Toll-like receptors (TLRs) act as receptors for numerous stimuli of immune cells, including bacterial cell wall constituents (lipopolysaccharide [LPS] from Gram-negative bacteria and lipopeptides from Gram-positive species), plasma proteins and extracellular matrix breakdown products. TLR2 and TLR4 bind lipopeptide and LPS respectively, mediating responses of alveolar macrophages and other immune cells to bacterial infection in the lungs. Exposure of lungs to LPS leads to pro-inflammatory responses of a number of cell types, including airway smooth muscle, which secretes a number of cytokines involved in leucocyte recruitment and the Th2 polarization of immune responses. Human airway smooth muscle cells were cultured with LPS in the absence and presence of peripheral blood mononuclear cells to determine direct and leucocyte-dependent TLR-mediated responses. (more…)

Airway remodelling is considered to be of major importance in the pathology of asthma, with subepithelial basement membrane thickening in particular being indicative of early development of the disease and characteristic of its progression. Airway fibroblasts are central cells in the processes of remodelling: increased deposition of fibroblast-derived connective tissue proteins and differentiation of fibroblasts into contractile myofibroblasts are consistent observations in morphological studies of moderate to severe asthmatic airways. The secretory function of fibroblasts is under the control of locally produced growth factors such as vascular endothelial cell growth factor (VEGF, see below) and platelet-derived growth factor (PDGF). (more…)

Despite optimum drug delivery and good compliance with inhaled corticosteroids, many patients experience symptoms and exacerbations. Dose–response studies using inhaled corticosteroids have generally been unable to demonstrate any significant difference between individual doses of inhaled corticosteroids. For example, a metaanalysis evaluated eight studies (2324 asthmatics) where the effects of at least two doses of inhaled fluticasone were measured. (more…)

Some of the immediate sequelae of injury are uncomfortably familiar: Soon after an injury occurs, the affected site and its surrounding tissues become reddened, warm, swollen, and painful. These four signs which are probably the most useful and ubiquitous diagnostic clues in all of clinical medicine are hallmarks of acute inflammation, the body’s initial physiologic reaction to tissue distress. In its simplest form, inflammation is a response carried out by blood vessels and by the endothelial cells that line them. (more…)

Normally present at very low levels in plasma, antibodies of the immunoglobulin E (IgE) isotype were first discovered in 1967, decades after the description of IgA, IgG, and IM. IgE antibodies are produced primarily by plasma cells in mucosal-associated lymphoid tissue and their levels are uniformly elevated in patients suffering from atopic conditions like allergic rhinitis, asthma and atopic dermatitis. Production of allergen-specific IgE in atopic individuals is driven both by a genetic predisposition to the synthesis of this isotype as well as by environmental factors, including chronic allergen exposure. (more…)

Some features seem to be common to severe asthma and Chronic Obstructive Pulmonary Disease with reversibility of airflow limitation. The neutrophil chemoattractant leukotriene B 4 (LTB 4) may play a role in Chronic Obstructive Pulmonary Disease and in some forms of asthma. In this study, 55 smokers with no disease, Chronic Obstructive Pulmonary Disease (with or without bronchodilator reversibility of airflow limitation) or asthma underwent measurement of LTB 4 in sputum supernatants and exhaled breath condensate asthma (EBC). Both Chronic Obstructive Pulmonary Disease and asthma patients had higher levels of LTB 4 than control subjects; patients with asthma or reversible Chronic Obstructive Pulmonary Disease exhibited significantly higher levels of LTB 4 than those with irreversible Chronic Obstructive Pulmonary Disease. (more…)

Roflumilast is an oral, once-daily inhibitor of phosphodiesterase type 4 (PDE4) that prevents the breakdown of cyclic adenosine monophosphate (cAMP) levels, leading to inhibition of pro-inflammatory signalling. This study investigated the effects of repeated doses of 250 or 500 µg of roflumilast on airway asthma responses to allergen. (more…)

Asthma control is improved by combining inhaled corticosteroids with long acting beta-agonists but patients still require reliever medication for breakthrough symptoms. Periodic fluctuations in symptoms and airway inflammation are characteristics of asthma, which means that treatment requirements, especially reliever use, can vary over time. (more…)

Allergen exposure plays a role in the development of asthma bronchial hyper-responsiveness and in the acute inflammatory response seen in asthmatic patients. Reduction of house dust mite allergens might lead to better lung function and reduction of asthma symptoms. (more…)

Most acute phase proteins are synthesized in the liver, although the genes for some are also expressed in cells and tissues elsewhere. Transcriptional control is the main mechanism for regulation of production hut mRNA stability contributes in some cases. A large number of cytokines, including interleukin I (IL-1), IL-6, tumours necrosis factor a and various interferons, are capable of inducing increased, or in some cases decreased, production of various acute phase proteins in vivo and in cultured hepatocytes and liver ccli Lines in vitro. Glucocorticoids and steroid sex hormones can play an important permissive role and neural and neuroendocrine influences may be significant in vivo. Results obtained in different laboratories with different acute phase proteins, different cytokines and different cell lines or experimental systems have shown much variation.

It has been difficult to reconcile all the findings and to identify the critical participation of particular mediators in control of particular reactants, especially because of the cascade effects by which some cytokines promote the production of others. Nevertheless it is striking that 11-6 knockout mice mount absolutely no acute phase response of serum amyloid A protein (SAA), serum amyloid P component (SAP) or complement component C3 following induction of sterile inflammation by casein or silver nitrate injection, whereas lipopolysaccharide (I .PS induces a definite, although subnormal, response.

Studies with transgenic mice bearing the human CRP gene, with transfected cells containing human SAA genes, and with hepatoma cell lines, have identified regulatory flanking regions of DNA which are targets for the action of nuclear Factors responsive to IL-6 and IL-I.

While the profile of acute phase plasma proteins is broadly similar across species there are nonetheless important differences. For example, SAP is a major acute phase reactant only in the mouse, and there are many other differences in normal levels and acute phase behaviour of other members of the pentraxin family of proteins to which it belongs. While these differences may be important for the usefulness of particular proteins as markers in clinical or experimental situations, they may not reflect, as has been pointed out above, the underlying metabolic regulation. On the other hand, some species differences are clearly of physiological and pathophysiological importance. Thus, although rats have a gene for a homolog of SAA, the expression of which is regulated as an acute phase protein, the product does not appear as a plasma lipoprotein and rats never get AA amyloidosis. This contrasts with the behaviour of SAA in all other mammals and birds which have been studied.