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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.

The mean age for patients in the study group was 4.9 months (55% male patients), and for the control subjects it was 4.4 months (52% male subjects). No procedure-related complications occurred. All patients were discharged from the hospital promptly after undergoing the WT, and 1.5 to 4.5 h after undergoing the DAT (median time, 2.1 h).
There was a high clinical agreement between investigators 1 (Y.S.) and 4 (A.D.) for the laryngo-malacia clinical scores with median scores of 8.0 for both investigators (range, 3 to 12 and 4 to 11, respectively; p = 0.36 [Wilcoxon test]). The correlations were high (Kendall coefficient of concordance, 0.932; and Spearman correlation coefficient [r value], 0.863; p < 0.0001). Similar agreements were obtained for the two components of the clinical score (ie, the history and the physical examination scores). More info
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Diagnosis of Laryngomalacia by Fiberoptic Endoscopy: Data and Statistical AnalysisAn additional 25 video recordings from infants with normal upper airways who underwent laryngoscopies (WT, 12 recordings; DAT, 13 recordings) for reasons unrelated to upper airways problems were also copied to the new video cassettes and served as healthy control subjects. The causes for performing FFL in these cases were nocturnal snoring, following adenoidectomy, chronic rhinorrhea, BAL, and suspected foreign body aspiration. Each video clip was edited to visualize the motion of the supraglottic structures only, and the observer was blinded to the patient, the clinical presentation, and the technique. Sound was not included so as not to influence the visual diagnosis. A total of 140 video clips were copied in a random sequence, and each clip was assigned a new number. Based on a previously applied scoring system for laryngomala-cia, each investigator assigned a score for each video clip that was composed of the following two parts: the “epiglottic score” (range, 0 to 4 points); and the “arytenoids score” (range, 0 to 4 points). Hence, the maximal possible laryngomalacia video score was 8 points (Table 2). generic yaz birth control
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The laryngoscopy performed using the WT was performed with the infant held awake in a sitting position by a parent. Topical anesthesia (lidocaine 1% and phenylephrine 0.25%) was applied to the nose, and FFL was performed to the level of the vocal cords. In the DAT, each infant received anesthesia with IV propofol. A dose of 2.5 mg/kg was injected slowly over 15 min as small boluses of 0.5 to 1.0 mL/kg. Additional boluses were added as needed. To prevent pain on injection, 0.3 mL of a 1% lidocaine solution was slowly injected prior to the injection of diluted propofol. All infants received 100% oxygen by a nonrebreathing mask during propofol loading and then a continuous flow of 2 to 3 L/min of 100% oxygen administered directly to the hypophar-ynx by an 8F feeding tube. The procedures were performed by a pediatric pulmonologist (Y.S.) in the pediatric ICU with the assistance of the pediatric ICU resident and a registered nurse. Oxygen saturation, respirations, BP (automatically every 2 min), and ECG were continuously monitored. The endoscopies were performed using a bronchoscope (model FB-10V or FB-8V; Pentax; Tokyo, Japan) with a distal outside diameter of 3.5 or 2.8 mm, respectively. Initially, only the upper airways were investigated looking for the cause of the stridor. Only when this stage was complete, was a 1% solution of lidocaine applied to the glottis and the bronchoscope advanced to visualize the trachea. All endoscopies were recorded on videotape. The study was approved by the institutional review board of our hospital.
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Diagnosis of Laryngomalacia by Fiberoptic EndoscopyLaryngomalacia is the most common cause of congenital stridor. It is usually a benign disorder resolving spontaneously by 12 to 18 months of age. The diagnosis of laryngomalacia requires dynamic visualization of the glottic and supraglottic area.
Since the introduction of video-recorded fiberoptic flexible laryngoscopy (FFL), the following two approaches have emerged for the endoscopic evaluation of congenital stridor, especially for laryngomalacia: a clinic-based awake laryngoscopy; and a drugassisted technique (DAT) using sedation and anesthesia. The awake technique (WT) is performed while the infant is held in a sitting position; topical anesthesia is applied to the nose, and endoscopy is performed to the level of the vocal cords. In the DAT, the patient is supine, and inspections of the subglottic area and the tracheobronchial tree are possible.
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Effect of Dobutamine on Lung Microvascular Fluid Flux in Sheep with “Sepsis Syndrome”: ConclusionTo further support our suggestion that dobutamine may have functionally reduced the effects of altered endothelial permeability characteristics on microvascular fluid flux in this study, Hakim et al concluded that (3-adrenergic receptors regulated pulmonary transendothelial transport of fluid and proteins since (3-adrenergic blockade with propranolol was associated with an increase in QL. Also, in the peripheral microvasculature, (3-adrenergic receptor agonists demonstrably inhibit edema formation and transmicrovascular protein flux, an observation that cannot be explained by their effects on microvascular pressure, blood flow, or surface area. The rationale underlying such a protective action of (3-adrenergic receptor agonists within the pulmonary microvasculature is purely speculative but may reflect the effects of enhanced cyclic AMP generation within the endothelium, perhaps thereby leading to relaxation of mediator-contracted endothelial cells. Read the rest of this entry »

Effect of Dobutamine on Lung Microvascular Fluid Flux in Sheep with “Sepsis Syndrome”: ObservationsNonseptic Study
The infusion of dobutamine was associated with a modest fall in the mean blood pressure at the 10μg/kg/ min dose but was without effect on the mean pulmonary arterial pressure at either dose (Table 1 ana r lg l). The cardiac output increased progressively with both doses, while the measured pulmonary arterial wedge pressure, left atrial pressure, and calculated Pmv remained unchanged. Systemic oxygen transport increased at both doses, and the Pv02 increased concurrently. Dobutamine did not signficantly affect QL or the [L/P]TP at either dose. The calculated mean 7rpmv fell with both doses (p<0.05), although the Trmv-TTpmv gradient was unchanged from baseline. Therefore, the CLP remained unchanged from baseline during the infusion of dobutamine of either dose. We found no significant relationship between changes in QL and cardiac output (CO) at either dose (5μLg/kg/min, AQL=1.3 —0.66 ACO; r= — 0.12) (10μg/kg/min, AQL = 1.70 — 0.311 ACO; r= -0.36), unlike data reported by Coates et al, where with exercise an increase in QL was significantly related to an increase in the cardiac output. Read the rest of this entry »

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