Role of Neutrophils in Mucus Hypersecretion in COPD and Implications for Therapy

Airway mucus hypersecretion is a serious and presently untreatable symptom of COPD. Over the past several years, emerging evidence has implicated epidermal growth factor receptor (EGFR) expression and activation in mucin production by airway epithelial (goblet) cells. Activated neutrophils recruited to the airways (and their secreted products) play several key roles in EGFR-dependent mucus hypersecretion: (i) activated neutrophils secrete tumor necrosis factor (TNF)-alpha, which induces EGFR expression in airway epithelial cells; (ii) activated neutrophils release reactive oxygen species, which activate EGFR; (iii) neutrophil elastase cleaves the EGFR proligand, pro-transforming growth factor (TGF)-alpha, releasing mature TGF alpha which activates EGFR in a ligand-dependent fashion; and (iv) neutrophil elastase causes potent goblet cell degranulation. The secretion of active products by neutrophils appears carefully regulated. The local release of neutrophil elastase requires close contact between the neutrophil and another cell, mediated by surface adhesion molecules, thus limiting proteolysis to the immediate pericellular environment. In the airway lumen, neutrophils undergo apoptosis and are cleared by macrophages without releasing their intracellular contents. In contrast, neutrophils that die by necrosis disgorge proteases and reactive oxygen species into the lumen. In COPD, conditions within the airway lumen promote neutrophil necrosis. It is concluded that neutrophil death via necrosis leads to the high concentrations of free neutrophil elastase and reactive oxygen species in the sputum of patients with airway neutrophilia and mucus hypersecretion. Inflammatory cells (neutrophils), molecules (neutrophil elastase and reactive oxygen species), signaling pathways (EGFR), and cellular processes (neutrophil necrosis) contribute to mucus hypersecretion in COPD, and are potential targets for therapy. Interventions that target EGFR, neutrophil elastase, and reactive oxygen species exist and can be evaluated as treatments for neutrophil-dependent mucus hypersecretion.     

Characterization of human tracheal epithelial cells transformed by an origin-defective simian virus 40.

To facilitate understanding of the mechanisms underlying pulmonary diseases, including lung cancer and cystic fibrosis, we have transformed and characterized cultures of human tracheal epithelial cells. Cells were transfected by calcium phosphate precipitation with a plasmid containing a replication-defective simian virus 40 (SV40) genome. Colonies of cells with enhanced growth potential were isolated and analyzed for transformation- and epithelial-specific characteristics. Precrisis cells were observed to express the SV40 large tumor antigen, produce cytokeratins, have microvilli, and form tight junctions. After crisis, cells continued to express the SV40 large tumor antigen as well as epithelial-specific cytokeratins and to display the apical membrane microvilli. Apical membrane Cl channels were opened in postcrisis cells exposed to 50 microM forskolin. These channels showed electrical properties similar to those observed in primary cultures. The postcrisis cells have been in culture for greater than 250 generations and are potentially "immortal." In addition to providing a useful in vitro model for the study of ion transport by human airway epithelial cells, the cells can be used to examine stages of neoplastic progression.     

Early lesions of follicular lymphoma: a genetic perspective

The pathogenesis of follicular lymphoma is a multi-hit process progressing over many years through the accumulation of numerous genetic alterations. Besides the hallmark t(14;18), it is still unclear which other oncogenic hits contribute to the early steps of transformation and in which precursor stages these occur. To address this issue, we performed high-resolution comparative genomic hybridization microarrays on laser-capture micro-dissected cases of follicular lymphoma in situ (n=4), partial involvement by follicular lymphoma (n=4), and duodenal follicular lymphoma (n=4), assumed to represent, potentially, the earliest stages in the evolution of follicular lymphoma. Cases of reactive follicular hyperplasia (n=2), uninvolved areas from follicular lymphoma in situ lymph nodes, follicular lymphoma grade 1–2 (n=5) and follicular lymphoma grade 3A (n=5) were used as controls. Surprisingly, alterations involving several relevant (onco)genes were found in all entities, but at significantly lower proportions than in overt follicular lymphoma. While the number of alterations clearly assigns all these entities as precursors, the pattern of partial involvement by follicular lymphoma alterations was quantitatively and qualitatively closer to that of follicular lymphoma, indicating significant selective pressure in line with its faster rate of progression. Among the most notable alterations, we observed and validated deletions of 1p36 and gains of the 7p and 12q chromosomes and related oncogenes, which include some of the most recurrent oncogenic alterations in overt follicular lymphoma (TNFRSF14, EZH2, MLL2). By further delineating distinctive and hierarchical molecular and genetic features of early follicular lymphoma entities, our analysis underlines the importance of applying appropriate criteria for the differential diagnosis. It also provides a first set of candidates likely to be involved in the cascade of hits that pave the path of the various progression phases to follicular lymphoma development.     

Brief report: imitation effects on children with autism

Twenty children with autism (mean age, 5 years) were recruited for the study from a school for children with autism. The children were randomly assigned to an imitation (n = 10) or contingently responsive (n = 10) interaction group based on a stratification table for gender and developmental and chronological age. The sessions consisted of four phases, with each phase lasting 3 minutes. In the first phase, the child walked into a room that was furnished with a sofa, a table, chairs, and two sets of identical toys. An adult was in the room sitting very still like a statue (first still-face condition). In the second phase, the adult either imitated the child or was contingently responsive to the child. In the third phase, the adult sat still again (second still-face condition), and in the fourth phase, the adult engaged in a spontaneous interaction. During the third phase (the second still-face condition), the children in the imitation group spent less time in gross motor activity and more time touching the adult, as if attempting to initiate an interaction. The contingency condition appeared to be a more effective way to facilitate a distal social behavior (attention), whereas the imitative condition was a more effective way to facilitate a proximal social behavior (touching).     

Pertussis is increasing in unimmunized infants: is a change in policy needed?

The proportion and trend in absolute number of pertussis notifications in young infants has increased each year in England and Wales since the accelerated immunization schedule was introduced. We report five infants all less than 3 months of age admitted with life threatening pertussis infection to two paediatric intensive care units. Despite aggressive cardiorespiratory support measures, three of the infants died. Pertussis remains a significant cause of morbidity and mortality in unimmunized infants. In this age group presentation is likely to be atypical and infection more severe. Public health measures to prevent the disease could be strengthened. Chemoprophylaxis should be offered to susceptible contacts and booster vaccinations against pertussis considered.     

New therapies and vaccines for bacterial meningitis

Acute bacterial meningitis remains an important cause of morbidity and mortality worldwide. There have recently been major advances in the prevention of the major causes of bacterial meningitis following improvements in vaccinology. The success of immunisation against Haemophilus influenzae type b infection is being mirrored with serogroup C conjugated meningococcal vaccine and pneumococcal conjugate vaccine. However, there remain major challenges, notably, serogroup B meningococcal infection and shifts in epidemiology caused by vaccine introduction. In addition, much of the world's population is unvaccinated. Therefore, improvements in management of acute bacterial meningitis are vital. In this review we attempt to summarise important advances in both prevention and treatment of acute bacterial meningitis.