Archive for the ‘Pulmonary Disease’ Category

bronchial mucosaAnti-inflammatory Effects

Inflammation contributes to the pathophysiology of many pulmonary diseases, including asthma and other hypersensitivity reactions, acute and chronic infections, and injuries induced by inhalation of noxious chemicals. The inflammatory process amplifies the deleterious effects of the initial injury and increases the interference with pulmonary function. In asthma, for example, the obstruction to air flow is not limited to the constriction of airway smooth muscle, but also includes mucous plugs and an exudate containing inflammatory cells and desquamated epithelium in the airway lumen, and edema and cellular infiltration of the bronchial mucosa and submucosa. IgE-mediated late-phase reactions to allergens are associated with inflammation. Studies of bronchial secretions and bronchial lavage fluids also demonstrate that an inflammatory response accompanies various non-IgE-medi-ated forms of bronchitis. In addition, as discussed later, there is increasing evidence that inflammation contributes to the airway hyperreactivity that is associated with a number of pulmonary diseases.

The development of an inflammatory reaction requires several essential components. First, there is absolute dependence on the presence of leukocytes. Neutrophils are required for acute inflammation; monocyte-macrophages and various recruited cells are needed for chronic inflammation and delayed hypersensitivity reactions. Chemoattractants aid in the recruitment of leukocytes and promote their migration into tissue. In addition, a vasoactive factor is needed to increase the permeability of the microvasculature and allow extravasation of fluid and cells. Mechanisms that enhance local blood flow increase the accumulation of fluids and leukocytes into inflammatory foci. If you cannot allow to buy the drugs you are prescribed you may order them at a considerable low price. It means to order drugs via the Internet for example see here.

Glucocorticoids suppress acute and chronic inflammation, irrespective of cause, by inhibiting each of the essential components of the inflammatory reaction. They inhibit recruitment of leukocytes for acute and chronic inflammation through their effects on leukocyte migration and distribution. The effects on neutrophils are illustrative. Within hours after administration of a single dose of glucocorticoids, neutrophils that are normally marginated on the capillary endothelium of storage sites in the lung and other tissues reenter the circulating pool. This is associated with depletion of tissue stores of neutrophils and diminished accumulation into inflammatory foci and inflammatory exudates. Glucocorticoids also suppress a number of leukocyte functions that contribute to glucocorticoidsimmunologic and inflammatory processes. These include suppression of the binding of complement components and antibody IgE and IgG to receptors on leukocytes and suppression of the synthesis of or the response to various lympholdnes. In addition, glucocorticoids suppress the leakage of fluids and cells into areas of inflammation by causing constriction of the microvasculature.

Influence on Mediators of Pulmonary Disease

Many of the anti-inflammatory actions of glucocorticoids stem from their influence on the formation of or the responses to various chemotactant and vasoactive substances that participate in the inflammatory response. In the past decade a number of these bioactive mediators have been characterized chemically and their biologic roles defined. It has become apparent that some of the mediators of inflammation are also responsible for other pathophysiologic processes in the lung, Tables 1 and 2 provide a partial listing of mediators that contribute to pulmonary disease and the effects of glucocorticoids in modifying their effects.

Arachidonate Metabolites: One group of compounds of particular interest in pulmonary disease are the products derived from arachidonic acid (AA), a polyunsaturated fatty acid that is a normal component of phospholipids in cell membranes. Stimulation of cells by a variety of mechanisms allows entry of Ca+ +and activates calcium-dependent phospholipases that cleave AA from phospholipids. The AA then serves as precursor for the formation of a large family of biologically active products, which include prostaglandins, thromboxane, and prostacyclin synthesized by the cyclooxygenase pathway and the leukotrienes synthesized by the lipoxygenase pathway. The latter products are proinflammatory and also have a large role in the pathogenesis of other disturbances of pulmonary function, including airway constriction with preferential action on peripheral airways, constriction of the pulmonary vasculature, and mucous secretion. In addition, during the metabolism of AA, toxic derivatives of oxygen are generated and contribute to tissue injury.

Platelet Activating Factor (PAF): PAF is another phospholipid derivative that is synthesized in part through the action of the enzyme phospholipase A. PAF is generated by basophils, alveolar macrophages, and platelets in response to IgE-mediated as well as non-immunologic stimuli. Its potent pro-inflammatory effects include vasodilation, increased vascular permeability, aggregation of platelets, recruitment and activation of leukocytes, and induction of the release of various bioactive products from activated leukocytes and platelets; the latter products include enzymes and cationic proteins that contribute to tissue injury and to the sustained inflammatory reaction induced by PAF. In addition, PAF causes bronchoconstriction, prolonged decrease in dynamic compliance, pulmonary hypertension and edema, systemic hypotension, constriction of coronary arteries and myocardial depression. Many of the effects of PAF mimic the changes induced by antigens in patients with allergy, including the wheal and flare responses to intradermal injection, biphasic early and late bronchoconstrictor responses to inhalation, and prolonged airway inflammation. Some effects of PAF, such as bron-choconstriction, are platelet-dependent; other effects are independent of platelet activation and stem from PAF interaction with other target tissues, such as macrophages and vascular epithelium.

pulmonary hypertensionHistamine: Histamine is a mediator of bronchocon-striction and inflammation that is released from basophils and mast cells by IgE-mediated mechanisms and is found in human plasma after allergen inhalation. Histamine can also be released by non-IgE-mediated mechanisms, including exposure to toxins, that induce entry of Ca++ and degranulation of the cells. Glucocorticoids suppress IgE-mediated release in basophils by influencing a step that precedes and prevents entry of Ca*+ into the cell.

Inhibition of Mediator Release

Role of Lipomodulin: Glucocorticoids suppress synthesis of all products derived from both pathways of AA metabolism by inhibiting the action of phospholipase enzymes that cleave precursor AA from membrane phospholipids. Glucocorticoids also suppress the initial stage in synthesis of phospholipid-derived PAF. These effects stem from the induction by glucocorticoids of an inhibitory protein (or group of proteins), termed lipomodulin or macrocortin, that block the actions of phospholipase enzymes. Lipomodulin is synthesized normally by neutrophils, macrophages and by cells in lung. Glucocorticoids have two effects: first, they induce the release of preformed lipomodulin; then they enhance synthesis of additional protein. Lipomodulin functions as an extracellular mediator that suppresses release and metabolism of AA in other cells; it also regulates the activity of phospholipases intracellularly. When injected into animals, the protein exhibits anti-inflammatory activity in experimental models of inflammation.

It is possible that glucocorticoid-induced proteins other than lipomodulin also contribute to the inhibition of mediator release. Additionally, as noted before, glucocorticoids modulate mediator release through their effects on Ca++ transport.

Although glucocorticoids have considerable influence on synthesis and release of the mediators, they are not fully suppressive in all instances. Thus, although IgE-mediated histamine release can be inhibited in human basophils and rodent mast cells by incubation with glucocorticoids in vitro for 16 hours, a recent report indicated that similar exposure to glucocorticoid did not suppress IgE-mediated release of histamine or the mast cell cyclooxygenase products (PGD2 and thromboxane) in isolated human lung mast cells or fragments of human lung; cyclooxygenase products synthesized by other lung cells were inhibited. Variations in cellular sensitivity to glucocorticoid action may account for these differences. The effects of short- and long-term administration of glucocorticoid may be due to their influence on the more sensitive cell populations.

Influence on Mediator Actions

Many of the mediators, including catecholamines, histamine, leukotrienes and probably PAF, produce their effects through interaction with specific cellular receptors. Glucocorticoids modify the tissue responses to such mediators by influencing the availability and binding affinity of the various receptors and the coupling of the receptors to intracellular enzymes. The influence of glucocorticoids on the beta adrenergic receptor system has been studied in detail (see below). Similar mechanisms modulate tissue responses to other mediators.