Backgroundp38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations.ObjectivesThese studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations.MethodsThe p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18–55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40–85 years with a diagnosis of COPD for >1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations.ResultsThe p38 isoform most relevant to lung inflammation was p38α, and AZD7624 specifically inhibited p38α and p38β isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-α by 56.6% and 85.4%, respectively (p<0.001). In the 213 patients randomized into the Proof of Principle study, there was no statistically significant difference between AZD7624 and placebo when comparing the number of days to the first moderate or severe exacerbation or early dropout.ConclusionAlthough p38α is upregulated in the lungs of COPD patients, AZD7624, an isoform-specific inhaled p38 MAPK inhibitor, failed to show any benefit in patients with COPD.

2,3-Dichloro-1-propanol is more chemically stable than its isomer, 1,3-dichloro-2-propanol, and is therefore more difficult to degrade. The isolation of bacteria capable of complete mineralization of 2,3-dichloro-1-propanol was successful only from enrichments at high pH. The bacteria thus isolated were found to be members of the ␣ division of the Proteobacteria in the Rhizobium subdivision, most likely Agrobacterium sp. They could utilize both dihaloalcohol substrates and 2-chloropropionic acid. The growth of these strains in the presence of 2,3-dichloro-1-propanol was strongly affected by the pH and buffer strength of the medium. Under certain conditions, a ladder of four active dehalogenase bands could be visualized from this strain in activity gels. The enzyme involved in the complete mineralization of 2,3-dichloro-1-propanol was shown to have a native molecular weight of 114,000 and consisted of four subunits of similar molecular weights.Epichlorohydrin (1-chloro-2,3-epoxypropane) and its precursors (1,3-dichloro-2-propanol [1,3-DCP], 2,3-dichloro-1-propanol [2,, and 3-chloro-1,2-propanediol [3-CPD]) are halohydrins used widely as solvents and as starting materials for resins, polymers, agrochemicals, and pharmaceuticals. 2,3-DCP, 1,3-DCP, and epichlorohydrin are carcinogenic, mutagenic, and genotoxic. According to a U.S. Environmental Protection Agency assessment (available at http://www.epa.gov /ngispgm3/iris/), 2,3-DCP showed significant effects on rats dosed with 35 mg of 2,3-DCP/kg of body weight/day. The resulting mortality is attributed to myocardial degeneration and kidney and liver malfunction. 2,3-DCP has been shown to be more toxic than 1,3-DCP to the testes and kidneys, though it is less hepatotoxic (7, 16). The Environmental Protection Agency Prioritized Chemical List showed that the overall score (as the sum of the persistence, bioaccumulation, and toxicity scores for human health risk potential added to the corresponding scores for ecological risk) for 1,3-DCP and epichlorohydrin were 11 out of 18 each. Both epichlorohydrin and 1,3-DCP have a high risk factor for animal and human toxicity with regards to the environment. No information was available for 2,3-DCP. However, due to its greater stability, 2,3-DCP is likely to be more persistent than 1,3-DCP and may pose a substantial environmental threat.To date, few bacteria capable of the complete degradation of 2,3-DCP have been isolated. A single Pseudomonas strain capable of growth on 2,3-DCP was isolated from 300 samples of contaminated soil (9). The same group later isolated 13 isolates from a further 1,000 similar samples, suggesting 2,3-DCP-degrading bacteria to be quite rare (10). These bacteria were shown to degrade only the S enantiomer of 2,3-DCP and were of use in enantiospecific preparation of (R)-2,3-DCP and (S)-epichlorohydrin. Haloalcohol dehalogenases with activity against 1,3-DCP have either no activity or only fractional activity (Ͻ50%) against racemic 2,3-DCP (2,10,15,21,22).The initial aim of this study was to isolate and ch...

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