinase (MYLK) in acute respiratory distress syndrome (ARDS). ARDS is mainly attributed to lipopolysaccharide-induced lung inflammation injury, resulting in increased lung vascular endothelial permeability. The study supports previous evidence that MYLK mediates the increase of lung vascular endothelial permeability. The disruption of the endothelial barrier results in build-up of water in the lungs. MYLK was also found to be essential for the movement of neutrophils through the endothelial barrier. In ARDS, neutrophils can enter the lung and cause profound injury.
Furthermore, the study investigates the cascade triggered by MYLK which enables the neutrophils to enter the lungs. The lung injury model demonstrated that the neutrophil transmigration activity of MYLK was mostly independent of the myosin II regulatory light chain, the only known substrate of MYLK. Jin-gsong Xu, lead author of the paper, comments, “To our surprise, the pathway was a completely novel one that did not involve the well-studied and expected target of MYLK.” These findings provide scope for further research into treatment for ARDS.
Source: Xu J, Gao XP, Ramchandran R, Zhao YY, Vogel SM, Malik AB. Nonmuscle myosin light-chain kinase mediates neutrophil transmigration in sepsis-induced lung inflammation by activating β2 integrins. Nat. Immunol. (2008) (Epub ahead of print).
Radiofrequency ablation for lung cancer treatment
Study: Radiofrequency abalation on lung tumors
Patients: 106 with 183 tumors
Parameters: Technical success, safety and tumor response
Conclusion: 88% complete response of target tumors lasting 1 year
Researchers from the University of Pisa, Italy, have conducted a study into the plausibility of radiofrequency to treat malignant lung tumors. They investigated both the safety aspects and effectiveness of this technique in this international study, with participants from seven centers in Europe, USA and Australia.
The study design was a prospective, intention-to-treat, single-arm, multicenter clinical trial involving 106 patients with 183 lung tumors that were 3.5cm in diameter or smaller (mean 1.7 cm [standard deviation: 1.3]). This included 33 patients with non-small-cell lung cancer. A biopsy was carried out in all patients to verify the malignancy status of the tumors. All participants were considered unsuitable for surgery, radiotherapy or chemotherapy.
The use of radiofrequency ablation in lung cancer is still at early, experimental stages, although its use in the treatment of liver cancer is more established. The minimally invasive procedure involves the insertion of a needle into a tumor. Tines are projected from the needle and the surgeon directs the tines around the tumor with guidance from a CT scanner. Radiofrequency ablation energy is then transferred through the needle and tines, annihilating small tumors or reducing the size of larger tumors.
In the study, radiofrequency ablation was performed on the participants according to the standard rules for CT-guided lung biopsy. End points were evaluated up to 2 years following the treatment. Primary end points were technical success (defined as the correct placement of the ablation device into all tumor targets with completion of the planned ablation protocol), safety (the incidence of treatment-related complications and alterations to pulmonary function) and confirmed complete response of tumors (according to a modified Response Evaluation Criteria in Solid Tumors). Secondary end points were overall survival, cancer-specific survival and quality of life.
The treatment was a technical success in all but one patient, attributed to the small size of the tumor rendering the device unable to be inserted. None of the patients died from the procedure.
However, 27 patients suffered from pneumothorax and four suffered from pleural effusion, which required drainage. With regards to pulmonary function, this was not observed to decline in any of the participants. Of the 85 assessable patients, an 88% complete response of target tumors lasting at least 1 year was observed.
The authors concluded that “percutaneous radiofrequency ablation yields high proportions of sustained complete responses in properly selected patients with pulmonary malignancies, and is associated with acceptable morbidity. Randomized controlled trials comparing radiofrequency ablation with standard non-surgical treatment options are warranted.”
Source: Lencioni R, Crocetti L, Cioni R et al. Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet Oncology (2008) (Epub ahead of print).
Insight into the role of omega-3 metabolite in resolving the inflammatory response
Scientists report a potential mechanism to compliment evidence that Resolvin E1 reduces the inflammatory airway response.
Previous studies have indicated that an increased intake of omega-3 fatty acids is associated with lower asthma prevalence; however, the reason for this has not been elucidated. The effects of an omega-3 metabolite, Resolvin E1 (RvE1), was investigated in a recent murine-based study. RvE1 is one of the specific signals and mediators that take part in an active process to control acute inflammation. The researchers from Boston (MA, USA) provide evidence that nanogram quantities of RvE1 promote the resolution of inflammatory airway response in part by directly suppressing the production of IL-23 and IL-6 in the lung. IL-23 is vital to the pathogenesis of chronic inflammation. The lungs of RvE1-treated mice were observed to have higher concentrations of IFN-γ. The authors propose that this association may also play a role in the RvE1-induced resolution of airway inflammation. The authors comment that their findings indicate a crucial role for IL-23 and IL-6 in the maintenance of inflammation and also identify RvE1 as a potential therapy for asthma.
Source: Haworth O, Cernadas M, Yang R, Serhan CN, Levy BD. Resolvin E1 regulates interleukin 23, interferon-γ and lipoxin A(4) to promote the resolution of allergic airway inflammation. Nat. Immunol. (2008) (Epub ahead of print).
Evidence for new drug target for TB
Mycobacterial fatty acid synthase II dehydratase enzyme Rv0636 has been proposed as a new target in TB drug development.
Mycolic acids are vital structures in the cell wall of some bacteria, including Mycobacterium tuberculosis. However, there have been uncertainties as to which genes are responsible for the formation of mycolic acid. Researchers in the UK have proposed that the gene Rv0636 controls a step imperative to the synthesis of the mycolic acid molecule.
This conclusion was drawn from a study focused on the mycolic acid synthesis inhibitors NAS-21 and NAS-91. Gurdyal Besra, corresponding author of the study, explained that the aims of their study were to look at the effect of NAS-21 and NAS-91 on Mycobacteria and also to elucidate if one of the enzymes is coded for by the Rv0636 gene.
In the study, modifications to NAS-21 and NAS-91 were made, creating libraries of NAS-21 and NAS-91 analogues. The whole-cell activity against the Mycobacterium bovis bacille Calmette-Guérin (BCG) of these analogues was determined. NAS-21 analogues 1 and 2 were found to have a higher inhibitory activity against M. bovis than the parental compound. With regards to the role of Rv0636, the authors conclude that it does code for an enzyme in the FAS-II complex (required for mycolic acid synthesis) as an M. bovis BCG strain overexpressing the dehydratase enzyme Rv0636 was resistant to these analogues. NAS-91 analogues with orthomodifications gave enhanced whole-cell activity. In both NAS-21 and NAS-91 analogues, extension with biphenyl modifications rendered their inhibitory effects reduced.
The researchers also looked at the in vitro activity of the analogues in cell-free extracts. Both analogues demonstrated in vitro activity against FAS-II but not FAS-I in cell-free extracts. The RV0636-overexpressing strain also had increased resistance to inhibition of FAS-II activity in both analogues. Further evidence to suggest that Rv0636 is a target for these analogues came from fatty acid methyl ester and mycolic acid methyl ester analysis. Besra concludes, “The emergence of drug-resistant strains of Mycobacterium tuberculosis has highlighted the need for new TB drugs. We hope our discovery will lead to a new rationale for the design of treatments.”
Source: Bhowruth V, Brown AK, Besra AG. Synthesis and biological evaluation of NAS-21 and NAS-91 analogues as potential inhibitors of the mycobacterial FAS-II dehydratase enzyme Rv0636. Microbiology 154, 1866–1875 (2008).