Chronic Obstructive Pulmonary Disease (COPD) is characterized by airspace enlargement and peribronchial lymphoid follicles; however, the immunological mechanisms leading to these pathologic changes remain undefined. Here we show that cigarette smoke is a selective adjuvant that augments in vitro and in vivo Th17, but not Th1, cell differentiation via the aryl hydrocarbon receptor. Smoke exposed IL-17RA−/− mice failed to induce CCL2 and MMP12 compared to WT mice. Remarkably, in contrast to WT mice, IL-17RA−/− mice failed to develop emphysema after 6 months of cigarette smoke exposure. Taken together, these data demonstrate that cigarette smoke is a potent Th17 adjuvant and that IL-17RA signaling is required for chemokine expression necessary for MMP12 induction and tissue emphysema.

Large-conductance calciumand voltage-gated potassium channels (BK or Slowpoke) serve as dynamic integrators linking electrical signaling and intracellular activity. These channels can mediate many different Ca 2+ -dependent physiological processes including the regulation of neuronal and neuroendocrine cell excitability and muscle contraction. To gain insights into the function of BK channels in vivo, we isolated a full-length cDNA encoding the alpha subunit of a Slowpoke channel from the tobacco hornworm, Manduca sexta (msslo). Amino acid sequence comparison of the deduced Manduca protein revealed at least 80% identity to the insect Slo channels. The five C-terminal alternative splice regions are conserved, but the cloned cDNA fragments contained some unique combinations of exons E, G and I. Our spatial profile revealed that transcript levels were highest in skeletal muscle when compared with the central nervous system (CNS) and visceral muscle. The temporal profile suggested that msslo expression is regulated developmentally in a tissue-and regional-specific pattern. The levels of msslo transcripts remain relatively constant throughout metamorphosis in the CNS, transiently decline in the heart and are barely detectable in the gut except in adults. A dramatic upregulation of msslo transcript levels occurs in thoracic but not abdominal dorsal longitudinal body wall muscles (DLM), suggesting that the msSlo current plays an important role in the excitation or contractile properties of the phasic flight muscle. Our developmental profile of msslo expression suggests that msSlo currents may contribute to the changes in neural circuits and muscle properties that produce stage-specific functions and behaviors.

A very large number of evolutionarily conserved potassium channels have been identified but very little is known about their function or modulation in vivo. Metamorphosis of the tobacco hornworm, Manduca sexta, is a compelling model system for such studies because it permits analysis to be conducted at the level of identified neurons whose roles in simple behaviors and endocrine regulation are known. We present here the characterization of the first ion channel to be cloned from this animal. Partial genomic sequence for Manduca sexta ether à-go-go (Mseag) and a cDNA clone encoding the Mseag open reading frame were obtained. Genomic Southern analysis indicates that Manduca contains a single member of the eag subfamily per haploid genome. When expressed in Xenopus oocytes, MsEag channels conduct a voltage-dependent, K+ selective outward current with an inactivating component that closely resembles the Drosophila eag current. Mseag transcripts were restricted to the nervous system, adult antenna, and one set of larval skeletal muscles. Steroid hormonal regulation of Mseag expression is suggested by the temporal correlation of developmental changes in transcript expression with the changing steroid titers that promote metamorphosis. These results provide the foundation for functional and modulatory studies of the Eag family of K+ channels in Manduca, which will complement the genetic analysis in Drosophila.