The lung responds to a variety of insults in a remarkably consistent fashion but with inconsistent outcomes that vary from complete resolution and return to normal to the destruction of normal architecture and progressive fibrosis. Increasing evidence indicates that diffuse lung disease results from an imbalance between the pro-inflammatory and anti-inflammatory mechanisms, with a persistent imbalance that favors pro-inflammatory mediators dictating the development of chronic diffuse lung disease. This review focuses on the mediators that influence this imbalance.

The study of genetic polymorphisms has touched every aspect of pulmonary and critical care medicine. We review recent progress made using genetic polymorphisms to define pathophysiology, to identify persons at risk for pulmonary disease and to predict treatment response. Several pitfalls are commonly encountered in studying genetic polymorphisms, and this article points out criteria that should be applied to design high-quality genetic polymorphism studies.

The availability of a draft sequence for the human genome will revolutionise research into airway disease. This review deals with two of the most important areas impinging on the treatment of patients: pharmacogenetics and pharmacogenomics. Considerable inter-individual variation exists at the DNA level in targets for medication, and variability in response to treatment may, in part, be determined by this genetic variation. Increased knowledge about the human genome might also permit the identification of novel therapeutic targets by expression profiling at the RNA (genomics) or protein (proteomics) level. This review describes recent advances in pharmacogenetics and pharmacogenomics with regard to airway disease.

I am delighted to welcome you to the first printed issue ofRespiratory Research. This new journal, available both on the World Wide Web and in print, will provide timely reviews and rapid publication of primary research in respiratory medicine. The online version ofRespiratory Researchwill be the primary place of publication, where articles appear in full, as soon as they are ready for publication. In fact, the journal website (http://respiratory-research.com) has been open since June 2000, and many of the articles appearing in this issue have been available online for many weeks. The online environment not only allows information to be widely disseminated, but also provides a forum for discussion and the possibility of rapid feedback. Many helpful comments have already been sent to us, and will be incorporated as the journal develops.

Pulmonary surfactant is a surface active material composed of both lipids and proteins that is produced by alveolar type II pneumocytes. Abnormalities of surfactant in the immature lung or in the acutely inflamed mature lung are well described. However, in a variety of subacute diseases of the mature lung, abnormalities of lung surfactant may also be of importance. These diseases include chronic obstructive pulmonary disease, asthma, cystic fibrosis, interstitial lung disease, pneumonia, and alveolar proteinosis. Understanding of the mechanisms that disturb the lung surfactant system may lead to novel rational therapies for these diseases.

The 97th American Thoracic Society meeting proved to be an excellent meeting, providing a wealth of new information on inflammatory diseases of the airways. Once again there appeared to be an increased emphasis on chronic obstructive pulmonary disease (COPD) with most of the major drug companies concentrating a large part of their efforts in this field. An assessment of the new British Thoracic Society guidelines, which are designed to promote better management of COPD, was also presented at the meeting. Potential new treatments for inflammatory diseases of the airways including COPD were described, ranging from phase III trial data with GlaxoSmithKline's PDE4 inhibitor, Cilomilast (Ariflo®) to the development of AstraZeneca's novel dual dopamine D2-receptor/β2-adrenoreceptor agonist, Viozan™. Of particular interest was Byk Gulden's Ciclesonide, a new corticosteroid with equivalent efficacy to the market leaders but with an improved safety profile. The same company also presented data on their PDE4 inhibitor, Roflumilast, which is now in phase II/III. Bayer presented data on their PDE4 inhibitor, BAY 19-8004, in a smoking animal model and claimed greater anti-inflammatory efficacy than with a steroid. Asta Medica (now known as Elbion) also described a new potent PDE4 inhibitor, AWD 12-281, with anti-inflammatory activity. In the bronchodilator field, an analysis of data from a one-year trial with Boehringer Ingelheim's Tiotropium revealed a possible improvement in lung function in COPD patients; this needs to be confirmed in a specifically designed study. Inhibitors of p38 (c-Jun NH2-terminal kinase and syk kinase) were also discussed as anti-inflammatory agents with potential in the treatment of COPD and asthma. GlaxoSmithKline's p38 kinase inhibitor, SB 239063, appeared to be the most advanced of these with clinical data expected in two to three years. Lyn kinase was also discussed as a novel target for inflammatory airway diseases.

Pulmonary surfactant is a complex mixture of phospholipids and proteins, which is present in the alveolar lining fluid and is essential for normal lung function. Alterations in surfactant composition have been reported in several interstitial lung diseases (ILDs). Furthermore, a mutation in the surfactant protein C gene that results in complete absence of the protein has been shown to be associated with familial ILD. The role of surfactant in lung disease is therefore drawing increasing attention following the elucidation of the genetic basis underlying its surface expression and the proof of surfactant abnormalities in ILD.

The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium are unique features of the lung that can facilitate systemic delivery via pulmonary administration of peptides and proteins. Physical and biochemical barriers, lack of optimal dosage forms and delivery devices limit the systemic delivery of biotherapeutic agents by inhalation. Current efforts to overcome these difficulties in order to deliver metabolic hormones (insulin, calcitonin, thyroid-stimulating hormone [TSH], follicle-stimulating hormone [FSH] and growth hormones) systemically, to induce systemic responses (immunoglobulins, cyclosporin A [CsA], recombinant-methionyl human granulocyte colony-stimulating factor [r-huG-CSF], pancreatic islet autoantigen) and to modulate other biological processes via the lung are reviewed. Safety aspects of pulmonary peptide and protein administration are also discussed.

Background The heterogeneity of conditions underlying respiratory distress, whether classified clinically as acute lung injury (ALI) or the more severe acute respiratory distress syndrome (ARDS), has hampered efforts to identify and more successfully treat these patients. Examination of postmortem lungs among cases clinically diagnosed as ARDS identified a cohort that showed a consistent morphology at the light and electron microscope levels, and featured pathognomonic structures which we termed elastin-staining laminar structures (ELS). Methods Postmortem tissues were stained using the Verhoeff-Van Gieson procedure for elastic fibers, and with Congo red for examination under a polarizing microscope. Similar samples were examined by transmission EM. Results The pathognomonic ELS presented as ordered molecular aggregates when stained using the Verhoeff-van Gieson technique for elastic fibers. In several postmortem lungs, the ELS also displayed apple-green birefringence after staining with Congo red, suggesting the presence of amyloid. Remarkably, most of the postmortem lungs with ELS exhibited no significant acute inflammatory cellular response such as neutrophilic reaction, and little evidence of widespread edema except for focal intra-alveolar hemorrhage. Conclusions Postmortem lungs that exhibit the ELS constitute a morphologically-identifiable subgroup of ARDS cases. The ordered nature of the ELS, as indicated by both elastin and amyloid stains, together with little morphological evidence of inflammation or edema, suggests that this cohort of ARDS may represent another form of conformational disease. If this hypothesis is confirmed, it will require a new approach in the diagnosis and treatment of patients who exhibit this form of acute lung injury.