Generation of Leukotriene B 4 by Human Lung Fragments and Purified Human Lung Mast Cells

The actions of adenosine on histamine release of human lung fragments were investigated. Histamine release was stimulated either with the calcium ionophore A 23187 or with concanavalin A. Adenosine and its analogue 5′-N-ethyl-carboxamidoadenosine alone had no significant effect on basal release or on the release elicited by A 23187 or concanavalin A. However, in the presence of the adenosine receptor antagonist 8-[4-[[[[(2-aminoethyl)amino]-carbonyl] methyloxy]-phenyl]-1,3-dipropylaxanthine (XAC), which itself did not affect the release, adenosine increased the stimulated histamine release. On the other hand, in the presence of the nucleoside transport inhibitor S-(p-nitro-benzyl)-6-thioninosine (NBTI), adenosine caused a reduction in stimulated histamine release. NBTI itself caused a stimulation of release. Thus, a stimulatory effect of adenosine was seen in the presence of XAC, whereas an inhibitory effect was unmasked by NBTI. From these data it is concluded that adenosine exerts two opposing effects on histamine release in the human lung which neutralize each other: it inhibits release via a site antagonized by XAC, which presumably represents an A₂ adenosine receptor, and it stimulates release via a mechanism that is blocked by NBTI, suggesting that adenosine needs to reach the interior of cells to exert this effect. The slight stimulatory effect of NBTI alone demonstrates that trapping intracellularly formed adenosine inside mast cells leads to sufficient concentrations of adenosine to stimulate histamine release. These findings suggest an important bimodal role of adenosine in regulating histamine release in the human lung.

Section: Discussionsupporting

confidence: 93%

Effects of Adenosine on Histamine Release from Human Lung Fragments

Ott

Klotz

Vogt-Moykopf³

et al. 1992

“…Nasal antigenic provocation has demonstrated the in vivo formation of LTC4/D4/E4 at levels of 8,270 ±2,340 pg/ml sample [21]. Lcukotriene B4 is detect ed in relatively low concentrations following anti gen challenge of both lung mast cells and the nasal mucosa [34]. This supports the hypothesis that mast cells are a contributory source of leukotrienes during the early allergic response, but other cells arc also known to generate LTC4.…”

Section: Discussionsupporting

confidence: 57%

Histamine Stimulation of the Nasal Mucosa Does Not Induce Prostaglandin or Leukotriene Generation or Induce Methacholine Hyperresponsiveness

Majchel

Hubbard²,

Naclerio

1991

To further define the role of histamine in the nasal mucosa, we studied the possible effect of histamine provocation on the generation of prostanoids and leukotrienes, and on the induction of hyperresponsiveness to methacholine. In separate experiments, we performed nasal challenges with histamine and measured by gas chromatography negative ion mass spectrometry and by radioimmunoassay after high-performance liquid chromatography the levels of prostanoids and leukotrienes, respectively, in recovered nasal lavages 10 min after challenge. Hyperresponsiveness to methacholine was tested in both nostrils 24 h after unilateral provocation with histamine. Our data suggest that histamine induced an immediate symptomatic response, but neither led to the generation of prostaglandins or leukotrienes nor induced hyperresponsiveness to methacholine. These results differ from those achieved after antigen stimulation and emphasize the importance of mediators in addition to histamine in the allergic reaction.

“…These cells release several mediators which have neutrophil chemotactic activity, including LTB4 and che motactic cytokines [13,14]. Recently, we demonstrated that IL-8, a potent leukocyte chemoattractant, induces in vivo neutrophil migration by stimulating the release of a neutro phil chemotactic factor from mast cells [15].…”

Section: Introductionmentioning

confidence: 99%

Role of Resident Mast Cells and Macrophages in the Neutrophil Migration Induced by LTB<sub>4</sub>, fMLP and C5a des arg

Ribeiro

Souza-Filho²,

Souza³

et al. 1997

In the present study, we have investigated the participation of resident peritoneal cells (macrophages and mast cells) in the neutrophil migration induced in rats by the intraperitoneal administration of LTB₄, fMLP or C5a des arg. The intraperitoneal injection of LTB₄ (10 nmol), fMLP (10 nmol) and C5a des arg (zymosan-activated plasma, 1 ml) caused an intense neutrophil migration compared to the saline control (1,000, 1,500 and 2,000%, respectively). An 83% depletion in the number of resident cells following peritoneal lavage reduced the LTB₄-stimulated neutrophil migration by 73.6% without affecting that caused by fMLP and C5a des arg. Increasing the peritoneal macrophage population (236%) by pretreating the cavities with thioglycollate enhanced the neutrophil migration induced by LTB₄ (129%), but did not alter that induced by fMLP and C5a des arg. Similarly, reducing the population of peritoneal mast cells containing toluidine-blue-staining granules by subchronically pretreating the cavities with compound 48/80 diminished the LTB₄-induced NM by 69% but had no effect on the responses to fMLP and C5a des arg. Pretreating the animals with dexamethasone strongly inhibited (70%) the neutrophil migration induced by the intraperitoneal injection of LTB₄, fMLP and C5a des arg. Indomethacin, BW A4C and NDGA had no such effect. The incubating medium from peritoneal macrophages and mast cells stimulated with LTB₄ induced neutrophil migration when injected into the peritoneal cavity of rats. This migration was strongly reduced (70%) by treating the cells with dexamethasone. In contrast, stimulating the cells with fMLP or C5a des arg did not result in the release of any promigratory activity into the incubating fluid. Our results suggest that LTB₄ induces neutrophil migration via a mechanism dependent on resident mast cells and macrophages while that induced by C5a des arg and fMLP seems to be independent of such cellular involvement. The neutrophil migration induced by LTB₄ is apparently mediated by factor(s) whose release is blocked by dexamethasone. fMLP and C5a appear to cause in vivo migration by the formation of a concentration gradient and by a glucocorticoid-sensitive mechanism different from that stimulated by LTB₄.