Identification of 9-cis-retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion.

The all-trans-retinoic acid (atRA) isomer, 9-cis-retinoic acid (9cRA), activates retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in vitro. RARs control multiple genes, whereas RXRs serve as partners for RARs and other nuclear receptors that regulate metabolism. Physiological function has not been determined for 9cRA, because it has not been detected in serum or multiple tissues with analytically validated assays. Here, we identify 9cRA in mouse pancreas by liquid chromatography/tandem mass spectrometry (LC/MS/MS), and show that 9cRA decreases with feeding and after glucose dosing and varies inversely with serum insulin. 9cRA reduces glucose-stimulated insulin secretion (GSIS) in mouse islets and in the rat ß-cell line 832/13 within 15 min by reducing glucose transporter type 2 (Glut2) and glucokinase (GK) activities. 9cRA also reduces Pdx-1 and HNF4α mRNA expression, ∼8- and 80-fold, respectively: defects in Pdx-1 or HNF4α cause maturity onset diabetes of the young (MODY4 and 1, respectively), as does a defective GK gene (MODY2). Pancreas ß-cells generate 9cRA, and mouse models of reduced ß-cell number, heterozygous Akita mice, and streptozotocin-treated mice have reduced 9cRA. 9cRA is abnormally high in glucose-intolerant mice, which have ß-cell hypertropy, including mice with diet-induced obesity (DIO) and ob/ob and db/db mice. These data establish 9cRA as a pancreas-specific autacoid with multiple mechanisms of action and provide unique insight into GSIS.

Endogenous LXA4 circuits are determinants of pathological angiogenesis in response to chronic injury.

Inflammation and angiogenesis are intimately linked, and their dysregulation leads to pathological angiogenesis in human diseases. 15-lipoxygenase (15-LOX) and lipoxin A(4) receptors (ALX) constitute a LXA(4) circuit that is a key feature of inflammatory resolution. LXA(4) analogs have been shown to regulate vascular endothelial growth factor (VEGF)-A-induced angiogenic response in vitro. 15-LOX and ALX are highly expressed in the avascular and immune-privileged cornea. However, the role of this endogenous LXA(4) circuit in pathological neovascularization has not been determined. We report that suture-induced chronic injury in the cornea triggered polymorphonuclear leukocytes (PMN) infiltration, pathological neovascularization, and up-regulation of mediators of inflammatory angiogenesis, namely VEGF-A and the VEGF-3 receptor (FLT4). Up-regulation of the VEGF circuit and neovascularization correlated with selective changes in both 15-LOX (Alox15) and ALX (Fpr-rs2) expression and a temporally defined increase in basal 15-LOX activity. More importantly, genetic deletion of 15-LOX or 5-LOX, key and obligatory enzymes in the formation of LXA(4), respectively, led to exacerbated inflammatory neovascularization coincident with increased VEGF-A and FLT4 expression. Direct topical treatment with LXA(4), but not its metabolic precursor 15-hydroxyeicosatetraenoic acid, reduced expression of VEGF-A and FLT4 and inflammatory angiogenesis and rescued 15-LOX knockout mice from exacerbated angiogenesis. In summary, our findings and the prominent expression of 15-LOX and ALX in epithelial cells and macrophages place the LXA(4) circuit as an endogenous regulator of pathological angiogenesis.

Antigen-induced release of slow reacting substance of anaphylaxis (SRS-A rat) in rats prepared with homologous antibody.

The polymorphonuclear leukocyte appears to be an essential cellular prerequisite for the antigen-induced release of SRS-A(rat) in the peritoneal cavity of rats prepared with homologous, hyperimmune antisera. Depletion of PMN leukocytes is associated with a marked suppression of SRS-A(rat) release, whereas depletion of circulating lymphocytes or peritoneal mast cells does not influence the antigen-induced release of SRS-A(rat). A local increase in the number of PMN leukocytes produced by the induction of a peritoneal exudate was associated with an enhanced release of SRS-A(rat). A distinct difference in the cellular requirements for the antigen-induced release of histamine and SRS-A(rat) in the rat was observed. Homocytotropic antibody-mediated histamine release could be achieved in leukopenic rats but not in mast cell-depleted animals. Conversely, SRS-A(rat) release was suppressed in leukopenic rats but was unaffected by mast cell depletion. Diethylcarbamazine inhibited the antigen-induced release of SRS-A(rat) following preparation with homologous, hyperimmune antisera but did not interfere with homocytotropic antibody-mediated histamine release. In preventing SRS-A(rat) release, diethylcarbamazine did not interfere with antigen-antibody interaction since desensitization of tissues was possible in the presence of this inhibitor. This observation is consistent with the view that diethylcarbamazine inhibits the reaction sequence leading to the formation and release of SRS-A(rat) at some step subsequent to antigen-antibody interaction. These studies support the view that the immunologic pathways leading to the release of SRS-A(rat) and histamine in the rat are distinctly different in terms of the immunoglobulins involved, the cellular prerequisites, and the effective pharmacologic inhibitors.

Immunological release of histamine and slow reacting substance of anaphylaxis from human lung.

The immunologic release of histamine and slow reacting substance of anaphylaxis (SRS-A) from human lung tissue can be enhanced by stimulation with either alpha adrenergic agents (phenylephrine or norepinephrine in the presence of propranolol) or cholinergic agents (acetylcholine or Carbachol). The finding that atropine prevents cholinergic but not comparable alpha adrenergic enhancement is consistent with the view that cholinergic and alpha adrenergic agonists interact with separate receptor sites on the target cells involved in the immunologic release of chemical mediators. The consistent qualitative relationship between the antigen-induced release of mediators and the level of cyclic adenosine monophosphate (cyclic AMP) as measured by the isolation of (14)C-labeled cyclic AMP after incorporation of adenine-(14)C into the tissues or by the cyclic AMP binding protein assay suggests that changes in the level of this cyclic nucleotide mediate adrenergic modulation of the release of histamine and SRS-A. The addition of 8-bromo-cyclic guanosine monophosphate (cyclic GMP) produces an enhancement of the immunologic release of mediators while dibutyryl cyclic AMP is inhibitory. As cholinergic-induced enhancement was not associated with a measurable change in the levels of cyclic AMP, the possibility is suggested that cyclic GMP may be the intracellular mediator of cholinergic-induced enhancement of the immunologic release of histamine and SRS-A.

Endogenous urea as an autacoid: extrarenal and renal focuses.

The present position article complies with selected own and literature data concerning the characterization of endogenous urea at extrarenal level in animal and human organism in functional aspect. With key pharmacological experiments, both under in vivo and in vitro conditions, we apply urea in concentrations corresponding to physiological and pathological ones. We established that endogenous urea (without use as an exogenous applied drug) possesses important properties. It is assumed that urea is an endogenous non-specific beta-adrenergic receptor antagonist (ENBARA), non-selective, non-competitive, reversible and non-toxic. Based on these data we develop a concept for endogenous beta-adrenergic receptor antagonists (EBARA). In agreement with proofs of RJ Lefkowitz' group in the 90-ies that "beta arrestines 1 and 2 antagonize three of four agonist-activated beta-adrenergic receptors" we accept that they act as relatively endogenous specific beta-adrenergic receptor antagonists (RESBARA). As regards for the last four beta-agonist-activated adrenergic receptor we propose that is controlled via ENBARA. That is why a new role of urea is to be in the list of endocoids (autacoids).

Effects of dexamethasone on mediator release from human lung fragments and purified human lung mast cells.

Purified human lung mast cells released histamine, leukotrienes, prostaglandin (PG) D2, thromboxane B2 (TxB2), and PGF2 alpha in response to anti-IgE stimulation. Incubation of the cells for 24 h with 10(-6) M dexamethasone, a treatment that inhibits mediator release from human basophils, had no effect on the release of these mediators from mast cells. Dexamethasone treatment of human lung fragments led to little or no inhibition of anti-IgE-induced release of the mast cell-derived mediator, histamine, but produced a significant inhibition of the release of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha. As was the case with purified mast cells, the steroid did not inhibit the release of PGD2 or TxB2 from human lung fragments. Comparison of the quantities of PGD2 and TxB2 produced by purified cells and human lung fragments reveals that the mast cells produce quantities of these metabolites sufficient to account for the entire amount produced by challenged lung fragments. Dexamethasone inhibited spontaneous release from lung fragments of all cyclooxygenase products measured. These results suggest that the human lung parenchymal mast cell phospholipase is not inhibited by dexamethasone, whereas other phospholipase(s) in the lung are inhibited by the steroid. These results may be useful in explaining the resistance of acute allergic reactions, including anaphylaxis, to steroids, despite the potent antiinflammatory activity of steroids on subacute and chronic inflammation, such as in bronchial asthma, which may be initiated by IgE-dependent mechanisms.

Release of a slow-reacting substance from rabbit platelets.

Washed rabbit platelets stimulated with platelet-activating factor, thrombin, or arachidonic acid, released a slow-reacting substance (SRS), whereas platelets aggregated by adenosine diphosphate did not. Production of platelet-derived SRS was neither affected by indomethacin nor aspirin but was reduced by large doses of eicosatetraynoic acid, an inhibitor of the cyclo-oxygenase and lipoxygenase. L-cysteine enhanced markedly the release of SRS from platelets. This SRS activity, which was antagonized by FPL 55712 and inactivated by arylsulfatase, followed the same elution pattern on Amberlite, silicic acid, and reverse phase high-pressure liquid chromatography columns as that described for the SRS from other origins. SRS activity released from platelets preincubated with [14C]arachidonic acid exhibited the same retention time as radioactivity in reverse phase high-pressure liquid chromatography. The release of a SRS from platelets is consistent with their implication in the pathogenesis of asthma and other lung diseases.

The role of autacoids and the autonomic nervous system in cardiovascular responses to radio-frequency energy heating.

Among the potential effects of exposure to high levels of radio-frequency energy (RFE) (which includes microwaves), an increase in body temperature is the primary consequence. Release of autacoids and activity of the autonomic nervous system may influence (or be directly responsible for) some of the physiological changes that occur in conjunction with this hyperthermia. The main focus of this review is the interaction of autacoids and the autonomic nervous system with cardiovascular changes during heating. Differences between environmental and RFE-induced heating (such as rate of temperature change and degree of skin vs. core heating) may be important when considering these effects. Antihistamines exhibited no beneficial effect on circulatory collapse during RFE-induced heating. The serotonergic blocker methysergide decreased survival time in rats during terminal RFE exposure, despite no effects on heart rate (HR) or blood pressure. Although blockade of platelet-activating factor resulted in lower HR before RFE exposure, there was a lack of effect on the subsequent increase in HR during heating. Nitric oxide did not contribute to the hypotension that occurs due to rapid heating by RFE exposure. There have been either no or very limited studies of effects of prostaglandins, bradykinin, or angiotensin on RFE-induced heating responses. beta-Adrenoceptor antagonism with propranolol resulted in significantly decreased survival times and lower final colonic temperatures during RFE exposure. A lack of effects of nadolol on survival time and temperature, coupled with its poor ability to traverse the blood-brain barrier, suggests that central beta-adrenergic stimulation rather than peripheral stimulation may alter thermoregulation. Effects of the autonomic nervous system (as studied by adrenoceptor blockade) on potassium changes during heating have not been fully investigated. Such changes could be important in animals' responses to RFE and other modalities of heating, and should be studied in future.

Generation of a small cell lung cancer variant resistant to lymphokine-activated killer (LAK) cells: association with resistance to a LAK cell-derived, cytostatic factor.

Cells of OS2-RA, a human small cell lung cancer line sensitive to lymphokine-activated killer (LAK) cells, were repeatedly cocultured with human LAK cells. Fourteen cycles of the coculture produced a variant, termed OS2-RA-R, capable of growing successfully in the presence of LAK cells. OS2-RA-R showed a moderate resistance to lysis by LAK cells in 4-h 51Cr release assays. OS2-RA-R acted positively as a cold target for lysis of OS2-RA by LAK cells, suggesting no loss of the binding site for LAK cells on the cell surface of the variant. On the other hand, LAK cells were shown to produce a factor capable of suppressing the proliferation of OS2-RA and certain other cell lines but not lymphocytes. Interestingly, OS2-RA-R exhibited a substantial resistance to the cytostatic activity of LAK cell supernatants. The cytostatic factor, eluted at the 57-kDa fraction in gel filtration, showed no activity of interleukin 1, gamma-interferon, transforming growth factor beta, or tumor necrosis factor. These results suggest that LAK cells exhibit antitumor activity through not only rapid cytolysis but also slow-acting cytokine production, and the successful growth of OS2-RA-R in a coculture with LAK cells is the result of acquiring resistance to these two different LAK cell phenomena.

Adenosine, a cytoprotective autocoid: effects of adenosine on neutrophil plasma membrane viscosity and chemoattractant receptor display.

At inflammatory sites neutrophils are stimulated to produce a variety of toxic agents, yet rarely harm the endothelium across which they migrate. We have recently found that endothelium releases adenosine which, acting via receptors on the surface of human neutrophils, inhibits generation of toxic metabolites by stimulated neutrophils but, paradoxically, promotes chemotaxis. Agents which diminish plasma membrane viscosity affect neutrophil function similarly, possibly by modulating chemoattractant receptor number or affinity. We therefore determined whether adenosine receptor agonists modulate neutrophil function by decreasing membrane viscosity and/or changing the affinity of chemoattractant (N-fMet-Leu-Phe, FMLP) receptors. Surprisingly, 5'-(N-ethylcarboxamido)adenosine (NECA, 10 microM), the most potent agonist at neutrophil adenosine receptors, increased plasma membrane viscosity, as measured by fluorescence anisotropy of the plasma membrane specific probe 1-(4-trimethylaminophenyl)-6-diphenyl-1,3,5-hexatriene (TMA-DPH), in unstimulated neutrophils from a mean microviscosity of 1.67 +/- 0.02 (S.E.) to 1.80 +/- 0.02 (p less than 0.001) while inosine (10 microM), a poor adenosine receptor agonist, had no effect (1.73 +/- 0.04, p = n.s. vs. control, p less than 0.01 vs. NECA). Adenosine receptor agonists increased plasma membrane viscosity in neutrophils with the same order of potency previously seen for inhibition of superoxide anion generation and enhancement of chemotaxis (NECA greater than adenosine = N6-phenylisopropyladenosine). The adenosine receptor antagonist 8-(p-sulfophenyl)theophylline reversed the effect of NECA on plasma membrane viscosity. Unlike other agents which modulate plasma membrane viscosity, NECA (10 microM) did not significantly change the number or affinity of [3H]FMLP binding sites on neutrophils. In contrast to the hypothesis of Yuli et al. these results indicate that occupancy of adenosine receptors on neutrophils increases plasma membrane viscosity without affecting chemoattractant receptor display.

The mast cell.

The mast cell is the cellular basis for immediate hypersensitivity reactions. The specificity of the immediate hypersensitivity reaction is attributable to IgE molecules fixed to specific membrane receptors which, when stimulated by specific antigen, initiates the process of degranulation of the mast cell. The granules provide three separate sources of biologic activity: performed or primary mediators, newly generated or secondary mediators, and activities associated with the granular matrix. A number of biologic consequences are generated in response to these mediators and these include: increased vascular permeability, vasodilation, smooth muscle spasm, polymorphonuclear leukocyte chemotaxis, stimulation of adenylate and guanylate cyclase, superoxide radical generation, prostaglandin formation, mucous and gastric acid secretion, hypotension, tissue destruction, and mononuclear leukocyte infiltration. This pharmacopia of activities accounts for the clinical aspects of allergic diseases, suggests that the mast cell granule may be involved in the host's defense against parasitic infections, and is compatible with a suggested role of the mast cell as a widely distributed, monocellular endocrine system.

Release of a stable cardiodepressant mediator after myocardial ischaemia during reperfusion.

OBJECTIVE: The aim of this study was to investigate whether cardiodepressant mediators are released after myocardial ischaemia during reperfusion. METHODS: Using a double heart model, the effect of the reoxygenated coronary effluent of an isolated guinea pig heart on a sequentially perfused second heart was studied under control conditions and after 10 min ischaemia of the first heart. Investigation of the modulating role of known autacoids took place by using free radical scavengers, an NO synthase inhibitor and adenosine receptor antagonists. In order to identify the chemical nature of cardiac metabolites, the coronary effluent was also subjected to different chemical treatment modes. RESULTS: No haemodynamic changes were observed during sequential perfusion under control conditions. After 10 min of global ischaemia in heart I, a marked decrease in LVP (-22%), LVdP/dtmax (-43%), LVdP/dtmin (-41%) and coronary perfusion pressure (-25%) was measured in heart II during sequential perfusion. The negative inotropic effect was rapid in onset and reversible within 5 min; free radicals, nitric oxide and adenosine were not involved. Storage of the coronary effluent of the first heart up to 24 h, heating, or protease treatment did not modify its cardiodepressant effects on the second sequentially perfused heart. CONCLUSIONS: These results suggest the release--from an isolated heart after ischaemia during reperfusion--of a cardiodepressant mediator which induces a potent reversible negative inotropic effect on a sequentially perfused heart. The mediator is stable and in all probability not a protein.

The terms 'autacoid', 'hormone' and 'chalone' and how they have shifted with time.

The increase of knowledge in a particular field (endocrinology) can be understood if one follows how certain key concepts were constructed and transformed over time. To explore such construction and transformation (shifts in meaning), we studied the use of the concepts 'autacoid' and 'chalone' in a period of one century (1916-2016), since the introduction of these concepts by the British professor of physiology Sir Sharpey-Schäfer. We could identify that the use of 'autacoid' shifted from a very broad category encompassing both stimulating and inhibiting hormones, in the period 1916-1960, to a much more specific use of the term for locally produced bioactive molecules, from the 1960s onwards. Histamine was the first compound seen as an 'autacoid', followed by prostaglandins, ATP, ADP and bradykinin, and from 1993 onwards, compounds such as 'palmitoylethanolamide' were also classified as 'autacoids'. For 'chalone', a comparable shift was noticed around the 1960s, when the concept suddenly changed from the category of inhibiting hormones into a substance that is produced within a tissue, inhibiting mitosis of the cells of that tissue. For both concept shifts, we could not find any argument. Around 1980, authors started to relate autacoids to various promising indications in the field of inflammation and immune modulation. The Nobel laureate Rita Levi-Montalcini gave an extra dimension to the concept autacoid in 1993, and introduced a new class of compounds modulating mast cells, the ALIAmides (from Autacoid Local Inflammation Antagonist), of which palmitoylethanolamide was the prototype. Our exploration demonstrates that biomedical concepts can be constructed and defined differently as time goes by, while concept transformations seem to emerge without arguments.

Basophil mediators and their release, with emphasis on BK-A.

During IgE-mediated events, basophils secrete small molecular weight mediators (histamine, slow reacting substance, Eosinophil chemotactic factor) which are thought to participate in inflammatory processes. We here describe the IgE-mediated secretion of large molecular weight mediators which have the potential for the activation of the Hageman factor dependent pathways, and the generation of biologically active peptides. These large molecular weight basophil derived mediators may, through the activation of the Hageman factor dependent pathways, influence mechanisms which participate in both acute and chronic cell-mediated inflammatory processes. We suggest that these proteases may participate not only as mediators of the immediate hypersensitivity reaction, but may also function in important aspects of the entire inflammatory response.

Contact lens-induced edema in vitro. Ion transport and metabolic considerations.

The relationship of contact lens-induced edema to epithelial and endothelial function was determined in isolated superfused rabbit corneas. Placement of a polymethyl methacrylate (PMMA) contact lens on the cornea caused swelling rates of 15-28 microns/hr compared to 0-6 microns/hr in paired control corneas. The edema increased with temperature (P less than 0.01). PMMA-induced swelling was significant in: 1) bicarbonate-free Ringer's solution; 2) chloride-free Ringer's; 3) 0.3 mM furosemide-treated corneas; and 4) deepithelialized corneas. The swelling did not occur in corneas with silicone oil replacing the endothelium to block fluid uptake. The effluent aqueous bathing fluid from edematous corneas did not induce edema in normoxic corneas. These studies demonstrate that contact lens-induced edema depends on metabolism, involves a significant stromal contribution, and requires fluid absorption across the endothelial layer, but is not a direct result of epithelial and endothelial ion transport inhibition.

Phagocytosis stimulates the release of a slow reacting substance in cultured macrophages.

1 A slow-reacting substance (SRS) was released from non-elicited mouse peritoneal macrophages during phagocytosis of zymosan particles, whereas no detectable SRS was produced by resting cells. 2 The macrophage SRS induced a delayed and slow contraction of the guinea-pig ileum but not of the chick rectum. 3 The myotonic activity was antagonized by low concentrations of FPL 55712 (sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1 -benzopyran-2 carboxylate) but was not affected by mepyramine or hyoscine, and was not associated with tachyphylaxis. 4 SRS release was increased by indomethacin and was abolished by the lipoxygenase and cyclooxygenase inhibitor, BW755C (3-amino-1-[m-(trifluoromethyl)-phenyl]-2-pyrazoline). 5 Addition of exogenous arachidonic acid or cysteine enhanced SRS production.

Effect of exogenous 5,8,11,14,17-eicosapentaenoic acid on cardiac anaphylaxis.

The effects of infusions of eicosapentaenoic acid (EPA) (6 X 10(-8) mol min-1 and 15 X 10(-8) mol min-1) on the coronary constriction and the release of immunoreactive sulphidopeptide-leukotrienes (SP-LT), thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha) from perfused anaphylactic guinea-pig hearts were investigated. EPA dose-dependently inhibited the profound early coronary flow reduction after antigen injection. The less pronounced late phase of anaphylactic coronary flow reduction was, however, not significantly affected. EPA (15 X 10(-8) mol min-1) significantly shortened the average duration of antigen-induced arrhythmias. EPA dose-dependently decreased release of immunoreactive TXB2 and 6-keto-PGF1 alpha from anaphylactic guinea-pig hearts. Release of immunoreactive SP-LT was dose-dependently increased after antigen challenge in the presence of EPA. Inhibiton of the release of SP-LT by the lipoxygenase inhibitor esculetin (1 X 10(-7) mol min-1) was accompanied by a significant attenuation of flow reduction during the late phase of anaphylactic vasoconstriction. Reversed phase h.p.l.c. of perfusates from anaphylactic guinea-pig hearts revealed immunoreactivity comigrating with authentic leukotriene C4 (LTC4), LTD4, and LTE4. In perfusates from hearts treated with EPA infusions, additional immunoreactivity was detected comigrating with LTC5, LTD5 and LTE5. In addition to immunoreactivity migrating with LTB4, as observed in control heart perfusates, in perfusates from EPA-treated hearts, a second peak was observed, which coincides with the retention time described for LTB5. Exogenous LTC5 (1 X 10(-12) mol min-1 and 20 X 10(-12) mol min-1) induced dose-dependent reductions of coronary flow and was found to be a slightly weaker constrictor than LTC4, but no significant differences were observed. Coronary vasoconstriction elicited by infusion of exogenous LTC4 (20 X 10(-12) mol min-1) was dose-dependently inhibited by infusions of EPA. However, the negative inotropic effect of LTC4 remained unaffected. Thus, in the isolated anaphylactic heart of the guinea-pig exogenous EPA was effectively metabolized via the 5-lipoxygenase pathway whereas the cyclo-oxygenase pathway of polyunsaturated fatty acid metabolism was found to be inhibited. The results are in agreement with the suggestion that cyclo-oxygenase products are mediators of the early phase of the anaphylactic coronary constriction, while vasoconstrictor SP-LT are involved in the later phase. However, in spite of enhanced release of SP-LT, EPA infusion did not result in increased coronary constriction. Considering the fact that EPA antagonizes LTC4-induced coronary constriction, it seems possible, that EPA might act as a functional antagonist of vasoconstrictor eicosanoids including EPA-derived SP-LT.

Alteration of fate of vasoactive autacoids in pulmonary circulation following monocrotaline-induced lung vascular injury in rats.

1. To learn how pulmonary vascular injury alters the ability of the lung to metabolize vasoactive autacoids, lung vascular lesions were produced in rats by a single subcutaneous injection of monocrotaline (90 mg kg-1), and the blood pressure responses to angiotensin I (AI), angiotensin II (AII), bradykinin, prostaglandin E2 (PGE2) and substance P were examined. Vasoactive agents were given intravenously or intra-arterially. 2. On histological examination of the lung at 3 weeks after monocrotaline treatment, degeneration or necrotization of endothelial cells was evident. 3. The conversion of AI to AII was only slightly depressed by monocrotaline treatment. On the other hand, the depressor response to intravenously injected bradykinin was enhanced in monocrotaline-treated rats. When the rats were pretreated with indomethacin the depressor response to intravenous bradykinin was the same for both control and monocrotaline-treated groups which suggests that endogenous prostaglandins are involved in the enhancement of the response to bradykinin. 4. In monocrotaline-treated rats the depressor response to intravenous PGE2 was significantly enhanced depending on the period following the treatment, while that to the intra-arterial injection did not differ from control. 5. The data suggest that monocrotaline-induced lung injury impairs the metabolism of PGE2 during pulmonary circulation but has little effect on the conversion of AI to AII and the degradation of bradykinin in rats.

The lung mast cell: its physiology and potential relevance to defense of the lung.

The mast cell, located at mucosal surfaces and surrounding venules, is uniquely positioned to respond rapidly to insults to the host by mediating the development of a wide-ranging inflammatory response. Activaton of the mast cell releases preformed granule-associated chemical mediators and generates de novo biologically active materials. The properties of the mast cell mediators permit development of both acute and prolonged inflammatory responses. the immediate response is characterized by edema and the delayed response by leukocyte infiltration and vascular damage. the mast cell mediators responsible for these inflammatory events are characterized functionally. The vasoactive/smooth muscle reactive mediators include preformed histamine and serotonin and newly-generated platelet activating factor, slow reacting substance of anaphylaxis and prostaglandins. Chemotactic mediators include eosinophil-selective ECF-A and ECF-oligopeptides, neutrophil-selective NCF, and lipid chemotactic mediators with broad specificity. These factors induce directed migration and localization of leukocytes. The mast cell releases the structural proteoglycan, heparin, which is anticoagulant and inhibits complement. Released mast cell enzymes include chymotryptic and tryptic proteases, arylsulfatase, beta-glucuronidase, and hexosaminidase. The proteolytic enzymes may activate inflammatory pathways while the others degrade ground substance. The capacity of the mast cell to enhance vascular permeability, to cause the influx of regulatory or inflammatory leukocytes, and to provide a variety of active enzymes permits regulation of inflammatory events at the site of tissue injury.