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. 1989;180(4):325–341. doi: 10.1007/BF00311165

Changes in epithelial secretory cells and potentiation of neurogenic inflammation in the trachea of rats with respiratory tract infections

Hung-Tu Huang 1,2, Amy Haskell 1,2, Donald M McDonald 1,2
PMCID: PMC7088180  PMID: 2552865

Summary

In rats respiratory tract infections due to Sendai virus and coronavirus usually are transient, but they can have long-lasting consequences when accompanied by Mycoplasma pulmonis infections. Morphological alterations in the tracheal epithelium and a potentiation of the inflammatory response evoked by sensory nerve stimulation (“neurogenic inflammation”) are evident nine weeks after the infections begin, but the extent to which these changes are present at earlier times is not known. In the present study we characterized these abnormalities in the epithelium and determined the extent to which they are present 3 and 6 weeks after the infections begin. We also determined the magnitude of the potentiation of neurogenic inflammation at these times, whether the potentiation can be reversed by glucocorticoids, and whether a proliferation of blood vessels contributes to the abnormally large amount of plasma extravasation associated with this potentiation. To this end, we studied Long-Evans rats that acquired these viral and mycoplasmal infections from other rats. We found that the tracheal epithelium of the infected rats had ten times as many Alcian blue-PAS positive mucous cells as did that of pathogen-free rats; but it contained none of the serous cells typical of pathogen-free rats, so the total number of secretory cells was not increased. In addition, the epithelium of the infected rats had three times the number of ciliated cells and had only a third of the number of globule leukocytes. In response to an injection of capsaicin (150 μg/kg i.v.), the tracheas of the infected rats developed an abnormally large amount of extravasation of two tracers Evans blue dye and Monastral blue pigment, and had an abnormally large number of Monastral blue-labeled venules, particularly in regions of mucosa overlying the cartilaginous rings. This abnormally large amount of extravasation was blocked by dexamethasone (1 mg/day i.p. for 5 days). We conclude that M. pulmonis infections, exacerbated at the outset by viral infections, result within three weeks in the transformation of epithelial serous cells into mucous cells, the proliferation of ciliated cells, and the depletion of globule leukocytes. They also cause a proliferation of mediator-sensitive blood vessels in the airway mucosa, which is likely to contribute to the potentiation of neurogenic inflammation that accompanies these infections.

Key words: Capsaicin, Mucous cells, Mycoplasmas, Neurogenic inflammation, Serous cells, Trachea, Vascular permeability

Footnotes

Funded in part by National Institutes of Health Pulmonary Program Project Grant HL-24136 from the US Public Health Service. Dr. Huang is the recepient of an award from the National Science Council of the Republic of China

References

  1. Andersson PT, Persson CG. Developments in anti-asthmaglucocorticoids. Agents Actions [Suppl] 1988;23:239–260. doi: 10.1007/978-3-0348-9156-1_18. [DOI] [PubMed] [Google Scholar]
  2. Bancroft JD, Stevens A. Theory and practice of histological techniques. 2nd edn. Edinburgh: Churchill Livingstone; 1982. [Google Scholar]
  3. Beckstead JH, Halverson PS, Ries CA, Bainton DF. Enzyme histochemistry and immunohistochemistry on biopsy specimens of pathologic human bone marrow. Blood. 1981;57:1088–1098. [PubMed] [Google Scholar]
  4. Bowen DL, Fauci AS. Adrenal corticosteroids. In: Gallin JI, Goldstein IM, Snyderman R, editors. Inflammation: Basic principles and Clinical Correlates. New York: Raven Press; 1988. pp. 877–895. [Google Scholar]
  5. Broderson JR, Lindsey JR, Crawford JE. The role of environmental ammonia in respiratory mycoplasmosis of rats. Am J Pathol. 1976;85:115–130. [PMC free article] [PubMed] [Google Scholar]
  6. Brokaw JJ, McDonald DM. the neurally-mediated increase in vascular permeability in the rat trachea: onset, duration and tachyphylaxis. Exp Lung Res. 1988;14:757–767. doi: 10.3109/01902148809087842. [DOI] [PubMed] [Google Scholar]
  7. Carroll SM, Mayrhofer G, Dawkins HJS, Grove DI. Kinetics of intestinal lamina propria mast cells, globule leukocytes, intraepithelial lymphocytes, goblet cells and eosinophils in murine strongyloidiasis. Int Arch Allergy Appl Immunol. 1984;74:311–317. doi: 10.1159/000233566. [DOI] [PubMed] [Google Scholar]
  8. Carthew P, Sparrow S. Sendai virus in nude and germ-free rats. Research in Veterinary Science. 1980;29:289–292. doi: 10.1016/S0034-5288(18)32629-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Castleman WL. Respiratory tract lesions in weanling outbred rats infected with Sendai virus. Am J Vet Res. 1983;44:1024–1031. [PubMed] [Google Scholar]
  10. Dalhamn T. Mucous flow and ciliary activity in the trachea of healthy rats and rats exposed to respiratory irritant gases. Acta Physiol Scand. 1956;36(Suppl 123):1–161. [PubMed] [Google Scholar]
  11. Eskelund V. Mucin staining with Alcian blue. Acta Pathol Microbiol Scand. 1957;40:107–109. [PubMed] [Google Scholar]
  12. Evans MJ, Shami SG, Cabral-Anderson LJ, Dekker NP. Role of nonciliated cells in renewal of the bronchial epithelium of rats exposed to NO2. Am J Pathol. 1986;123:126–133. [PMC free article] [PubMed] [Google Scholar]
  13. Florey H, Carleton HM, Wells AQ. Mucus secretion in the trachea. Br J Exp Pathol. 1932;13:269–284. [Google Scholar]
  14. Frederix M, Baert J. Naphthol-AS-D-chloroacetate esterase activity in globule leukocytes in the tracheal epithelium of rats. Acta Anat (Basel) 1986;125:93–95. doi: 10.1159/000146143. [DOI] [PubMed] [Google Scholar]
  15. Gamse R, Holzer P, Lembeck F. Decrease of substance P in primary afferent neurones and impairment of neurogenic plasma extravasation by capsaicin. Br J Pharmac. 1980;68:207–213. doi: 10.1111/j.1476-5381.1980.tb10409.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gomori G. Chloroacyl esters as histochemical substrates. J Histochem Cytochem. 1953;1:469–470. doi: 10.1177/1.6.469. [DOI] [PubMed] [Google Scholar]
  17. Greig N, Ayers M, Jeffery PK. The effect of indomethacin on the response of bronchial epithelium to tobacco smoke. J Pathol. 1980;132:1–9. doi: 10.1002/path.1711320102. [DOI] [PubMed] [Google Scholar]
  18. Hayashi M, Huber GL. Quantitative differences in goblet cells in the tracheal epithelium of male and female rats. Am Rev Respir Dis. 1977;115:595–599. doi: 10.1164/arrd.1977.115.4.595. [DOI] [PubMed] [Google Scholar]
  19. Howard CJ, Stott EJ, Taylor G. The effect of pneumonia induced in mice with Mycoplasma pulmonis on resistance to subsequent bacterial infection and the effect of a respiratory infection with Sendai virus on the resistance of mice to Mycoplasma pulmonis. J Gen Microbiol. 1978;109:79–87. doi: 10.1099/00221287-109-1-79. [DOI] [PubMed] [Google Scholar]
  20. Huntley JF, Newlands GFJ, Gibson S, Ferguson A, Miller HRP. Histochemical demonstration of chymotrypsin like serine esterases in mucosal mast cells in four species including man. J Clin Pathol. 1985;38:375–384. doi: 10.1136/jcp.38.4.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jacoby RO, Bhatt PN, Jonas AM. Pathogenesis of sialodacryoadenitis in gnotobiotic rats. Vet Pathol. 1975;12:196–209. doi: 10.1177/030098587501200305. [DOI] [PubMed] [Google Scholar]
  22. Jacoby RO, Bhatt PN, Jonas AM. Viral diseases. In: Baker HJ, Lindsey JR, Weisbroth SH, editors. The Laboratory Rat, vol 1. New York: Academic Press; 1979. pp. 243–269. [Google Scholar]
  23. Jancso N. Role of the nerve terminals in the mechanism of inflammatory reactions. Bulletin of the Millard Fillmore Hospital (Buffalo) 1960;7:53–77. [Google Scholar]
  24. Jancso N, Jancso-Gabor A, Szolcsanyi J. Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol Chemother. 1967;31:138–151. doi: 10.1111/j.1476-5381.1967.tb01984.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jeffery PK. Respiratory Tract Mucus. Amsterdam Oxford New York: Elsevier Excerpta Medica North-Holland; 1978. Structure and function of mucus-secreting cells of cat and goose airway epithelium; pp. 5–23. [DOI] [PubMed] [Google Scholar]
  26. Jeffery PK, Reid L. New observations of rat airway epithelium: a quantitative and electron microscopic study. J Anat. 1975;120:295–320. [PMC free article] [PubMed] [Google Scholar]
  27. Jeffery PK, Reid LM. The effect of tobacco smoke, with or without phenylmethyloxadiazole (PMO), on rat bronchial epithelium: a light and electron microscopic study. J Pathol. 1981;133:341–359. doi: 10.1002/path.1711330406. [DOI] [PubMed] [Google Scholar]
  28. Jones R, Bolduc P, Reid L. Goblet cell glycoprotein and tracheal gland hypertrophy in rat airways: the effect of tobacco smoke with or without the anti-inflammatory agent phenylmethyloxadiazole. Br J Exp Pathol. 1973;54:229–239. [PMC free article] [PubMed] [Google Scholar]
  29. Joris I, DeGirolami U, Wortham K. Vascular labelling with Monastral blue B. Stain Technol. 1982;57:177–183. doi: 10.3109/10520298209066611. [DOI] [PubMed] [Google Scholar]
  30. Kent JF. Distribution and fine structure of globule leucocytes in respiratory and digestive tracts of the laboratory rat. Anat Rec. 1966;156:439–454. doi: 10.1002/ar.1091560408. [DOI] [PubMed] [Google Scholar]
  31. Lamb D, Reid L. Mitotic rates, goblet cell increase and histochemical changes in mucus in rat bronchia epithelium during exposure to sulphur dioxide. J Pathol Bact. 1968;96:97–111. doi: 10.1002/path.1700960111. [DOI] [PubMed] [Google Scholar]
  32. Lamb D, Reid L. Goblet cell increase in rat bronchial epithelium after exposure to cigarette and cigar tobacco smoke. Br Med J. 1969;1:33–35. doi: 10.1136/bmj.1.5635.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lamb D, Reid L. Histochemical types of acidic glycoprotein produced by mucous cells of the tracheobronchial glands in man. J Pathol. 1969;98:213–229. doi: 10.1002/path.1710980402. [DOI] [PubMed] [Google Scholar]
  34. Lindsey JR, Baker HJ, Overcash RG, Cassell GH, Hunt CE. Murine chronic respiratory disease. Am J Pathol. 1971;64:675–716. [PMC free article] [PubMed] [Google Scholar]
  35. Lindsey JR, Davidson MK, Schoeb TR, Cassell GH. Murine mycoplasmal infections. In: Hamm TE Jr, editor. Complications of Viral and Mycoplasmal Infections in Rodents to Toxicology Research and Testing. Washington New York London: Hemisphere Publishing Corporation; 1986. pp. 91–121. [Google Scholar]
  36. Lundberg JM, Brodin E, Hua X, Saria A. Vascular permeability changes and smooth muscle contraction in relation to capsaicin-sensitive substance P afferents in the guinea pig. Acta Physiol Scand. 1984;120:217–227. doi: 10.1111/j.1748-1716.1984.tb00127.x. [DOI] [PubMed] [Google Scholar]
  37. Lundberg JM, Martling C-R, Saria A, Folkers K, Rosell S. Cigarette smoke-induced airway oedema due to activation of capsaicin-sensitive vagal afferents and substance P release. Neuroscience. 1983;10:1361–1368. doi: 10.1016/0306-4522(83)90117-3. [DOI] [PubMed] [Google Scholar]
  38. Lundberg JM, Saria M. Capsaicin-sensitive vagal neurons involved in control of vascular permeability in rat trachea. Acta Physiol Scand. 1982;115:521–523. doi: 10.1111/j.1748-1716.1982.tb07116.x. [DOI] [PubMed] [Google Scholar]
  39. Lundberg JM, Saria A. Capsaicin-induced desensitization of airway mucosa to cigarette smoke, mechanical and chemical irritants. Nature. 1983;302:251–253. doi: 10.1038/302251a0. [DOI] [PubMed] [Google Scholar]
  40. Makara GB, Gyorgy L, Molnar J. Circulatory and respiatory responses to capsaicin, 5-hydroxytryptamine and histamine in rats pretreated with capsaicin. Arch Int Pharmacodyn. 1967;170:39–45. [PubMed] [Google Scholar]
  41. McDonald DM. Respiratory infections increase susceptibility to neurogenic inflammation in the rat trachea. Am Rev Respir Dis. 1988;137:1432–1440. doi: 10.1164/ajrccm/137.6.1432. [DOI] [PubMed] [Google Scholar]
  42. McDonald DM. Neurogenic inflammation in the rat trachea. I. Changes in venules, leucocytes, and epithelial cells. J Neurocytol. 1988;17:583–603. doi: 10.1007/BF01260988. [DOI] [PubMed] [Google Scholar]
  43. McDonald DM, Michell RA, Gabella G, Haskell A. Neurogenic inflammation in the rat trachea. II. Identity and distribution of nerves mediating the increase in vascular permeability. J Neurocytol. 1988;17:605–628. doi: 10.1007/BF01260989. [DOI] [PubMed] [Google Scholar]
  44. Mitchell HW, Tomlin J, Ward RJ. Reflex changes in respiration and heart rate evoked by intravenous and left ventricular injection of 5-HT and capsaicin in anaesthetized rats: a comparison of mechanisms. Lung. 1984;162:153–163. doi: 10.1007/BF02715643. [DOI] [PubMed] [Google Scholar]
  45. Nelson JB, Lyons MJ. Phase-contrast and electron microscopy of murine strains of Mycoplasma. J Bacteriol. 1965;90:1750–1763. doi: 10.1128/jb.90.6.1750-1763.1965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Pack RJ, Al-Ugaily LH, Morris G, Widdicombe JG. The distribution and structure of cells in the tracheal epithelium of the mouse. Cell Tissue Res. 1980;208:65–84. doi: 10.1007/BF00234174. [DOI] [PubMed] [Google Scholar]
  47. Persson CGA, Erjefalt I, Andersson P. Leakage of macromolecules from guinea-pig tracheobronchial microcirculation. Effects of allergen, leukotrienes, tachykinins, and anti-asthma drugs. Acta Physiol Scand. 1986;127:95–105. doi: 10.1111/j.1748-1716.1986.tb07880.x. [DOI] [PubMed] [Google Scholar]
  48. Piedimonte G, Umeno E, McDonald DM, Nadel JA. Sendai virus infection potentiates neurogenic inflammation in the rat trachea. Am Rev Respir Dis. 1989;139:A230. doi: 10.1152/jappl.1990.68.2.754. [DOI] [PubMed] [Google Scholar]
  49. Reid L. An experimental study of hypersecretion of mucus in the bronchial tree. Br J Exp Path. 1963;44:437–445. [PMC free article] [PubMed] [Google Scholar]
  50. Rhodin J, Dalhamn T. Electron microscopy of the tracheal ciliated mucosa in rat. Z Zelforsch. 1956;44:345–412. doi: 10.1007/BF00345847. [DOI] [PubMed] [Google Scholar]
  51. Saria A, Lundberg JM. Evans blue fluorescence: quantitative and morphological evaluation of vascular permeability in animal tissues. J Neurosci Methods. 1983;8:41–49. doi: 10.1016/0165-0270(83)90050-x. [DOI] [PubMed] [Google Scholar]
  52. Saria A, Lundberg JM, Skofitsch G, Lembeck F. Vascular protein leakage in various tissues induced by substance P, capsaicin, bradykinin, serotonin, histamine and by antigen challenge. N-S Arch Pharmacol. 1983;324:212–218. doi: 10.1007/BF00503897. [DOI] [PubMed] [Google Scholar]
  53. Schoeb TR, Kervin KC, Lindsey JR. Exacerbation of murine respiratory mycoplasmosis in gnotobiotic F344/N rats by Sendai virus infection. Vet Pathol. 1985;22:272–282. doi: 10.1177/030098588502200310. [DOI] [PubMed] [Google Scholar]
  54. Schoeb TR, Lindsey JR. Exacerbation of murine respiratory mycoplasmosis by sialodacryoadenitis virus infection in gnotobiotic F344 rats. Vet Pathol. 1987;24:392–399. doi: 10.1177/030098588702400505. [DOI] [PubMed] [Google Scholar]
  55. Spicer SS, Mochizuki I, Setser ME, Martinez JR. Complex carbohydrates of rat tracheobronchial surface epithelium visualized ultrastructurally. Am J Anat. 1980;158:93–109. doi: 10.1002/aja.1001580109. [DOI] [PubMed] [Google Scholar]
  56. Spicer SS, Schulte BA, Chakrin LW. Ultrastructural and histochemical observations of respiratory epithelium and gland. Exp Lung Res. 1983;4:137–156. doi: 10.3109/01902148309055010. [DOI] [PubMed] [Google Scholar]
  57. Svensjo E, Roempke K. Time-dependent inhibition of bradykinin-and histamine-induced microvascular permeability increase by local glucocorticoid treatment. Prog Resp Res. 1985;19:173–180. [Google Scholar]
  58. Tam E, Calonico LD, Nadel JA, McDonald DM. Globule leukocytes and mast cells in the rat trachea: Their number, distribution, and response to compound 48/80 and dexamethasone. Anat Embryol. 1988;178:107–118. doi: 10.1007/BF02463644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Ventura J, Goucher S. Bronchial epithelial mucin in rats infected with Mycoplasma pulmonis. Arch Environ Health. 1966;13:593–596. doi: 10.1080/00039896.1966.10664623. [DOI] [PubMed] [Google Scholar]
  60. Weibel E. Stereological Methods, Volume 1. Practical Methods for Biological Morphometry. London: Academic Press; 1979. [Google Scholar]

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