Small airways disease (SAD) is a cardinal feature of chronic obstructive pulmonary disease (COPD) first recognized in the nineteenth century. The diverse histopathological features associated with SAD underpin the heterogeneous nature of COPD. Our understanding of the key molecular mechanisms which drive the pathological changes are not complete. In this article we will provide a historical overview of key histopathological studies which have helped shape our understanding of SAD and discuss the hallmark features of airway remodelling, mucous plugging and inflammation. We focus on the relationship between SAD and emphysema, SAD in the early stages of COPD, and the mechanisms which cause SAD progression, including bacterial colonization and exacerbations. We discuss the need to specifically target SAD to attenuate the progression of COPD.

Conformational control limits most electron transfer (ET) reactions in biology, but we lack general insight into the extent of conformational space explored, and specifically the properties of the associated energy landscape. Here we unite electron-electron double resonance (ELDOR) studies of the diradical (disemiquinoid) form of human cytochrome P450 reductase (CPR), a nicotinamide adenine phosphate dinucleotide (NADPH)-linked diflavin oxidoreductase required for P450 enzyme reduction, with functional studies of internal ET to gain new insight into the extent and properties of the energy landscape for conformationally controlled ET. We have identified multiple conformations of disemiquinoid CPR, which point to a rugged energy landscape for conformational sampling consistent with functional analysis of ET using high-pressure stopped-flow, solvent, and temperature perturbation studies. Crystal structures of CPR have identified discrete "closed" and "open" states, but we emphasize the importance of a continuum of conformational states across the energy landscape. Within the landscape more closed states that favor internal ET are formed by nucleotide binding. Open states that enable P450 enzymes to gain access to electrons located in the FMN-domain are favored in the absence of bound coenzyme. The extent and nature of energy landscapes are therefore accessible through the integration of ELDOR spectroscopy with functional studies. We suggest this is a general approach that can be used to gain new insight into energy landscapes for biological ET mediated by conformational sampling mechanisms.

Twelve lung neuroendocrine tumors with morphologic features of carcinoid tumors but with mitotic count >10/2 mm are reported. There were 7 males and 5 females, with age ranging from 56 to 78 years. Four cases were from never-smokers. All tumors showed architectural and cytomorphologic features of carcinoid tumor, including organoid nesting, insular, trabecular, or acinar growth, and tumor cells with low nucleocytoplasmic ratio, abundant cytoplasm, ovoid to round nuclei, and salt and pepper chromatin. Angulated or confluent nesting, insular or lobular growth pattern was also seen. Nuclear irregularities and anisonucleosis were focally present. Mitotic count ranged from 11 to 61/2 mm. Punctate-type necrosis was present in 8 tumors. Anaplastic cytology, large infarct-type necrosis, desmoplasia, or marked inflammatory infiltrate was not found in any of the tumors. One tumor occurred in the background of diffuse idiopathic pulmonary neuroendocrine hyperplasia. All tumors were treated by resection, and all but 1 patient subsequently developed metastasis, and 7 died of the tumor. For metastatic tumors, 4 patients were treated by platinum-based chemotherapy with no apparent response, whereas 3 other patients were treated by combined capecitabine and temozolomide-novel chemotherapy for well-differentiated neuroendocrine tumor/carcinoid tumor-2 of them responded. This subset of tumor would be classified as large cell neuroendocrine carcinoma according to the current WHO classification scheme, but their clinical and pathologic features appear to have more in common with the carcinoid tumor group than large cell neuroendocrine carcinoma, therefore, identification of this subset may be relevant for further therapeutic management.

P450s (cytochrome P450 mono-oxygenases) are a superfamily of haem-containing mono-oxygenase enzymes that participate in a wide range of biochemical pathways in different organisms from all of the domains of life. To facilitate their activity, P450s require sequential delivery of two electrons passed from one or more redox partner enzymes. Although the P450 enzymes themselves show remarkable similarity in overall structure, it is increasingly apparent that there is enormous diversity in the redox partner systems that drive the P450 enzymes. This paper examines some of the recent advances in our understanding of the biodiversity of the P450 redox apparatus, with a particular emphasis on the redox systems in the pathogen Mycobacterium tuberculosis.