Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality in the United States and worldwide. They share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by the incidence of these diseases in only a fraction of smokers. The presence of COPD increases the risk of lung cancer up to 4.5-fold. To investigate commonalities in disease mechanisms and perspectives for disease chemoprevention, the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI) held a workshop. The participants identified four research objectives: 1) clarify common epidemiological characteristics of lung cancer and COPD; 2) identify shared genetic and epigenetic risk factors; 3) identify and validate biomarkers, molecular signatures, and imaging-derived measurements of each disease; and 4) determine common and disparate pathogenetic mechanisms. These objectives should be reached via four research approaches: 1) identify, publicize, and enable the evaluation and analysis of existing datasets and repositories of biospecimens; 2) obtain phenotypic and outcome data and biospecimens from large studies of subjects with and/or at risk for COPD and lung cancer; 3) develop and use animal and other preclinical models to investigate pathogenetic links between the diseases; and 4) conduct early-phase clinical trials of potential chemopreventive agents. To foster much needed research interactions, two final recommendations were made by the participants: 1) incorporate baseline phenotyping and outcome measures for both diseases in future longitudinal studies of each disease and 2) expand collaborative efforts between the NCI and NHLBI.

Long-term oxygen treatment (LTOT) prolongs life in patients with chronic obstructive pulmonary disease (COPD) and severe resting hypoxemia. Although this benefit is proven by clinical trials, scientific research has not provided definitive guidance regarding who should receive LTOT and how it should be delivered. Deficiencies in knowledge and in current research activity related to LTOT are especially striking in comparison to the importance of LTOT in the management of COPD and the associated costs. The National Heart, Lung, and Blood Institute, in collaboration with the Centers for Medicare and Medicaid Services, convened a working group to discuss research on LTOT. Participants in this meeting identified specific areas in which further investigation would likely lead to improvements in the care of patients with COPD or reductions in the cost of their care. The group recommended four clinical trials in subjects with COPD: (1 ) efficacy of ambulatory O 2 supplementation in subjects who experience oxyhemoglobin desaturation during physical activity but are not severely hypoxemic at rest; (2 ) efficacy of LTOT in subjects with severe COPD and only moderate hypoxemia; (3 ) efficacy of nocturnal O 2 supplementation in subjects who show episodic desaturation during sleep that is not attributable to obstructive sleep apnea; and (4 ) effectiveness of an activitydependent prescription for O 2 flow rate that is based on clinical tests performed at rest, during exercise, and during sleep.

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Chronic obstructive pulmonary disease (COPD) is a common condition, and one difficult to manage. Available treatments, other than smoking cessation, are only minimally effective, and the knowledge basis for clinical decision making is limited. To identify areas in which further clinical research may lead to significant improvements in the care of patients with COPD, the National Heart, Lung, and Blood Institute convened a Working Group, entitled "Clinical Research in COPD: Needs and Opportunities," on March 21-22, 2002. This group of experts identified important questions in the field and made the following recommendations: (1) establish a multicenter Clinical Research Network to perform multiple, short-term clinical trials of treatments in patients with moderate-to-severe COPD; (2) create a system for the standardized collection, processing, and distribution of lung tissue specimens and associated clinical and laboratory data; (3) develop standards for the classification and staging of COPD; (4) characterize the development and progression of COPD using measures and biomarkers that relate to current concepts of pathogenesis; and (5) evaluate indications for long-term oxygen therapy for patients with COPD.

Three intravenous anesthetics evaluated in this study decreased the ICa of porcine tracheal smooth muscle cells but with subtle electrophysiologic differences. Hence, thiopental, ketamine, and propofol each inhibit L-type voltage-dependent Ca2+ channels of porcine tracheal smooth muscle cells but the molecular mechanisms involved may be agent specific. This inhibition may contribute to the airway smooth muscle relaxant effects of these agents observed in vitro at concentrations greater than those encountered clinically.

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Recent discoveries indicate that disorders of protein folding and degradation play a particularly important role in the development of lung diseases and their associated complications. The overarching purpose of the National Heart, Lung, and Blood Institute workshop on "Malformed Protein Structure and Proteostasis in Lung Diseases" was to identify mechanistic and clinical research opportunities indicated by these recent discoveries in proteostasis science that will advance our molecular understanding of lung pathobiology and facilitate the development of new diagnostic and therapeutic strategies for the prevention and treatment of lung disease. The workshop's discussion focused on identifying gaps in scientific knowledge with respect to proteostasis and lung disease, discussing new research advances and opportunities in protein folding science, and highlighting novel technologies with potential therapeutic applications for diagnosis and treatment.

Increased sensitivity to intracellular Ca2+ concentration ([Ca2+]) is an important mechanism for agonist-induced contraction of airway smooth muscle, but the signal transduction pathways involved are uncertain. We studied Ca2+ sensitization with acetylcholine (ACh) and endothelin (ET)-1 in porcine tracheal smooth muscle by measuring contractions at a constant [Ca2+] in strips permeabilized with α-toxin or β-escin. The peptide inhibitor G protein antagonist 2A (GP Ant-2A), which has selectivity for Gq over Gi, inhibited contractile responses to ET-1, ACh, and guanosine 5′- O-(3-thiotriphosphate) (GTPγS), but the proportional inhibition of ACh responses was less than that of ET-1. Pretreatment with pertussis toxin reduced ACh contractions but had no effect on those of ET-1 or GTPγS. Clostridium botulinum C3 exoenzyme, which inactivates Rho family monomeric G proteins, caused similar reductions in contractile responses to ACh, ET-1, and GTPγS. Farnesyltransferase inhibition, which inhibits Ras G proteins, reduced responses to ET-1. We conclude that the heterotrimeric G proteins Gq and Gi both contribute to Ca2+ sensitization by ACh, whereas ET-1 responses involve Gq but not Gi. Both Gq and Gi pathways likely involve Rho family small G proteins. A Ras-mediated pathway also contributes to Ca2+ sensitization by ET-1 in airway smooth muscle.