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PubMed1998

Release of epithelium-derived PGE2 from canine trachea after antigen inhalation.

To investigate the role of prostaglandin (PG) E2 in allergen-induced hyperresponsiveness, dogs inhaled either the allergen Ascaris suum or vehicle (Sham). Twenty-four hours after inhalation, some animals exposed to allergen demonstrated an increased responsiveness to acetylcholine challenge in vivo (Hyp-Resp), whereas others did not (Non-Resp). Strips of tracheal smooth muscle, either epithelium intact or epithelium denuded, were suspended on stimulating electrodes, and a concentration-response curve to carbachol (10(-9) to 10(-5) M) was generated. Tissues received electrical field stimulation, and organ bath fluid was collected to determine PGE2 content. With the epithelium present, all three groups contracted similarly to 10(-5) M carbachol, whereas epithelium-denuded tissues from animals that inhaled allergen contracted more than tissues from Sham dogs. In response to electrical field stimulation, Hyp-Resp tissues contracted less than Sham tissues in the presence of epithelium and more than Sham tissues in the absence of epithelium. PGE2 release in the muscle bath was greater in Non-Resp tissues than in Sham or Hyp-Resp tissues when the epithelium was present. Removal of the epithelium greatly inhibited PGE2 release. We conclude that tracheal smooth muscle is hyperresponsive in vitro after in vivo allergen exposure only when the modulatory effect of the epithelium, largely through PGE2 release, is removed.

Administration, Inhalation↗
PubMed1988

Arachidonic acid evokes epithelium-dependent relaxations in canine airways.

Responses to arachidonate were examined in rings with and without epithelium of lobar, segmental, and subsegmental canine bronchi. Arachidonate evoked epithelium-dependent relaxations, which were less pronounced in subsegmental bronchi and abolished by indomethacin and meclofenamate. Nordihydroguairetic acid (NDGA) and nafazatrom reduced epithelium-dependent relaxations only in lobar but unmasked epithelium-independent relaxations to arachidonate in all bronchi. Prostaglandin E2 and prostacyclin relaxed all tissues similarly. In lobar bronchi without epithelium, basal release of prostaglandin E2 was reduced by indomethacin but unaffected by NDGA. Arachidonate augmented prostaglandin E2 release more in subsegmental than in lobar bronchi with epithelium; in bronchi without epithelium the rise was absent (lobar) or attenuated (subsegmental). Arachidonate augmented the release of 6-ketoprostaglandin F1 alpha more in lobar bronchi with than without epithelium; this was inhibited by indomethacin, but not NDGA. Thus arachidonate releases prostaglandin E2 (possibly produced by cyclooxygenase inaccessible to inhibitors and activated by lipoxygenase products) but not prostacyclin from the epithelium. Heterogeneity in response to arachidonate is not due to different sensitivity to, or production of, prostaglandins.

Animals↗
PubMed1993

Responsiveness of the guinea pig trachea to stretch: role of the epithelium and cyclooxygenase products.

The role of the epithelium and cyclooxygenase products was investigated in the responses of isolated airways to sudden stretch. Strips of guinea pig trachea, in some of which the epithelium had been removed mechanically, were suspended in organ chambers; isometric tension was recorded. After rapid stretching to their optimal tension, the preparations (with and without epithelium) relaxed initially and then contracted to a level close to the imposed tension. Afterward, tissues with epithelium maintained this level of tension, but those without epithelium relaxed. After treatment with papaverine or isoproterenol (at concentrations causing maximal relaxation), stretch was followed only by a decrease in tension; a similar response to stretch was also obtained in tissues treated with indomethacin or acetylsalicylic acid (inhibitors of cyclooxygenase). Dazmegrel (an inhibitor of thromboxane synthase) and SQ-29548 (an antagonist of prostaglandin H2 or thromboxane A2 receptors) did not affect the response of tissues with epithelium but abolished the stretch-induced contraction in those without epithelium. Tranylcypromine, which inhibits prostacyclin synthase, and tetrodotoxin, which blocks local reflexes, did not significantly affect the responses of the tissues to stretch. These observations suggest that thromboxane may mediate the epithelium-independent contraction and that another product of cyclooxygenase contributes to the maintenance of tension on stretching observed in tissues with epithelium.

Animals↗
PubMed2004

Decreased pigment epithelium-derived factor is associated with metastatic phenotype in human and rat prostate tumors.

Pigment epithelium-derived factor, a potent angiogenesis inhibitor in the eye, is also expressed in the prostate. Prostate size and angiogenesis is increased in pigment epithelium-derived factor knockout mice, and pigment epithelium-derived factor is down-regulated in some prostate cancers. To investigate whether pigment epithelium-derived factor expression correlates with tumor progression, we examined 5 Dunning rat prostate sublines with different growth rates, differentiation, androgen dependence, vascular density, and metastatic ability and 26 human prostate cancers of Gleason score 8-10 obtained from patients at transurethral resection selected to represent two groups, with and without metastases at diagnosis. By Western blot, real-time quantitative reverse transcription-PCR, and immunostaining, pigment epithelium-derived factor was detected in highly differentiated, nonmetastatic, androgen-sensitive Dunning tumors and in the anaplastic, androgen insensitive but nonmetastatic Dunning tumors. In contrast, the metastatic Dunning tumor sublines showed very low pigment epithelium-derived factor expression levels. In human cancer tissues, by immunohistochemistry and real-time quantitative reverse transcription-PCR, patients without metastases at diagnosis had higher tumor pigment epithelium-derived factor levels than tumors from patients with metastases at diagnosis. In both the rat model and in the human tumors, the proliferation index and vascular count, as determined by Ki-67 staining and endoglin and/or factor VIII-related antigen staining, inversely correlated with pigment epithelium-derived factor mRNA levels. These observations indicate that loss of pigment epithelium-derived factor expression could be associated with the progression toward a metastatic phenotype in prostate cancer.

Adenocarcinoma↗
PubMed1986

Ultrastructural studies of the transitional zone in the nasopharyngeal epithelium, with special reference to the keratinizing process in the mouse.

In the nasopharynx of the SMA mouse, the 'intermediate epithelium' occupies the transitional zone between the ciliated columnar and the stratified squamous epithelia. The intermediate epithelium showed gradations ranging from ciliated stratified low-columnar through stratified cuboidal to stratified squamous type. It is suggested that the intermediate epithelium shows the various stages of the epithelium transforming from the ciliated columnar to the stratified squamous epithelium, and that the basal cells of the ciliated columnar epithelium serve as the germinal layer for the transformation. The intermediate epithelium containing a few keratohyalin granules and many membrane-coating granules represented earlier stages of keratinization. The width of the microprojections in the stratified squamous epithelium was about doubled compared to that in the intermediate epithelium. It is suggested that the difference in width is caused by cell membrane distortion associated with keratinization and is regarded as an important marker of the start of keratinization.

Animals↗
PubMed2004

Role of p38 MAP kinase in regulation of cell migration and proliferation in healing corneal epithelium.

PURPOSE: The purpose of the present study was to examine the roles of signaling pathways potentially activated by TGFbeta (i.e., Smad and p38 mitogen-activated kinase [MAPK]) in regulation of cell migration and proliferation of healing mouse corneal epithelium. METHODS: Activation of Smads or p38MAPK was evaluated by immunohistochemistry in healing mouse corneal epithelium after debridement. The role of endogenous TGFbeta or p38MAPK in epithelial healing was determined in organ-cultured mouse corneas with an epithelial defect, in the presence or absence of a TGFbeta-neutralizing antibody or p38MAPK inhibitors, respectively. Cell proliferation was evaluated by incorporation of bromodeoxyuridine. RESULTS: Migrating mouse corneal epithelium had minimal cell proliferation. Smad3 and -4 were found in nuclei of normal corneal epithelium, whereas they were absent in nuclei of migrating cells in association with Smad7 upregulation on epithelial debridement. Administration of TGFbeta-neutralizing antibody reduced the protein expression of Smad7 in vivo after a corneal injury. In contrast, phosphorylation and nuclear translocation of p38MAPK were markedly evident in migrating epithelium during healing, but not in uninjured epithelium. In organ culture, addition of p38MAPK inhibitors blocked cell migration more markedly than neutralizing TGFbeta-antibody and enhanced cell proliferation in the injured corneal epithelium, in association with phosphorylation of Erk. CONCLUSIONS: Endogenous TGFbeta enhances migration of corneal epithelium during wound healing in mice. The p38MAPK, but not the Smad, cascade plays a major role in promoting cell migration and in suppressing cell proliferation in migrating epithelium.

Animals↗
PubMed1988

Effect of aging on kinetic parameters of 5 alpha-reductase in epithelium and stroma of normal and hyperplastic human prostate.

Altered 5 alpha-dihydrotestosterone (DHT) metabolism and stromal-epithelial cell interactions are two factors hypothesized to explain the development of benign prostatic hyperplasia (BPH). Furthermore, the development of BPH is clearly age dependent. Therefore, we studied the age-dependent alteration of 5 alpha-reductase, the enzyme that catalyzes the irreversible conversion of testosterone to DHT in epithelium and stroma of the human prostate. For this purpose kinetic parameters [Km Vmax] of 5 alpha-reductase were determined separately in epithelium and stroma of normal prostatic tissue (NPR) from 5 and BPH tissue from 20 men, and the results were correlated with the age of the donors (15-86 yr). The mean Km in epithelium [NPR, 14.3 +/- 1.8 (+/- SE); BPH, 29.5 +/- 2.7 nmol/L] was significantly (P less than 0.0001) lower than that in stroma (NPR, 78.4 +/- 8.5; BPH, 185.8 +/- 13.6 nmol/L). The mean Vmax in epithelium [NPR, 23.8 +/- 3.9 (+/- SE); BPH, 27.9 +/- 3.0 pmol/mg protein.h] was significantly (P less than 0.0001) lower than that in stroma (NPR, 68.3 +/- 4.4; BPH, 173.8 +/- 12.2 pmol/mg protein.h). The DHT-forming index (Vmax/Km) in NPR epithelium [1.6 +/- 0.2 (+/- SE)] was significantly (P less than 0.01) higher than that in NPR stroma (0.9 +/- 0.1), while in BPH the DHT-forming index was nearly identical in epithelium (1.1 +/- 0.1) and stroma (1.0 +/- 0.1). The Km values in epithelium and stroma both correlated positively (P less than 0.01) with age, but the Vmax values correlated positively with age (P less than 0.0001) only in stroma. The DHT-forming index decreased significantly with age in epithelium (P less than 0.01), but remained constant in stroma. These results indicate that there is a nonuniform age-dependent alteration of Km and Vmax in epithelium and stroma of the human prostate independent of the presence of BPH, which might have an impact on the conversion rate of testosterone to DHT with advancing age.

Adult↗
PubMed1989

Nasal polyps: epithelium and goblet cell density.

The density of goblet cells was determined in 14 anterior and 15 posterior nasal polyps using the whole-mount method. The specimens were then serial cut and the type of epithelium was determined in nine localities in each polyp. The goblet cell density was correlated to the epithelial type. Pseudostratified, cylindrical epithelium was the prevailing type, occurring in 62% of anterior localities and 78% of posterior localities. Transitional types of epithelium were found in 33% of the anterior and 19% of the posterior localities. Stratified squamous epithelium occurred in 5% and 3%, respectively. The goblet cell density was highest in hyperplastic pseudostratified epithelium, whereas it was four times lower in transitional epithelium and even lower in squamous epithelium. Marked differences in the distribution of epithelium and goblet cell density were found between anterior and posterior polyps, illustrating that the epithelium constantly changes under the influence of air current, contact with other polyps, infection, growth, and age of the polyp as well as other unknown factors.

Cell Count↗
PubMed1990

Postnatal transformation and location of mitoses in the epithelium lining the mouse vomeronasal organ.

The structure and the postnatal transformation of the epithelium lining the vomeronasal organ of the mouse was observed. The medial wall of the middle segment of the organ was lined with the sensory epithelium similar to the olfactory epithelium, and was not undergone any transformation in the postnatal life. The lateral wall of the middle segment and the entire lumen of the rostral segment were covered with the stratified cuboidal epithelium in the newborn mouse. The stratified cuboidal epithelium transformed into the ciliated columnar epithelium with advancing ages, excepting in the vomeronasal duct where the epithelium changed into the stratified squamous one. In the mouse aged between 4 and 10 days, mitotic figures were observed not only in the boundary between the sensory epithelium and the ciliated columnar one in the middle segment, but also in the rostral segment of which the entire lumen was covered with the ciliated columnar epithelium.

Animals↗
PubMed2006

Ultrastructural analysis of in vivo expanded corneal epithelium on amniotic membrane.

The purpose of this study is to characterize and compare the ultrastructural changes occurring during the in vivo cultivation of corneal epithelium on amniotic membrane (AM) at several different time points. Corneal burn patients (n=7) with a corneal epithelial defect and severe limbal damage were selected. Initially, AM transplantation with limbal autograft was performed at the acute stage of corneal burn to reconstruct the damaged ocular surface. One to six (mean interval; 3.3+/-1.2) months later, the central part of AM containing an in vivo expanded corneal epithelium was excised and retransplanted in adjacent lesions. The excised epithelium with AM was examined by electron microscopy and immunohistochemical study. By electron microscopy, one and two months after expansion, cultivated epithelium on AM showed an undifferentiated epithelium and an incomplete basement membrane (BM). But, after three months, the cultivated epithelium began to differentiate into a multilayered epithelium with a continuous BM with increased hemidesmosomes. These findings were further confirmed by immunohistochemical study, that cytokeratin K3 was expressed in the cultivated corneal epithelium and newly formed BM was partially positive of collagen IV at three months. At least 3 months may be needed for the proliferation and differentiation of in vivo cultivated corneal epithelium on AM.

Adult↗
PubMed1995

Effects of epithelium on the mechanism of mediator release from guinea pig tracheal tissues sensitized by IgG1 versus IgE antibody.

In the present work, we have examined the effect of PAF, removal of epithelium, the mechanism of desensitization, and the substances that increases the level of intracellular c-AMP on the differences of mediator release from superfused tracheal strips after passive sensitization with IgG1 versus IgE Ab. In the passive sensitized tracheal tissues, the effect of PAF and the mechanism of desensitization have been examined by PAF antagonist, CV 3988 and DFP, respectively. The epithelium was stripped from one-half of each trachea by mechanical means. Both superfused tracheal tissues were challenged with Ox-Ag. Inhibitors of mediator release were added into a superfused buffer. Hist released was determined by spectrophotofluorometer, and LT by radioimmunoassay. PAF known to mediate the allergic reaction was not released by Ag after both Ab sensitization. Epithelium removal resulted in similar contraction, Hist and LT release after IgG1 Ab activation, but in the IgE Ab activation, epithelium removal resulted in smaller contraction and Hist release. In the L-cysteine and indomethacin pretreatment after two Ab sensitization, epithelium removal decreased the release of Hist and LT. The compound 48/80 pre-challenge and epithelium removal resulted in the increase of Hist release, but in the decrease of LT release after IgG1 or IgE sensitization. The Amount of LT released by Ag after compound 48/80 pre-challenge increased in the absence or presence of epithelium after both Ab sensitization. Mediator release from tissues sensitized with both Abs was not changed by DFP. The responses of inhibitors to prevent the mediator release were more effective on the IgE Ab than on the IgG1 Ab sensitization. These studies suggest that the tracheal epithelium can act to inhibit immune- and non-immune-induced airway responses. Non-immunological responses may in part reflect the role of epithelium as a diffusion barrier and modulator of mediator release. These data also suggest that immunological responses are related to the localization and functional heterogeneity of tissue mast cells.

Animals↗
PubMed1994

Detection of a shared colon epithelial epitope on Barrett epithelium by a novel monoclonal antibody.

OBJECTIVE: To determine if there is a reactive epitope common to colonic epithelium and Barrett epithelium, a premalignant metaplastic columnar-lined esophagus, usually arising as a complication of chronic reflux esophagitis. DESIGN: A monoclonal antibody, 7E12H12 (IgM isotype), developed against a colonic epithelial protein was used in a sensitive immunoperoxidase assay using formalin-fixed, paraffin-embedded tissue. One hundred sixteen tissue specimens from the esophagus, stomach, duodenum, and jejunum were examined. Twenty-two biopsy specimens were taken from 22 patients with benign Barrett epithelium, and 12 specimens were obtained from 12 patients with adenocarcinoma of the esophagus arising in Barrett epithelium. The remaining 85 tissue specimens were obtained from various parts of the upper gastrointestinal tract of patients with or without disease states. RESULTS: 21 of 22 (95%) Barrett epithelium specimens and all 12 adenocarcinomas arising from Barrett epithelium reacted with the 7E12H12 monoclonal antibody. Other tissues from esophagus, gastroesophageal junction, stomach, duodenum, or jejunum did not react. Squamous cell carcinoma of the esophagus also did not react. CONCLUSIONS: Barrett epithelium shares phenotypic expression of colonic epithelium. The 7E12H12 monoclonal antibody may provide insight into the origin and cellular lineage of Barrett epithelium.

Adenocarcinoma↗
PubMedDate not supplied

Lugol staining pattern in background epithelium of patients with esophageal squamous cell carcinoma.

BACKGROUND/AIMS: Squamous cell carcinoma of the esophagus often arises in the setting of chronic esophagitis. We investigated whether chronic esophagitis was associated with carcinogenesis in the esophageal squamous epithelium. METHODOLOGY: Videoendoscopy with Lugol staining was performed in 70 patients with invasive carcinoma of the esophagus. We especially focused the study on background epithelium of the esophagus, then background epithelium was classified into two groups according to differences in Lugol staining patterns. Following Lugol solution spraying, background epithelium showing uniform greenish-brown staining was defined as having a uniform pattern. In contrast, when multiple Lugol-unstained speckles were present throughout the esophagus, the pattern was defined as speckled. Furthermore, we also investigated whether glycogenic acanthosis is present or not in background epithelium. RESULTS: Chronic esophagitis was present in 11 of 70 patients (16%) with invasive carcinoma, indicating a speckled pattern in background epithelium following Lugol solution spraying. The remaining 84% of patients with invasive carcinoma showed normally uniform Lugol staining background epithelium. Glycogenic acanthosis was found in 65 (93%) of 70 patients. CONCLUSIONS: Approximately 80% of patients with esophageal squamous cell carcinoma showed normal Lugol staining of background epithelium. Field carcinogenesis is postulated to be not predominant in the development of esophageal squamous cell carcinoma in our Japanese subjects. In contrast, glycogenic acanthosis of the esophagus was associated with the background epithelium accompanied with esophageal squamous cell carcinoma.

Adult↗
PubMed1992

Effects of formaldehyde on xenotransplanted human respiratory epithelium.

A laboratory animal model that permits the exposure of xenotransplanted human respiratory epithelium to formaldehyde was used to study the effects of formaldehyde alone or in combination with the ultimate carcinogenic metabolite of benzo[a]pyrene, benzo[a]pyrene diol epoxide. Epithelial cells obtained from autopsies of full-term human fetuses or infants less than one year old were isolated, amplified in primary cultures, and then inoculated into rat tracheas from which the epithelial layer had been removed. These tracheas then were sealed and transplanted subcutaneously into irradiated athymic nude mice. Four weeks after transplantation, the tracheal lumen was completely covered by epithelium, most of which was of the mucociliary respiratory type. At this stage, tracheal transplants containing tracheobronchial epithelium from 20 different human infant donors were exposed to silastic devices containing 0, 0.5, 1, or 2 mg of formaldehyde. The tracheal transplants were examined histologically 2, 4, 8, or 16 weeks after transplantation. Before being killed, all animals were injected with a single pulse of tritiated thymidine. Important epithelial alterations were seen in the transplants treated with formaldehyde, with a maximum effect visible two weeks after exposure. In most cases, the highest dose of 2 mg produced numerous areas of epithelial erosion and inflammation; however, this effect was not as evident with the lower doses. All doses produced areas of hyperplastic epithelium alternating with areas of atrophic epithelium. Although the differences in predominance of different types of epithelium were not clearly dependent on dose, the labeling index showed dose dependence between two and four weeks after the initiation of exposure. The maximum mean labeling index was three to four times higher than normal, although in some focal hyperplastic-metaplastic lesions the labeling index increased up to 20 times. These studies show that formaldehyde, although toxic at higher doses, is able to elicit at lower doses a proliferative response of the human infant tracheobronchial epithelium that is not preceded by a massive toxic effect. Similar studies were performed using xenotransplanted human adult nasal respiratory epithelium (Study 2). The response pattern was very similar to that of the xenotransplanted human tracheobronchial epithelium from human infants (Study 1). In Study 3, using cells obtained from 11 human infant tracheobronchial epithelia, the formaldehyde applied simultaneously or sequentially with benzo[a]pyrene diol epoxide did not induce epithelial alterations different from those observed with formaldehyde treatments alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Effect of over-expression of pigment epithelium derived factor (PEDF) on developing retinal vasculature in the mouse.

PURPOSE: Pigment epithelium derived factor (PEDF) is a secreted protein with demonstrated anti-angiogenic properties, and with potential application for the treatment of neovascular disease. Delivery of pigment epithelium derived factor to the retina via virus mediated gene transfer has been shown to inhibit neovascularization in a number of experimental models. While pigment epithelium derived factor is endogenously expressed in the retina, its role in guiding normal vessel development and growth is not yet known. This study aimed to determine whether over-expression of pigment epithelium derived factor alters the normal pattern of retinal vessel development. METHODS: Neonatal (age postnatal day 2 (P2)) CD1 mice were injected subretinally unilaterally with AAV2/1.CMV.PEDF while contralateral eyes were injected subretinally with AAV2/1.CMV.EGFP as control. Cohorts of animals were sacrificed at P7 to P21 and the retinal vasculature was co-labeled through fluorescein-dextran perfusion and immunohistochemistry. Vascular size, localization, and structure were analyzed using light and confocal microscopy. Additional cohorts were use to obtain quantitative levels of pigment epithelium derived factor protein through ELISA. RESULTS: The extent of vessel growth from the optic disk to periphery over time (i.e., the radius of retinal vasculature), and the area of expansion of the neural retina were unaffected by over-expression of pigment epithelium derived factor to levels at least 3.5 fold higher than endogenous levels. The thicknesses of the various retinal layers were similar in AAV2/1.CMV.PEDF treated and control injected eyes. Three dimensional analysis of confocal images shows a slight delay in the rate of growth of vasculature into the deeper layers of the retina in pigment epithelium derived factor treated eyes compared to EGFP treated control eyes. However, the normal differentiation of vessels into arterioles, and venules, and the formation of a capillary network continued to occur, achieving normal and complete maturation of vascular structure by P21. CONCLUSIONS: Over-expression of pigment epithelium derived factor in the developing retina exerted no marked or permanent effects on retinal vessel growth and differentiation. The findings are relevant to the safety of the potential therapeutic use of pigment epithelium derived factor in human retinal disease.

Animals↗
PubMed1990

An examination of the influence of the epithelium on contractile responses to peptidoleukotrienes and blockade by ICI 204,219 in isolated guinea pig trachea and human intralobar airways.

The influence of the epithelium on antagonism by ICI 204,219 of contractile responses to peptide leukotriene (LT) agonists was examined in guinea pig tracheal and human bronchial rings. The -log molar KB values for ICI 204,219 were found to be independent of the epithelium in both tissues. Even though uninfluenced by the epithelium, the -log molar KB values for ICI 204,219 were about 10-fold smaller in human airways than in guinea pig trachea. Removal of the epithelium from guinea pig trachea resulted in small leftward shifts of the concentration-response curves to LTC4 and LTD4 and rightward shifts of the concentration-response curves to LTE4 when examined in the presence of indomethacin. The potentiation of LTC4 and LTD4 by epithelium removal was not seen in the presence of inhibitors of the transformation of LTC4 to LTD4 and LTD4 to LTE4. The influence of the epithelium on responses to LTE4 remained in the presence of these metabolic inhibitors. The lipoxygenase inhibitors nordihydroguaiaretic acid, B755C, Rev 5901 and AA861 antagonized responses to LTE4 in the presence, but not in the absence of epithelium. In human airways, epithelium removal resulted in a small leftward shift of the concentration-response curve to LTD4 whereas responses to LTC4 and LTE4 were unaltered. This effect was not observed in the presence of indomethacin, relating it to reduced release of cyclooxygenase products. These data suggest that contractile responses of guinea pig trachea to LTE4 are modulated by LTE4-induced release of 5-lipoxygenase product(s) only when the epithelium is present.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Effect of removal of epithelium on antigen-induced smooth muscle contraction and mediator release from guinea pig isolated trachea.

We examined the effect of removal of the epithelium on antigen-induced smooth muscle contraction and the release of mediators of inflammation from superfused, sensitized guinea-pig tracheal spirals in vitro. The epithelium was stripped from one-half of each trachea by mechanical means, and immunologic responses were evaluated by paired analysis. Removing the epithelium potentiated antigen-induced contraction, as reflected by a 5-fold leftward shift in the antigen dose-response curve, but the maximum response to antigen was not altered. This potentiation was not inhibited by pretreating the tissues with indomethacin (5 X 10(-6) M). At maximum concentrations of antigen removing the epithelium had no effect on the magnitude or kinetics of release of immunoreactive sulfidopeptide leukotrienes, prostaglandin (PG) D2, PGF2 alpha or thromboxane B2. Removing the epithelium did, however, significantly decrease the release of PGE and 6-keto-PGF1 alpha, a prostacyclin metabolite. Antigen-induced histamine release was enhanced by removing the epithelium; this effect varied inversely with antigen concentration. Selectively exposing either the luminal or serosal surface of an intact, superfused trachea to antigen resulted in the release of less than 5% of the total tissue histamine. Removing the epithelium from the intact trachea increased histamine release to approximately 25% following luminal but not serosal exposure to antigen. These studies demonstrate that the tracheal epithelium can act to inhibit antigen-induced airway contraction in vitro. This may in part reflect the role of the intact epithelium as a diffusion barrier which can limit the rate of influx of antigen molecules and thereby influence tissue mast cell activation.

Animals↗
PubMed1987

Arachidonic acid metabolites and airway epithelium-dependent relaxant factor.

Exogenous arachidonic acid (10(-8) to 10(-4) M) contracted epithelium-free guinea pig tracheal strips. Intact tracheal strips were contracted slightly by low concentrations of arachidonic acid (10(-8) to 10(-5) M), but higher concentrations relaxed them. In contrast, when tracheal strips were precontracted with histamine or carbachol, exogenous arachidonic acid had no effect on epithelium-free preparations but induced concentration-dependent (10(-8) to 10(-4) M) relaxation of intact tracheal strips. The effects of arachidonic acid both in epithelium-free and epithelium-containing trachea were blocked by either indomethacin (10(-6) M) or aspirin (10(-4) M). Studies on the effects of exogenous arachidonic acid, performed with a "sandwich protocol," demonstrated that the postulated airway epithelium-dependent relaxant factor released by an intact tracheal strip relaxes an adjacent epithelium-free strip in the same organ bath. This relaxation is antagonized by indomethacin suggesting the involvement of a cyclooxygenase product in this phenomenon. Comparison of concentration-response curves for contractile agonists in epithelium-free preparations and in one containing epithelium suggests the mobilization of airway epithelium-dependent relaxant factor by histamine but not by carbachol. The effects of cyclooxygenase and lipoxygenase inhibitors indicated that both relaxant and contractile arachidonic acid metabolites are generated by epithelial and nonepithelial cells alike in response to contractile agonists.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗