The need to monitor inflammation in the lungs has led to the exploration of exhaled gases and condensates, that may assist in differential diagnosis of pulmonary diseases, assessment of disease severity and response to treatment [, , ]. A proof-ofconcept study often will involve an examination of effects on a surrogate marker that is not guaranteed to produce a quick readout, such as effects on, for example neutrophilia or neutrophil activation in chronic obstructive pulmonary disease (COPD).
Airway mucus hypersecretion is now recognized as a key pathophysiological feature in many patients with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapies, including anticholinergics, β2‐adrenoceptor agonists, corticosteroids, mucolytics and macrolide antibiotics, have variable efficacy in inhibiting airway mucus hypersecretion, and are less effective in COPD than in asthma. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity (e.g. large conductance calcium‐activated potassium, BKCa, channel activators), tachykinin receptor antagonists, epoxygenase inducers (e.g. benzafibrate), inhibitors of mucin exocytosis (e.g. anti‐myristoylated alanine‐rich C kinase substrate (MARCKS), peptide and Munc‐18B blockers), inhibitors of mucin synthesis and goblet cell hyperplasia (e.g. epidermal growth factor (EGF), receptor tyrosine kinase inhibitors, p38 mitogen‐activated protein (MAP), kinase inhibitors, MAP kinase kinase/extracellular signal‐regulated kinase (MEK/ERK), inhibitors, human calcium‐activated chloride (hCACL2), channel blockers and retinoic acid receptor‐α antagonists), inducers of goblet cell apoptosis (e.g. Bax inducers or Bcl‐2 inhibitors), and purinoceptor P2Y2 antagonists to inhibit mucin secretion or P2Y2 agonists to hydrate secretions. However, real and theoretical differences delineate the mucus hypersecretory phenotype in asthma from that in COPD. More information is required on these differences to identify specific therapeutic targets which, in turn, should lead to rational design of anti‐hypersecretory drugs for treatment of airway mucus hypersecretion in asthma and COPD.
The effect of thrombolysis in acute myocardial infarction on enzymatic infarct size, left ventricular function, and early mortality was studied in subsets of patients in a randomized trial at The Netherlands Interuniversity Cardiological Institute during a 5-year period. Early thrombolytic therapy with intracoronary streptokinase (152 patients) or with intracoronary streptokinase preceded by intravenous streptokinase (117 patients) was compared to conventional treatment (264 patients). All 533 patients were admitted to the coronary care unit within 4 hours after onset of symptoms indicative of acute myocardial infarction. There were 488 patients eligible for this detailed analysis, of whom 245 were allocated for thrombolytic therapy. Early angiography was performed in 212 of the 245 patients. Patency of the infarct-related artery was achieved in 181 patients (85%). Enzymatic infarct size measured from cumulative alpha HBDH release was smaller in patients allocated to thrombolytic therapy (median 760 U/l vs. 1179 U/l in controls, p = 0.0001). LVEF measured by radionuclide angiography before discharge was higher after thrombolytic therapy (median 50% vs. 43% in controls, p = 0.0001). The 12-month mortality was lower in patients allocated to thrombolytic therapy (8% vs. 16% in the control group, p < 0.01). In multivariate regression analysis, infarct size limitation, improvement of LVEF, and a 3-month mortality were predicted by ST, time from onset of symptoms to admission, and Killip class at admission. Thrombolysis was most useful in patients admitted within 2 hours after onset of symptoms and in patients with ST of 1.2 mV or more. On the other hand, no beneficial effects of streptokinase on enzymatic infarct size, left ventricular function, or mortality were observed in the subset of patients with ST less than 1.2 mV admitted 2 to 4 hours after onset of symptoms.
Alveolar macrophages play a critical role as orchestrators of inflammation in chronic obstructive pulmonary disease (COPD). The numbers of alveolar macrophages are markedly increased in the lungs of patients with COPD as a result of increased recruitment, proliferation and survival. Alveolar macrophages secrete many inflammatory mediators, oxidants, proteins and proteinases in response to cigarette smoke extract and other stimuli. In COPD there is amplified secretion of these inflammatory products which may be related to defective histone deacetylase-2, which may also account for the steroid resistance of these cells in COPD patients. There are several novel therapeutic strategies targeted at macrophages.
Cytokines are usually extracellular signalling proteins, usually less than 80 kD in size, and many are glycosylated. They are produced by many different cell types that are involved in cell-to-cell interactions acting through specific receptors on the surface of target cells. Cytokines usually have an effect on closely adjacent cells and therefore function in a predominantly paracrine fashion, although they may also act at a distance (endocrine) and may have effects on the cell of origin (autocrine). Cytokines may be regarded as a mechanism for cell-cell communication, and within this group may be included growth factors and cytokines with primarily chemoattractant properties (chemokines). They act on target cells to cause a wide array of cellular functions including activation, proliferation, chemotaxis, immunomodulation, release of other cytokines or mediators, growth and cell differentiation, and apoptosis. Cytokines were originally characterised (and named) according to some aspect of their functional activity that was initially discovered, but the cloning of the genes for these cytokines has now provided a better insight into their classification and grouping. It is apparent that there is a wide pleiotropy and element of redundancy in the cytokine family in that each cytokine has many overlapping functions, with each function potentially mediated by more than one cytokine. The effect of an individual cytokine in the context of disease may not be easy to predict because it may be influenced by other cytokines released simultaneously from the same cell or from target cells following activation by the cytokine. The effects of cytokines are mediated by binding to cell surface high affinity receptors usually present in low numbers. The number of these receptors can be upregulated with cell activation, and there the effect of a cytokine may depend on the modulation of its receptors. Cytokines themselves may induce the expression of receptors which may …
