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Biomedical subjects

E J Goetzl

Publications and source records attributed to E J Goetzl.

At least 127 records · Page 7Linked to original sources
PubMed1987

Selective localization of vasoactive intestinal peptide and substance P in human eosinophils.

Extracts of purified human eosinophils had a mean concentration of 72 fmol of immunoreactive vasoactive intestinal peptide and 21 fmol of substance P per 10(7) eosinophils, that were significantly higher than the content of immunoreactivity of the same neuropeptides in neutrophils, mononuclear leukocytes, and platelets. In contrast, the lower concentrations of calcitonin gene-related peptide and somatostatin were similar in extracts of all leukocytes. Chromatography of the peptides from eosinophils confirmed their identity with vasoactive intestinal peptide and substance P from neuroendocrine sources. Stores of some neuropeptides may endow eosinophils with unique roles in host defense and hypersensitivity reactions.

Chromatography, High Pressure Liquid↗
PubMed1987

Hyperalgesia onset latency suggests a hierarchy of action.

Hyperalgesia onset latencies of inflammatory mediators were quantified by measuring the threshold of the nociceptive flexion reflex in the rat at 1 min intervals after intradermal injection. Prostaglandin E2 and 8(R), 15(S)-dihydroxyicosa-(5E,9,11,13Z)-tetraenoic acid induced hyperalgesia with short onset latencies, compatible with a direct action on primary afferent nociceptors. Bradykinin, norepinephrine and leukotriene B4 induced hyperalgesia with a significant delay in onset, compatible with their known indirect mechanisms of producing hyperalgesia. We propose that use of this approach, rapid frequent measurement of nociceptive threshold, can be used to determine the hierarchy of action of mediators in hyperalgesic mechanisms.

Animals↗
PubMed1987

Recognition of human polymorphonuclear leukocyte receptors for leukotriene B4 by rabbit anti-idiotypic antibodies to a mouse monoclonal antileukotriene B4.

Rabbit anti-idiotypic IgG antibodies to the combining site of a mouse monoclonal IgG2b antibody to leukotriene B4 (LTB4) cross-reacted with human polymorphonuclear (PMN) leukocyte receptors for LTB4. Anti-idiotypic IgG and Fab both inhibited the binding of [3H]LTB4, but not [3H]N-formylmethionyl-leucylphenylalanine (fMLP), to PMN leukocytes with similar concentration-effect relationships, whereas neither nonimmune rabbit IgG nor Fab had any inhibitory activity. At a concentration of anti-idiotypic IgG that inhibited by 50% the binding of [3H] LTB4 to PMN leukocytes, the antibodies preferentially recognized high affinity receptors. Anti-idiotypic IgG and Fab inhibited PMN leukocyte chemotactic responses to LTB4, but not fMLP, with concentration-effect relationships resembling those characteristic of the inhibition of binding of [3H] LTB4, without altering the LTB4-induced release of beta-glucuronidase. Chemotaxis and increases in the cytoplasmic concentration of calcium equal in magnitude to those elicited by optimal concentrations of LTB4 were attained at respective concentrations of anti-idiotypic IgG equal to and 1/25 the level required for inhibition of binding of [3H]LTB4 by approximately 50%. Thus, the anti-idiotypic antibodies bound to PMN leukocyte receptors for LTB4 with a specificity, preference for high affinity sites, and capacity to alter PMN leukocyte functions that were similar to LTB4.

Animals↗
PubMed1987

Immunological mediators of wound healing and fibrosis.

T-lymphocytes, monocytes, and macrophages, which are the central constituents of immunological and chronic inflammatory reactions, generate numerous polypeptides and other factors capable of stimulating and modulating the proliferation and functions of fibroblasts. These principles differ widely in structure, target cell preference, and functional specificity. The involvement of immunological mediators of fibroblast activities in normal wound healing has not been defined, but a role in some chronic fibrosing disorders, including rheumatoid arthritis, has been suggested by the findings of functionally relevant concentrations in affected tissues. The elucidation of both the pathways of production of fibroblast-activating factors (FAFs) and the determinants of fibroblast responses will permit new approaches to the diagnosis and treatment of deficiencies in wound healing and of abnormal fibrosis.

Antigens, Neoplasm↗
PubMed1987

Interleukin-3 modulation of mouse bone marrow derived mast cell receptors for somatostatin.

Receptors for somatostatin (SOM) were identified on mouse bone marrow derived mast cells (MBMMC) and shown to vary in expression with the state of proliferation and differentiation of the MBMMC. Flow cytometric studies of the binding of fluorescein-labeled SOM and concurrent analyses of the binding of [125I]SOM demonstrated that the population of MBMMC capable of recognizing SOM specifically is that exhibiting a proliferative response to interleukin-3. The MBMMC that bound SOM reached a maximal number at 72 hr following the addition of interleukin-3, and were distributed principally in the G2/M phase of the cell cycle. SOM did not influence directly the proliferative responses of MBMMC to interleukin-3. The level of expression of SOM receptors thus may reflect the state of differentiation of mast cells, as well as determining the functional sensitivity to the inhibitory effects of SOM.

Animals↗
PubMed1987

Preferential human eosinophil chemotactic activity of the platelet-activating factor (PAF) 1-0-hexadecyl-2-acetyl-sn-glyceryl-3-phosphocholine (AGEPC).

The chemotactic responses of human blood neutrophils and of eosinophils of two different densities, which were resolved by centrifugation on gradients of polyvinylpyrrolidone-coated silica gel (Percoll), were quantified in modified Boyden micropore filter chambers using highly purified synthetic 1-0-hexadecyl-2-acetyl-sn-glyceryl-3-phosphocholine (AGEPC or PAFacether) and leukotriene B4 (LTB4) as stimuli. Maximal chemotactic responses of the densest eosinophils, less dense eosinophils, and neutrophils were evoked by 1 nM, 100 nM, and 1 microM PAFacether, respectively, and by 30-100, 30-100, and 10 nM LTB4. The magnitude of the maximal chemotactic response to PAFacether of the densest eosinophils was significantly greater than that of neutrophils. The eosinophil responses to PAFacether were chemotactic, as distinguished from chemokinetic, and were not influenced by the percentage of contaminating neutrophils. PAFacether is a more potent chemotactic factor for eosinophils than neutrophils and selectively attracts the densest population of human blood eosinophils.

Chemotactic Factors, Eosinophil↗
PubMed1987

Leukotriene and prostaglandin sensitization of cutaneous high-threshold C- and A-delta mechanonociceptors in the hairy skin of rat hindlimbs.

Single C- and A-delta fibers were isolated from dissected filaments of the saphenous nerve in pentobarbital anesthetized rats and the corresponding cutaneous receptive fields mapped with calibrated von Frey hairs. Nociceptors were characterized by their responses to noxious mechanical, thermal and chemical stimuli, including intradermal injections of leukotriene B4, prostaglandin E2, bradykinin and capsaicin. Leukotriene B4 decreased the mean mechanical threshold by a maximum of 80% within 10 min and for more than 3 h after intradermal injection of 75 ng of leukotriene B4. The degrees of sensitization of a fiber by leukotriene B4 and prostaglandin E2 were highly correlated. A potentiation effect also was observed, in that injection of prostaglandin E2 or leukotriene B4 1 h after the other eicosanoid further lowered the mechanical threshold of a sensitized fiber, whereas fibers that were not sensitized by leukotriene B4 were unaffected by prostaglandin E2. The sensitizing action of leukotriene B4 and prostaglandin E2 was directed to multiple classes of cutaneous nociceptors including 73% of C-polymodal, 60% of C-mechano-heat, 42% of C-mechano-cold nociceptors and 70% of A-delta high-threshold mechanonociceptors. The pain-evoking substances bradykinin and capsaicin activated 81% and 88%, respectively, of the sensitized C-polymodal nociceptors, 17% and 84% of the sensitized-C-mechano-heat nociceptors, 12% and 37% of the sensitized C-mechano-cold nociceptors, and 17% and none of the sensitized A-delta high-threshold mechanociceptors. The responses of C-fibers to bradykinin and capsaicin were highly correlated.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗
PubMed1987

Inhibition by leukotriene B5 of leukotriene B4-induced activation of human keratinocytes and neutrophils.

Leukotriene B5 (LTB5) that is generated enzymatically from eicosapentaenoic acid (EPA), was compared with arachidonic acid-derived LTB4 for its DNA synthetic effect on cultured human epidermal keratinocytes and for its chemokinetic effect on human blood neutrophils. Leukotriene B5 was much less potent than LTB4 in stimulating DNA synthesis and in inducing chemokinesis. Furthermore, the maximum response to LTB5 was only a mean of 38% that of LTB4 for mitogenesis and 70% that of LTB4 for chemokinesis. At an optimally active concentration of LTB4 (10(-10) M) the addition of LTB5 suppressed the enhancement by LTB4 of DNA synthesis in keratinocytes by a mean of 21%, 33%, and 54%, respectively, at 10(-9) M, 10(-8) M, and 10(-7) M LTB5. Leukotriene B5 inhibited to a lesser extent the maximum neutrophil chemokinetic response elicited by 10(-10) M LTB4 with mean inhibition of 10%, 20%, and 18%, respectively, by 10(-9) M, 10(-8) M, 10(-7) M LTB5; LTB5 was without effects on N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-elicited neutrophil chemokinesis and on thrombin-stimulated keratinocyte DNA synthesis. The dietary introduction of n-3 fatty acids, such as EPA, may reduce the epidermopoiesis and neutrophil migration evoked by LTB4 through decreases in generation of LTB4 and the capacity of LTB5 to inhibit the effects of LTB4.

Chemotaxis, Leukocyte↗
PubMed1987

Substance P receptor-dependent responses of leukocytes in pulmonary inflammation.

Pulmonary immunologic responses may be mediated and modulated in part by neuropeptides released from the endings of nerve fibers that innervate the airways. Bronchoconstriction, mucosal edema, and increased airway secretions may be mediated by multiple locally generated neuropeptides. The neuropeptides affect directly and indirectly through other mediators the functions of endothelial cells, smooth muscle cells, blood vessels, and leukocytes. The high content of diverse potent neuropeptides in the ganglionated plexuses close to pulmonary smooth muscle bundles, along blood vessels, and in neural projections into the bronchial epithelium and regions containing acini of mucus glands provide tissue concentrations well within the range required to attain such biologic effects. The airway responses mediated principally by neuropeptides exhibit unique mechanisms of specificity attributable to the selective distribution of each neuropeptide in a distinct subset of nerve fibers that react differently to each stimulus and to the target cell specificity of the neuropeptides. At physiologically relevant in vitro concentrations, many of the neuropeptides have different effects on mast cells, basophils, monocytes, and lymphocytes. The direct actions of substance P (SP) and the capacity to initiate and modulate leukocyte responses are described in relation to the physiologic and pathopharmacologic consequences of pulmonary nerve stimulation. Selected cellular and molecular characteristics of the interactions of SP with mast cells, basophils, lymphocytes, endothelial cells, and smooth muscle cells also will be presented in order to define the functionally critical properties of receptors for the neuropeptide and to expose possible means of specifically modifying the interactions.

Animals↗
PubMed1987

Stimulation by leukotriene D4 of increases in the cytosolic concentration of calcium in dimethylsulfoxide-differentiated HL-60 cells.

The C6-sulfidopeptide leukotrienes C4 (LTC4) and D4 (LTD4) evoked increases in the cytosolic concentration of intracellular calcium ([Ca+2]i) in dimethylsulfoxide-differentiated HL-60 cells, as assessed by the fluorescence of quin-2. The increases in [Ca+2]i reached a peak within 15-90 s, attained 50% of the maximum level at 1.2 nM LTD4 and 60 nM LTC4, were greater in maximal magnitude for LTD4 than LTC4, and subsided in 5-7 min. Flow cytometric evaluation of the LTD4-induced increases in [Ca+2]i, reflected in increases in the fluorescence of intracellular indo-1, revealed that a mean of 77% of differentiated HL-60 cells responded, as contrasted with lesser increases in only 50% of undifferentiated HL-60 cells. The capacity of pretreatment of HL-60 cells with LTD4 to prevent subsequent responses of [Ca+2]i to LTC4 and LTD4, and the finding that the serine-borate inhibitor of conversion of LTC4 to LTD4 suppressed concurrently both LTC4-induced rises in [Ca+2]i and increases in adherence to Sephadex G-25 indicated that the responses of HL-60 cells to LTC4 required conversion to LTD4. That pertussis toxin and a chemical antagonist of LTD4 reduced the [Ca+2]i response suggested a dependence on LTD4 receptors. The LTD4-induced increases in [Ca+2]i were dependent on extracellular calcium and diminished by lanthanum, but not affected by nifedipine nor associated with changes in membrane potential, as measured with the fluorescent probe 3,3'-dipentyloxacarbocyanine. Thus, the increase in [Ca+2]i in HL-60 cells, which is coupled to an increase in adherence, appears to involve LTD4 receptor-specific and voltage-independent calcium channels in the plasma membrane.

Aminoquinolines↗
PubMed1987

Contribution of the nervous system to the pathophysiology of rheumatoid arthritis and other polyarthritides.

Some clinical features of rheumatoid arthritis (RA) (for example, preferential joint involvement and bilateral symmetry), taken together with the strong evidence of neurogenic inflammatory processes, suggest that the nervous system contributes to the inflammatory component of RA and other polyarthritides. The authors propose that the increased risk and severity of disease in particular joints reflects a greater innervation of those joints by unmyelinated afferent and sympathetic efferent fibers. Release of the proinflammatory peptide, substance P, from the peripheral terminals of nociceptive joint afferent fibers, through interactions with many nonneural cells, exacerbates the inflammatory process. Release of mediators from sympathetic efferents (including norepinephrine) also contributes to the inflammation, either through an independent mechanism or by acting in concert with the nociceptive afferent-derived substances. Therapies directed at interruption of the nervous system contribution to the pathophysiology of these diseases should offer a new direction to treatment.

Animals↗
PubMed1987

Specificity and cellular distribution of human polymorphonuclear leucocyte receptors for leukotriene C4.

Human polymorphonuclear (PMN) leucocytes bind synthetic [3H]-labelled leukotriene C4 ([3H]LTC4) with rapid saturation and reversibility of approximately 90%, by a 700-fold higher concentration of non-radioactive LTC4. [3H]LTC4 is recognized specifically by 10,778 +/- 6260 (mean +/- SD) sites per PMN leucocyte that exhibit a KD of 34.3 +/- 1.7 nM. The specificity of the LTC4 receptors is supported by the competitive inhibition of binding of [3H]LTC4 by LTC4, LTC4-sulphone, LTD4, and LTE4 with relative potencies of approximately 100:20:3:1. The four-fold higher level of specific binding of [3H]LTC4 by sonicates than by intact PMN leucocytes is attributable to intracellular receptors. Of the total number of receptors recovered in sonicates of PMN leucocytes, one-third are associated with membranes and the other two-thirds with lysosomal granules. The affinity of the membrane receptors for LTC4 is indistinguishable from that of receptors on intact PMN leucocytes, whereas the affinity of granule receptors is significantly higher. The characteristics of the receptors are consistent with a role in mediating uptake and metabolism of LTC4 by PMN leucocytes.

Binding Sites↗
PubMed1987

Molecular and cellular properties of human polymorphonuclear leukocyte receptors for leukotriene B4.

The distinctive characteristics of human polymorphonuclear (PMN) leukocyte receptors for leukotriene B4 (LTB4) have been elucidated by studies of binding of [3H]LTB4, the structure of protein constituents of the receptors isolated from plasma membranes, and the effects of antireceptor antibodies. A high-affinity class of 4400 receptors with a KD of 0.4 nM mediates chemotaxis and increased adherence of PMN leukocytes, whereas a low-affinity class of 270,000 receptors with a KD of 61 nM mediates the release of lysosomal enzymes and increases in oxidative metabolism. The low-affinity receptors are composed of a 60,000-dalton protein-binding unit. The high-affinity receptors are composed of the same binding unit in association with a 40,000-dalton guanine nucleotide-binding protein. That antireceptor antibodies as well as LTB4 distinguish the two classes of receptors with different functional consequences suggests the possibility of unique approaches to the regulation of leukocyte function at the receptor level.

Antibodies, Monoclonal↗