Effects Of Inflammatory Mediators Research Articles

Effects of inflammatory mediators on canine airway neuromuscular function.

Inflammatory mediators can both enhance or inhibit canine airway reactivity. PGE2 and PGI2 in general are inhibitory, interfering with release of acetylcholine and with responses to bronchoconstrictors. These prostaglandins may be more effective against agonists that open voltage-dependent Ca2+ channels to induce Ca2+ influx and contraction compared with those agonists that release internal Ca2+. Other mediators are excitatory: histamine, PGD2, thromboxane A2 (TxA2), and leukotrienes (LT) C4, D4, and E4. In canine airway only histamine and TxA2 have effects in the absence of indomethacin, i.e., in the presence of the large amounts of PGE2 and PGI2 produced in vitro LTs are ineffective. Effects of TxA2 and histamine may be potentiated if the synthesis of these inhibitory PGs is inhibited. Whether histamine or TxA2 normally promote synthesis and release of PGE2 and PGI2 in a kind of homeostasis remains to be explored. It is also unclear whether pre- as well as post-junctional TxA2 receptors exist and have different pharmacological sensitivities to antagonists. LTC4 and LTD4 also constrict canine bronchi but only when PGE2 and PGI2 synthesis is blocked and, again, whether this is a result of LT-induced release of inhibitory mediators is unknown. The concept that airway responsiveness can be caused by turning off PGE2 and PGI2 production and turning on TxA2 or LT production (or unmasking their actions) needs further exploration. Our recent data suggest that such a mechanism may explain ozone-induced responsiveness in dogs.

Effect of Inflammatory Mediators on Airway Nerves and Muscle

The neuromuscular mechanisms underlying airway hyperresponsiveness have been reviewed on the basis of studies of the changes induced by ozone inhalation in dogs. In vivo, there is increased, nonspecific airway hyperresponsiveness based on studies of the response to inhaled acetylcholine or histamine. The underlying inflammatory mechanism involves release of LTB4 and/or other chemotactic agents from epithelial or lumenal cells, ingress of macrophages, neutrophils, and platelets from the blood vessels between the muscle and epithelium, and migration of mast cells into the epithelium. The hyperresponsiveness seems to depend upon the influx of neutrophils and actions of thromboxane A2 released from the neutrophils. In vitro, there is increased responsiveness to field stimulation of cholinergic nerves and to acetylcholine (not to KCI) in tracheal strips. These effects can be mimicked by a thromboxane A2 analog (U44619). In the sucrose gap, the TxA2 analog does not affect the excitatory junction potential, but in low concentration it increases and prolongs a series of fading membrane oscillations closely related to the contractions. We consider these oscillations to reflect ongoing release and/or action of acetylcholine. In high concentrations the analog causes a small depolarization and a tonic contraction, but it does not enhance the sensitivity to acetylcholine. TxA2 may be acting either presynaptically or postsynaptically or both to produce these effects; however, changes in release of an epithelial-derived relaxing factor do not seem to be involved. We conclude that TxA2 actions probably underlie hyperresponsiveness developed in vivo and in vitro after ozone inhalation.

The effect of inflammatory mediators on neutrophil function.

The adult respiratory distress syndrome (ARDS) is a form of acute lung injury that most commonly afflicts patients who have suffered major trauma or sepsis. The magnitude of this clinical problem is appreciated in statistics that estimate there being approximately 200,000 cases per year in the United States, costing several billion dollars in medical expenditure. The serious nature of this problem is further amplified by an ARDS mortality rate of 40 to 70%. Despite thirty years of intense research we are only beginning to appreciate the pathophysiology of the disease, prevention is nonexistent and therapeutic measures are merely supportive (1,2).

Effects of Inflammatory Mediators on the Responsiveness of Isolated Human Airways to Methacholine

Several studies have suggested that in asthmatics the quantities of inflammatory mediators such as histamine, thromboxane A2 (TxA2), prostaglandin D2 (PGD2), prostaglandin F2 alpha (PGF2 alpha), and leukotriene C4 (LTC4) that are present in the airway lumen are related to the degree of bronchial responsiveness to inhaled methacholine (MCh). Therefore, we studied the effect of these mediators on the cholinergic responsiveness of isolated human airway segments. Lung tissue collected at thoracotomy from 30 patients was studied. Dose-response curves to MCh were obtained from bronchial segments before, during, and after incubation with either a subthreshold or a threshold concentration of histamine (10(-10) or 10(-8) M), the stable TxA2 analogue U46619 (10(-11) or 10(-9) M), PGD2 (5 x 10(-9) or 5 x 10(-7) M), PGF2 alpha (10(-9) or 10(-7) M), or LTC4 (10(-11) or 10(-9) M). With the exception of LTC4, the presence of any of these mediators at either concentration increased the sensitivity to MCh by a factor of 1.1 to 2 (p less than 0.05, ANOVA). This increase did not depend on the dose of the mediator (p greater than 0.05, ANOVA). These data indicate that mediator-induced muscle hypersensitivity can explain a small part of the leftward shift of the dose-response curve to inhaled MCh as observed in asthma.

Prostaglandin biosynthesis by human decidual cells: Effects of inflammatory mediators

There is substantial evidence that decidual activation, in association with infection, is linked with the onset of both preterm and term labor. We therefore undertook the present study to evaluate prostaglandin production and its potential regulation by inflammatory mediators in human decidual cells in primary monolayer culture. Upon attaining confluence, the cells were incubated with endotoxin, interleukin 1α (IL1α), interleukin 1β (IL1β); or tumor necrosis factor (TNF). Production of prostaglandin (PG) E 2 and PGF 2α was determined using specific radioimmunoassays. Endotoxin and these cytokines all induced significant concentration-dependent increases in PGE 2 and PGF 2α production. Our results suggest that term human decidual cells are responsive to endotoxin and cytokines and that generation of these substances in the decidua or nearby (eg. in response to infection) will lead to increased prostaglandin production and uterine contractions.

Intranasal Challenge of Cynomolgus Monkeys with Ascaris, Ragweed, Bradykinin, and Histamine

Seven feral monkeys with Ascaris hypersensitivity confirmed by intradermal skin test were challenged with single doses of Ascaris extract (105 PNU/nostril), ragweed extract (103 PNU/nostril) and diluent; with increasing doses of bradykinin (0.1, 1, and 5 mg/nostril) and histamine (0.1, 1, and 5 mg/nostril), and with repeated doses of PBS diluent. Total mean nasal resistance (TMNR) was measured by rhinomanometry and eustachian tube function by the forced-response test. For single dose challenges, testing was conducted before and 5, 15, 40, and 50 minutes after the challenge and for multiple dose challenges before, 5 and 15 minutes after each dose, and 40 and 50 minutes after the final dose. Mean TMNR (cm H2O/L/sec) was increased from 28.9 ± 9 at baseline to peak at 124 ± 46 after Ascaris challenge. In contrast, TMNR was unaffected in six of seven monkeys challenged with diluent and in all monkeys challenged with ragweed. Progressive TMNR increases from baseline (25 ± 8) were observed for bradykinin (peak = 64 ± 46) and histamine (peak 108.4 ± 59) challenges. Eustachian tube function data showed no significant changes after intranasal provocation with either allergens or mediators. Provocative intranasal allergen challenge in actively sensitized monkeys is an effective method for evaluating the pathophysiology of allergic rhinitis and the effect of inflammatory mediators on nasal resistance.

Mediator-induced activation of xanthine oxidase in endothelial cells.

Rat pulmonary artery endothelial cells incubated with human serum that has been complement-activated by addition of cobra venom factor reveal a pronounced conversion of xanthine dehydrogenase to xanthine oxidase. This process requires the availability of the fifth component of complement (C5) but not the presence of other components (C2 and C6-C9). The phenomenon can be reproduced by addition to endothelial cells of purified human recombinant C5a but not C5a desArg or C3a. The enzyme conversion process is relatively rapid (occurring within 5-10 min), requires the presence of intact endothelial cells, and does not require protein synthesis. Similar effects on endothelial cells have been obtained with human recombinant tumor necrosis factor alpha and the chemotactic peptide N-formyl-Met-Leu-Phe. In contrast, bradykinin, recombinant human interleukin 1 beta, and phorbol ester lack this biological activity. These findings suggest novel effects of inflammatory mediators on endothelial cells.

Induction of interleukin 6 (IL-6) production by mesangial cells: Autocrine effects of inflammatory mediators

Induction of interleukin 6 (IL-6) production by mesangial cells: Autocrine effects of inflammatory mediators

Tumor-promoting phorbol esters inhibit monocyte adherence to endothelial cells.

Monocyte adherence to endothelial cells (EC) is an important event in the development of a monocytic inflammatory response, yet the effects of inflammatory mediators on monocyte adherence to EC are not well described. We compared the effects of phorbol esters known to activate protein kinase C, including phorbol myristate acetate (PMA) and phorbol 12,13-dibutyrate (PDA), on monocyte adherence to bovine aortic EC. Human monocytes (purity 90 +/- 1% SE) were isolated by centrifugal elutriation to obtain monocytes not previously exposed to a surface. Kinetic studies revealed that 51Cr-labeled monocyte adherence to EC reached a plateau after a 45-min incubation. Concentrations of PMA between 10 and 1,000 ng/ml significantly decreased monocyte adherence to EC (26 +/- 10 and 35 +/- 8% decrease compared with control, respectively). Concentrations of PDA of 100 and 1,000 ng/ml had a similar inhibitory effect. In contrast, the chemotactic stimulus, zymosan-activated serum, significantly increased monocyte adherence (40 +/- 14% increase compared with control). Thus inflammatory stimuli have different effects on the adhesive interaction of monocytes to EC. This may provide a mechanism to selectively modulate monocyte egress from the circulation into extravascular inflammatory sites.

Differential Effect of Inflammatory Mediators on Microvascular Permeability in Different Parts of the Guinea Pig Airways

Differential Effect of Inflammatory Mediators on Microvascular Permeability in Different Parts of the Guinea Pig Airways

Effects of inflammatory mediators on the glomerular localization of intravenously administered ferritins.

Effects of inflammatory mediators such as serotonin, histamine, and bradykinin upon glomerular localization of i.v. administered ferritins have been investigated. These mediators appear to enhance accumulation of the i.v. injected ferritins in the glomerular capillary walls of rats.

Effect of Inflammatory Mediators on Nasal Mucosa

A technique used for study of permeability and vasodilation in the middle ear has been adapted to study the response of nasal mucosa to common inflammatory mediators involved in the natural production of allergic or infectious rhinitis. All of the mediators tested (histamine, prostaglandin E1, bradykinin, the C3a fraction of complement, Escherichia coli endotoxin, and lysozyme) were found to increase nasal permeability to the isotopic tracer 99mTc as the pertechnetate ion. Histamine increased the permeability of nasal mucosa to technetium-labeled plasma protein. Results indicate that the nasal mucosa is approximately ten times as permeable to the pertechnetate ion as middle ear mucosa. Nasal mucosa was also noted to be permeable to protein, even in the absence of inflammatory mediator, in contrast to prior studies of middle ear mucosa that showed little or no permeability in the absence of inflammatory mediator. In almost all cases, a corresponding change in vasodilation accompanied permeability changes.