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| 2. |
- Erjefält, Jonas, et al.
(författare)
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Acute allergic responses induce a prompt luminal entry of airway tissue eosinophils.
- 2003
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1535-4989. ; 29:4, s. 439-448
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Tidskriftsartikel (refereegranskat)abstract
- Traditionally, traffic and activation of eosinophils in asthmatic airways are thought to take place during the late-phase allergic reaction. The present study tests the hypothesis that when eosinophils are present in the tissue before allergen exposure, as in chronically inflamed asthmatic airways, acute anaphylactic reactions initiate an eosinophil response. Using a guinea-pig allergic model, where eosinophilia is present at baseline conditions, the traffic of resident eosinophils was examined in vivo immediately after allergen challenge. By 2 min after challenge, eosinophils had moved up to apical epithelial positions. Within 10 min, a marked migration of eosinophils into the airway lumen was demonstrated. Along with the allergen-induced egression of eosinophils, acute luminal entry of plasma proteins and eotaxin occurred. Eosinophil egression was effectively inhibited by the antiexudative drug formoterol, whereas the proexudative drug bradykinin could in naive animals evoke a prompt luminal entry of eosinophils. In conclusion, the present study demonstrates that acute allergic reactions initiate a prompt transepithelial migration of resident eosinophils. Our data further suggest that this response in part is initiated by the plasma exudation response, which may alter the transepithelial gradient of eosinophil chemoattractants including eotaxin. We propose that prompt eosinophil response is a significant component of the acute phase of allergic reactions when occurring in airways where these cells are already present in the mucosa.
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| 3. |
- Erjefält, Jonas, et al.
(författare)
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Airway epithelial repair: breathtakingly quick and multipotentially pathogenic
- 1997
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Ingår i: Thorax. - 1468-3296. ; 52:11, s. 1010-1012
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Tidskriftsartikel (refereegranskat)abstract
- Epithelial shedding, even to the point of airway denudation, had already been described as a common and unifying feature of asthma by the latter half of the 19th century. However, the repair processes that specifically follow the shedding-like loss of epithelial cells have only recently been examined in vivo. This paper discusses the exceedingly fast epithelial restitution and the potential pathogenic sequelae to epithelial shedding alone that have been unravelled. Epithelial cytoprotection emerges as an important property of future therapeutic drugs for the treatment of airways inflammatory conditions.
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| 4. |
- Erjefält, Jonas, et al.
(författare)
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Allergen-induced eosinophil cytolysis is a primary mechanism for granule protein release in human upper airways
- 1999
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 160:1, s. 304-312
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Tidskriftsartikel (refereegranskat)abstract
- Cytotoxic eosinophil granule proteins are considered important in the pathogenesis of allergic airway diseases such as rhinitis and asthma. To explore the cellular mechanisms behind eosinophil granule release in human allergic airways, 16 symptom-free patients with seasonal allergic rhinitis were challenged daily with allergen during 1 wk. Nasal lavage samples and biopsies, obtained before and 24 h after the last allergen exposure, were processed for immunohistochemical and electron microscopic analysis. The allergen challenges produced nasal symptoms, marked tissue eosinophilia, and an increase in lavage fluid levels of eosinophil cationic protein (ECP). The nasal mucosa areas with intense extracellular immunoreactivity for ECP were associated with abundant free eosinophil granules. Electron microscopy confirmed the free granules and revealed that all mucosal eosinophils were involved in granule release, either by cytolysis (33%) or piecemeal degranulation (PMD) (67%). Resting or apoptotic eosinophils were not observed. Cytolytic eosinophils had less signs of intracellular granule release (p < 0. 001) and a higher content of intact granules (p < 0.001) compared with viable eosinophils in the same tissue. This study demonstrates eosinophil cytolysis (ECL) as a distinct mechanism for granule mediator release in human allergic airway mucosa. The nature and extent of the ECL and its product (i.e., protein-laden extracellular granules) indicate that allergen-induced cytolysis is a primary and major mechanism for the release of eosinophil proteins in human allergic airway inflammation in vivo.
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| 5. |
- Erjefält, Jonas, et al.
(författare)
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Association between inflammation and epithelial damage-restitution processes in allergic airways in vivo
- 1997
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 1365-2222 .- 0954-7894. ; 27:11, s. 1344-1355
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Associations between allergen challenge-induced sites of epithelial damage and the distribution of leucocytes and extravasated plasma remain unexplored. OBJECTIVE: To study neutrophils, eosinophils, and fibrinogen at allergen challenge-induced patchy epithelial damage-restitution sites in guinea-pig trachea. METHODS: After local challenge tracheal tissue (cryo sections and whole-mounts) and lumen (selective tracheal lavage) were examined at 1, 5, and 24 h. Eosinophils, neutrophils and fibrinogen were identified by histochemistry. RESULTS: Neutrophils increased markedly in tracheal lavage fluids and in tissue and were strongly associated with the challenge-induced epithelial craters of damage-restitution. At 1 and 24 h eosinophils were increased in the tracheal lumen whereas the surrounding tissue displayed a reversed pattern. Gels rich in fibrinogen, neutrophils, and eosinophils were present in epithelial crater areas, protruding into the lumen. Clusters of free eosinophil granules, Cfegs, released through lysis of eosinophils, and neutrophils with long cytoplasmatic protrusions abounded in these crater areas. CONCLUSION: The present findings provide important new insights into allergic airways where sites of epithelial damage-restitution processes emerge as the major loci for eosinophil, neutrophil, and plasma protein activities, the latter likely causing leukocyte adhesion and activation in vivo. The distribution of eosinophils in this study suggests roles of these cells both in airway mucosa and in regional lymph nodes. Based on the present study we also propose that lysis of eosinophils and Cfegs generation are a major paradigm for activation of these cells in vivo.
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| 6. |
- Erjefält, Jonas, et al.
(författare)
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Effects of topical budesonide on epithelial restitution in vivo in guinea pig trachea
- 1995
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Ingår i: Thorax. - 1468-3296. ; 50:7, s. 785-792
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND--Continuous epithelial shedding and restitution processes may characterise the airways in diseases such as asthma. Epithelial restitution involves several humoral and cellular mechanisms that may potentially be affected by inhaled anti-asthma drugs. The present study examines the effect of a topical steroid on epithelial restitution in vivo in the guinea pig. METHODS--The airway epithelium was mechanically removed from well defined areas of guinea pig trachea without surgery and without damage to the basement membrane or bleeding. An anti-inflammatory dose of budesonide (1 mg) was administered repeatedly to the tracheal surface by local superfusion 24 hours before, at (0 hours), and 24 hours after the denudation. Migration of epithelial cells, formation of a plasma exudation-derived gel, and appearance of luminal leucocytes were recorded by scanning electron microscopy. Cell proliferation was visualised by bromodeoxyuridine immunohistochemistry and tissue neutrophils and eosinophils by enzyme histochemistry. RESULTS--Immediately after creation of the denuded zone ciliated and secretory cells on its border dedifferentiated, flattened out, and migrated speedily (mean (SE) 2.3 (0.3) micron/min) over the basement membrane. After 48 hours the entire denuded zone (800 microns wide) was covered by a tightly sealed epithelium; at this time increased proliferation was observed in new and old epithelium and subepithelial cells. Budesonide had no detectable effect on epithelial dedifferentiation, migration, sealing, or proliferation. Immediately after denudation and continuously during the migration phase plasma was extravasated creating a fibrinous gel rich in leucocytes, particularly neutrophils, over the denuded area. Budesonide had no effect on either the gel or the leucocyte density. CONCLUSIONS--These observations suggest that topical glucocorticoids may not interfere with a fast and efficient restitution of the epithelium in the airways.
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| 7. |
- Erjefält, Jonas, et al.
(författare)
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Epithelial barrier formation by airway basal cells
- 1997
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Ingår i: Thorax. - 1468-3296. ; 52:3, s. 213-217
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Epithelial shedding processes in airway inflammation and defence may produce damaged areas where basal cells are the main remaining epithelial cell type. The present study examines the capacity of basal cells to form an epithelial barrier structure after loss of columnar epithelial cells. METHODS: A technique was developed which allows selective removal of columnar epithelial cells from isolated airways. A drop of tissue adhesive glue was applied on the mucosal surface shortly after excision of guinea pig trachea and human bronchus. Gentle removal of the glue, together with attached columnar cells, left a single layer of cobbled, solitary basal cells. The tissue was kept in culture media. Morphological changes of the basal cells were monitored by immuno-histochemistry and scanning and transmission electron microscopy at several time points. RESULTS: After 20 minutes the basal cells had undergone extensive flattening and established contact with each other. The basement membrane thus became covered by a poorly differentiated epithelium in both guinea pig and human airways. Abundant interdigitating cytoplasmic protrusions were observed at cell borders. CONCLUSIONS: Basal cells promptly flatten out to cover the basement membrane at loss of neighbouring columnar cells. These data may explain why the epithelial barrier function may be uncompromised in desquamative airway diseases. Furthermore, they suggest the possibility that sacrificial release of columnar epithelial cells and prompt creation of a barrier structure constitute important roles of basal cells in airway defence against severe insults.
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| 8. |
- Erjefält, Jonas, et al.
(författare)
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Epithelial pathways for luminal entry of bulk plasma
- 1995
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 1365-2222. ; 25:2, s. 187-195
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Tidskriftsartikel (refereegranskat)abstract
- Inflammatory challenges of the airway mucosa cause luminal entry of bulk plasma. Extravasation of plasma is well described but the routes for epithelial passage of plasma are largely unknown. Using colloidal gold (5 nm) as tracer we have now examined the fate of extravasated plasma in the airways. The tracer was given intravenously to anaesthetized, ovalbumin-sensitized guinea-pigs 2min prior to airway mucosal challenge with 12pmol ovalbumin (the dose was selected from a separate dose-response study). Tissue specimens were collected 30s, 3 and 6 min after end of challenge (separate time course experiments suggested that the peak rate of entry of plasma occurred at about 5 min). The colloidal gold particles were visualized by autometallographic silver intensification. The gold produced no circulatory disturbance and had a uniform vascular distribution with negligible adherence to vascular endothelium. After challenge gold was first widely distributed in the lamina propria. At 3 and 6 min the tracer was also in the epithelium and airway lumen. It appeared that plasma was moved distinctly between and all around each epithelial cell. Bright field-, scanning-, and transmission electron-microscopy indicated that the luminal entry of plasma did not affect the integrity of the epithelial lining. This study demonstrates that the plasma exudate moves across an intact epithelial layer through ubiquitous paracellular pathways. Even at a pronounced acute plasma exudation response exceedingly small amounts of plasma may pass around a single cell explaining the non-injurious nature of mucosal exudation of bulk plasma in health and disease.
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| 9. |
- Erjefält, Jonas, et al.
(författare)
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In vivo restitution of airway epithelium
- 1995
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Ingår i: Cell and Tissue Research. - 1432-0878. ; 281:2, s. 305-316
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Tidskriftsartikel (refereegranskat)abstract
- Epithelial shedding occurs in health and, extensively, in inflammatory airway diseases. This study describes deepithelialisation, reepithelialisation and associated events in guinea-pig trachea after shedding-like epithelial denudation in vivo. Mechanical deepithelialisation of an 800-microns wide tracheal zone was carried out using an orotracheal steel probe without bleeding or damage to the basement membrane. Reepithelialisation was studied by scanning- and transmission electron microscopy and light microscopy. Nerve fibres were examined by immunostaining. Cell proliferation was analysed by [3H]-thymidine autoradiography. Immediately after epithelial removal secretory and ciliated (and presumably basal) epithelial cells at the wound margin dedifferentiated, flattened and migrated rapidly (2-3 microns/min) over the denuded basement membrane. Within 8-15 h a new, flattened epithelium covered the entire deepithelialised zone. At 30 h a tight epithelial barrier was established and after 5 days the epithelium was fully redifferentiated. After completed migration an increased mitotic activity occurred in the epithelium and in fibroblasts/smooth muscle beneath the restitution zone. Reinnervating intraepithelial calcitonin gene-related peptide-containing nerve fibres appeared within 30 h. We conclude that (1) reproducible shedding-like denudation, without bleeding or damage to the basement membrane, can be produced in vivo; (2) secretory and ciliated cells participate in reepithelialisation by dedifferentiation and migration; (3) the initial migration is very fast in vivo; (4) shedding-like denudation may cause strong secretory and exudative responses as well as proliferation of epithelium, and fibroblasts/smooth muscle. Rapid restitution of airway epithelium may depend on contributions from the microcirculation and innervation.
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