Skip to main content
Log in

In vivo restitution of airway epithelium

  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

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-μm 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 μm/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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Albers R, Timens W (1993) Immunohistology in bronchial asthma. Respir Med 87[Suppl B]:13–21

    Google Scholar 

  • Beasley R, Roche WR, Roberts JA, Holgate ST (1989) Cellular events in the bronchi in mild asthma after bronchial provocation. Am Rev Respir Dis 139:806–817

    Google Scholar 

  • Bitterman PB, Adelberg S, Crystal RG (1983) Mechanisms of pulmonary fibrosis. Spontaneous release of the alveolar macrophage-derived growth factor in the interstitial lung disorders. J Clin Invest 72:1801–1813

    Google Scholar 

  • Bousquet J, Chanez P, Lacoste JY, Enander I, Venge P, Peterson C, Ahlstedt S, Michel FB, Godard P (1991) Indirect evidence of bronchial inflammation assessed by titration of inflammatory mediators in BAL fluid of patients with asthma. J Allergy Clin Immunol 88:649–660

    Google Scholar 

  • Bousquet J, Chanez P, Lacoste JY, White R, Vic P, Godhard P, Michel FB (1992) Asthma: a disease remodeling the airways. Allergy 47:3–11

    Google Scholar 

  • Brewster CEP, Howarth PH, Djukanovic R, Wilson R, Holgate ST, Roche W (1993) Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 3:507–511

    Google Scholar 

  • Caroll N, Elliot J, Morton A, James A (1993) The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 147:405–410

    Google Scholar 

  • Dahlgren SE, Dalen H, Dalhamn T (1972) Ultrastructural observations on chemically induced inflammation in guinea-pig trachea. Virchows Arch [B] 11:211–223

    Google Scholar 

  • Dunnill MS (1960) The pathology of asthma with special reference to the change in the bronchial mucosa. J Clin Pathol 13: 27–33

    Google Scholar 

  • Erjefält I, Persson CGA (1991) Pharmacologic control of plasma exudation into tracheobronchial airways. Am Rev Respir Dis 143:1008–1014

    Google Scholar 

  • Erjefält I, Greiff L, Alkner U, Persson CGA (1993a) Allergen-induced biphasic plasma exudation responses in guinea-pig large airways. Am Rev Respir Dis 148:695–701

    Google Scholar 

  • Erjefält JS, Odselius R, Sundler F, Grundström N (1993b) Airway epithelium isolated from guinea-pig trachea—a close look. Am Rev Respir Dis 147:A49

    Google Scholar 

  • Erjefält JS, Erjefält I, Sundler F, Persson CGA (1994a) Mucosal nitric oxide may tonically suppress airways plasma exudation. Am J Respir Crit Care Med 150:227–232

    Google Scholar 

  • Erjefält JS, Erjefält I, Sundler F, Persson CGA (1994b) Microcirculation-derived factors in epithelial repair. Microvasc Res 148:161–178

    Google Scholar 

  • Erjefält JS, Erjefält I, Sundler F, Persson CGA (1994c) Denudation and repair of airway epithelium in vivo: Role of plasma exudation. Am J Respir Crit Care Med 149:A997

    Google Scholar 

  • Hilding AC (1965) Regeneration of respiratory epithelium after minimal surface trauma. Ann Otol Rhinol Laryngol 74:903–914

    Google Scholar 

  • Houston JC, DeNavasquez S, Trounce JR (1953) A clinical and pathological study of fatal cases of status asthmaticus. Thorax 8:207–213

    Google Scholar 

  • Jeffery PK, Wardlaw AJ, Nelson FL, Collins JV, Kay AB (1989) Bronchial biopsies in asthma—an ultrastructural quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 140:1745–1753

    Google Scholar 

  • Jones HB, Clark AB, Barrass NC (1993) Phenobarbital-induced hepatocellular proliferation: Anti-bromodeoxyuridine and anti-proliferating cell nuclear antigen immunohistochemistry. J Histochem Cytochem 41:21–27

    Google Scholar 

  • Keenan KP, Combs JW, McDowell EM (1982a) Regeneration of hamster tracheal epithelium after mechanical injury. I. Focal lesions: Quantitative morphologic study of cell proliferation. Virchows Arch [B] 41:193–214

    Google Scholar 

  • Keenan KP, Combs JW, McDowell EM (1982b) Regeneration of hamster tracheal epithelium after mechanical injury. II. Multifocal lesions: Statchmokinetic and autoradiographic studies of cell proliferation. Virchows Arch [B] 41:215–229

    Google Scholar 

  • Keenan KP, Combs JW, McDowell EM (1982c) Regeneration of hamster tracheal epithelium after mechanical injury. III. Large and small lesions: Comparative stathmokinetic and single pulse and thymidine labelling autoradiographic studies. Virchows Arch [B] 41:231–252

    Google Scholar 

  • Keenan KP, Wilson TS, McDowell EM (1983) Regeneration of hamster tracheal epithelium after mechanical injury. IV. Histochemical, immunocytochemical and ultrastructural studies. Virchows Arch [B] 43:213–240

    Google Scholar 

  • Kelley J (1990) Cytokines of the lung. Am Rev Respir Dis 141:765–788

    Google Scholar 

  • Kovacs EJ, DiPietro LA (1994) Fibrogenic cytokines and connective tissue production. FASEB J 8:854–861

    Google Scholar 

  • Kvinnsland I, Heyeraas KJ, Byers MR (1991) Regeneration of calcitonin gene-related peptide immunoreactive nerves in replanted rat molars and their supporting tissue. Arch Oral Biol 36:815–826

    Google Scholar 

  • Laitinen LA, Heino W, Laitinen A, Kava T, Haahtela T (1985) Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 131:599–606

    Google Scholar 

  • Laitinen LA, Laitinen A, Persson CGA (1993) Role of epithelium. In: Weiss EB, Stein M (eds) Bronchial asthma; mechanisms and therapeutics. Little Brown, Boston, pp 296–308

    Google Scholar 

  • Lane BP, Gordon R (1974) Regeneration of rat tracheal epithelium after mechanical injury. The relationship between mitotic activity and cellular differentiation. Proc Soc Exp Biol Med 145:1139–1144

    Google Scholar 

  • Loeb L (1919) A comparative study of the mechanism of wound healing. J Med Res xli:247–81

    Google Scholar 

  • Lozewics S, Wells C, Gomez E, Ferguson H, Richman P, Devalia J, Davies RJ (1990) Morphological integrity of the bronchial epithelium in mild asthma. Thorax 45:12–15

    Google Scholar 

  • Lundberg JM, Martling CR, Hökfelt T (1988) Airways, oral cavity and salivary glands: classical transmitters and peptides in sensory and autonomic motor neurons. In: Björklund A, Hökfelt T, Owman C (eds) Handbook of chemical neuroanatomy, vol 6: The peripheral nervous system. Elsevier, Amsterdam, pp 391–444

    Google Scholar 

  • Luts A, Widmark E, Ekman R, Waldeck B, Sundler F (1990) Neuropeptides in guinea-pig trachea: Distribution and evidence for the release of CGRP into the tracheal lumen. Peptides 11:1211–1216

    Google Scholar 

  • McDowell EM, Becci PJ, Schurch W, Trump BF (1978) The respiratory epithelium. IV. Epidermoid metaplasia of hamster tracheal epithelium during regeneration folowing mechanical injury. J Natl Cancer Inst 62:995–1008

    Google Scholar 

  • Naylor B (1962) The shedding of the mucosa of the bronchial tree in asthma. Thorax 17:69–72

    Google Scholar 

  • O'Corell N, Beattie J (1956) The characteristics of regeneration of respiratory epithelium. Surg Gynecol 209–211

  • Rennard SI, Beckman JD, Robbins RA (1991) Biology of airway epithelial cells. In: Crystal RG, West JB (eds) The Lung:Scientific Foundations. Raven Press, New York, pp 157–167

    Google Scholar 

  • Rickard KA, Taylor J, Spurzem JR, Rennard SI (1992) Extracellular matrix and bronchial epithelial cell migration. Chest 101:17s-18s

    Google Scholar 

  • Rickard A, Taylor J, Rennard SI, Spurzem JR (1993) Migration of bovine bronchial epithelial cells to extracellular matrix components. Am J Respir Cell Mol Biol 8: 63–68

    Google Scholar 

  • Robinson NP, Venning L, Widdicombe JG (1986) Quantification of the secretory cells of the ferret tracheobronchial tree. J Anat 145:173–188

    Google Scholar 

  • Roche WR (1991) Fibroblasts and asthma. Clin Exp Allergy 21:545–548

    Google Scholar 

  • Romberger DJ, Beckman JD, Classen L, Ertl RF, Rennard SI (1992) Modulation of fibronectin production of bovine epithelial cells by transforming growth factor-β. Am J Respir Cell Mol Biol 7:149–155

    Google Scholar 

  • Sanghavi JN, Rabe KF, Kim JS, Magnussen H, Leff AF, White SR (1994) Migration of human and guinea-pig airway epithelial cells in response to calcitonin gene-related peptide. Am J Respir Cell Mol Biol 11:181–187

    Google Scholar 

  • See NA, Singaram C, Epstein ML, Dahl JL, Bass P (1992) Reinnervation of villi of rat jejunum following severe mucosal damage. Dig Dis Sci 37:438–448

    Google Scholar 

  • Shimizu T, Nishihara, Kawaguchi S, Sakakura Y (1994) Expression of phenotypic markers during regeneration of rat tracheal epithelium following mechanical injury. Am J Respir Cell Mol Biol 11:85–94

    Google Scholar 

  • Shoji S, Rickard KA, Takizawa H, Ertl RF, Linder J, Rennard SI (1990) Lung fibroblasts produce growth stimulatory activity for bronchial epithelial cells. Am Rev Respir Dis 141:433–439

    Google Scholar 

  • Söderberg M, Hellström S, Sandström T, Lundgren R, Bergh A (1990) Structural characterization of bronchial mucosal biopsies from healthy volunteers: a light and electron microscopical study. Eur Respir J 3:261–66

    Google Scholar 

  • Stewart AG, Tomilson PR, Wilson J (1993) Airway wall remodelling in asthma: a novel target for the development of antiasthma drugs. TiPS 14:275–279

    Google Scholar 

  • Sundler F, Brodin E, Ekblad E, Håkanson R, Uddman R (1985) Sensory nerve fibers: Distribution of substance P, neurokinin A and calcitonin gene-related peptide. In: Håkanson R, Sundler F (eds) Tachykinin antagonists. Elsevier, Amsterdam, pp 3–12

    Google Scholar 

  • Sundler F, Ekblad E, Absood A, Håkanson R, Köves K, Arimura A (1992) Pituitary adenylate cyclase-activating peptide: A novel vasoactive intestinal peptide-like neuropeptide in the gut. Neuroscience 46:439–454

    Google Scholar 

  • Takizawa H, Beckman J, Shoji S, Classen LR, Ertl RF, Linder J, Rennard SI (1990) Pulmonary macrophages can stimulate cell growth of bovine bronchial epithelial cells. Am J Respir Cell Mol Biol 2:233–234

    Google Scholar 

  • Tielemans Y, Chen D, Sundler F, Håkanson R, Willems G (1992) Reversibility of the cell kinetic changes induced by omeprazole in the rat oxyntic mucosa. Scand J Gastroenterol 27:155–160

    Google Scholar 

  • Uddman R, Luts A, Arimura A, Sundler F (1991) Pituitary adenylate cyclase-activating peptide (PACAP), a new vasoactive intestinal peptide (VIP)-like peptide in the respiratory tract. Cell Tissue Res 265:197–201

    Google Scholar 

  • White SR, Hershenson BM, Sigrist KS, Zimmermann A, Solway J (1993) Proliferation of guinea-pig tracheal epithelial cell induced by calcitonin gene-related peptide. Am J Respir Cell Mol Biol 8:592–596

    Google Scholar 

  • Wilhelm DL (1953) Regeneration of tracheal epithelium. J Pathol Bacterol Vol LXV:543–550

    Google Scholar 

  • Zahm JM, Chevillard M, Puchelle E (1991) Wound repair of human surface respiratory epithelium. Am J Respir Cell Mol Biol 5:242–248

    Google Scholar 

  • Ziche M, Morbidelli L, Paccini M, Dolara P, Maggi CA (1990) NK1-receptors mediate the proliferative response of human fibroblasts to tachykinins. Br J Pharmacol 100:11–14

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Erjefält, J.S., Erjefält, I., Sundler, F. et al. In vivo restitution of airway epithelium. Cell Tissue Res. 281, 305–316 (1995). https://doi.org/10.1007/BF00583399

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00583399

Key words

Navigation