Abstract
BACKGROUND—There is controversy about whether the inflammatory response observed in the cystic fibrosis (CF) lung occurs secondary to bacterial infection or is caused by a dysregulation of the inflammatory response associated with the basic cellular defect of CF. AIMS—To study the inflammatory response in the gastrointestinal tract of children with CF; and to investigate whether there is increased inflammation in the gastrointestinal tract of CF children with fibrosing colonopathy. METHODS—Whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF and fibrosing colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, α1 antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin 1β) were measured. RESULTS—Compared to controls, the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1β, and interleukin 8. Similar values were obtained for the CF patients with fibrosing colonopathy. CONCLUSIONS—These data suggest that there is immune activation in the gastrointestinal mucosa of children with cystic fibrosis, which may result from the basic cellular defect. Fibrosing colonopathy does not appear to be associated with increased inflammation.
Full Text
The Full Text of this article is available as a PDF (152.2 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- ANDERSON C. M., LANGFORD R. F. Bacterial content of small intestine of children in health, in coeliac disease, and in fibrocystic disease of pancreas. Br Med J. 1958 Apr 5;1(5074):803–806. doi: 10.1136/bmj.1.5074.803. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Antonowicz I., Lebenthal E., Shwachman H. Disaccharidase activities in small intestinal mucosa in patients with cystic fibrosis. J Pediatr. 1978 Feb;92(2):214–219. doi: 10.1016/s0022-3476(78)80007-9. [DOI] [PubMed] [Google Scholar]
- Armstrong D. S., Grimwood K., Carzino R., Carlin J. B., Olinsky A., Phelan P. D. Lower respiratory infection and inflammation in infants with newly diagnosed cystic fibrosis. BMJ. 1995 Jun 17;310(6994):1571–1572. doi: 10.1136/bmj.310.6994.1571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Balough K., McCubbin M., Weinberger M., Smits W., Ahrens R., Fick R. The relationship between infection and inflammation in the early stages of lung disease from cystic fibrosis. Pediatr Pulmonol. 1995 Aug;20(2):63–70. doi: 10.1002/ppul.1950200203. [DOI] [PubMed] [Google Scholar]
- Birrer P., McElvaney N. G., Rüdeberg A., Sommer C. W., Liechti-Gallati S., Kraemer R., Hubbard R., Crystal R. G. Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. Am J Respir Crit Care Med. 1994 Jul;150(1):207–213. doi: 10.1164/ajrccm.150.1.7912987. [DOI] [PubMed] [Google Scholar]
- Bonfield T. L., Panuska J. R., Konstan M. W., Hilliard K. A., Hilliard J. B., Ghnaim H., Berger M. Inflammatory cytokines in cystic fibrosis lungs. Am J Respir Crit Care Med. 1995 Dec;152(6 Pt 1):2111–2118. doi: 10.1164/ajrccm.152.6.8520783. [DOI] [PubMed] [Google Scholar]
- Briars G. L., Dean T. P., Murphy J. L., Rolles C. J., Warner J. O. Faecal interleukin-8 and tumour necrosis factor-alpha concentrations in cystic fibrosis. Arch Dis Child. 1995 Jul;73(1):74–76. doi: 10.1136/adc.73.1.74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cantin A. Cystic fibrosis lung inflammation: early, sustained, and severe. Am J Respir Crit Care Med. 1995 Apr;151(4):939–941. doi: 10.1164/ajrccm.151.4.7697269. [DOI] [PubMed] [Google Scholar]
- Choudari C. P., O'Mahony S., Brydon G., Mwantembe O., Ferguson A. Gut lavage fluid protein concentrations: objective measures of disease activity in inflammatory bowel disease. Gastroenterology. 1993 Apr;104(4):1064–1071. doi: 10.1016/0016-5085(93)90275-h. [DOI] [PubMed] [Google Scholar]
- Choudari C. P., O'Mahony S., Brydon G., Mwantembe O., Ferguson A. Gut lavage fluid protein concentrations: objective measures of disease activity in inflammatory bowel disease. Gastroenterology. 1993 Apr;104(4):1064–1071. doi: 10.1016/0016-5085(93)90275-h. [DOI] [PubMed] [Google Scholar]
- Conley M. E., Delacroix D. L. Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defense? Ann Intern Med. 1987 Jun;106(6):892–899. doi: 10.7326/0003-4819-106-6-892. [DOI] [PubMed] [Google Scholar]
- Croft N. M., Marshall T. G., Ferguson A. Direct assessment of gastrointestinal inflammation and mucosal immunity in children with cystic fibrosis. Postgrad Med J. 1996 Mar;72 (Suppl 2):S32–S36. [PubMed] [Google Scholar]
- Croft N. M., Marshall T. G., Ferguson A. Gut inflammation in children with cystic fibrosis on high-dose enzyme supplements. Lancet. 1995 Nov 11;346(8985):1265–1267. doi: 10.1016/s0140-6736(95)91864-7. [DOI] [PubMed] [Google Scholar]
- Dean T. P., Dai Y., Shute J. K., Church M. K., Warner J. O. Interleukin-8 concentrations are elevated in bronchoalveolar lavage, sputum, and sera of children with cystic fibrosis. Pediatr Res. 1993 Aug;34(2):159–161. doi: 10.1203/00006450-199308000-00010. [DOI] [PubMed] [Google Scholar]
- FREYE H. B., KURTZ S. M., SPOCK A., CAPP M. P. LIGHT AND ELECTRON MICROSCOPIC EXAMINATION OF THE SMALL BOWEL OF CHILDREN WITH CYSTIC FIBROSIS. J Pediatr. 1964 Apr;64:575–579. doi: 10.1016/s0022-3476(64)80351-6. [DOI] [PubMed] [Google Scholar]
- Falchuk Z. M., Taussig L. M. IgA synthesis by jejunal biopsies from patients with cystic fibrosis and hereditary pancreatitis. Pediatrics. 1973 Jan;51(1):49–54. [PubMed] [Google Scholar]
- Handy L. M., Ghosh S., Ferguson A. Investigation of neutrophils in the gut lumen by assay of granulocyte elastase in whole-gut lavage fluid. Scand J Gastroenterol. 1996 Jul;31(7):700–705. doi: 10.3109/00365529609009153. [DOI] [PubMed] [Google Scholar]
- Khan T. Z., Wagener J. S., Bost T., Martinez J., Accurso F. J., Riches D. W. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med. 1995 Apr;151(4):1075–1082. doi: 10.1164/ajrccm/151.4.1075. [DOI] [PubMed] [Google Scholar]
- Koller D. Y., Götz M., Eichler I., Urbanek R. Eosinophilic activation in cystic fibrosis. Thorax. 1994 May;49(5):496–499. doi: 10.1136/thx.49.5.496. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koller D. Y., Götz M., Wojnarowski C., Eichler I. Relationship between disease severity and inflammatory markers in cystic fibrosis. Arch Dis Child. 1996 Dec;75(6):498–501. doi: 10.1136/adc.75.6.498. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Konstan M. W., Hilliard K. A., Norvell T. M., Berger M. Bronchoalveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation. Am J Respir Crit Care Med. 1994 Aug;150(2):448–454. doi: 10.1164/ajrccm.150.2.8049828. [DOI] [PubMed] [Google Scholar]
- Maiuri L., Raia V., De Marco G., Coletta S., de Ritis G., Londei M., Auricchio S. DNA fragmentation is a feature of cystic fibrosis epithelial cells: a disease with inappropriate apoptosis? FEBS Lett. 1997 May 19;408(2):225–231. doi: 10.1016/s0014-5793(97)00347-5. [DOI] [PubMed] [Google Scholar]
- Meyer K. C., Lewandoski J. R., Zimmerman J. J., Nunley D., Calhoun W. J., Dopico G. A. Human neutrophil elastase and elastase/alpha 1-antiprotease complex in cystic fibrosis. Comparison with interstitial lung disease and evaluation of the effect of intravenously administered antibiotic therapy. Am Rev Respir Dis. 1991 Sep;144(3 Pt 1):580–585. doi: 10.1164/ajrccm/144.3_Pt_1.580. [DOI] [PubMed] [Google Scholar]
- Miele L., Cordella-Miele E., Xing M., Frizzell R., Mukherjee A. B. Cystic fibrosis gene mutation (deltaF508) is associated with an intrinsic abnormality in Ca2+-induced arachidonic acid release by epithelial cells. DNA Cell Biol. 1997 Jun;16(6):749–759. doi: 10.1089/dna.1997.16.749. [DOI] [PubMed] [Google Scholar]
- Morin C. L., Roy C. C., Lasalle R., Bonin A. Small bowel mucosal dysfunction in patients with cystic fibrosis. J Pediatr. 1976 Feb;88(2):213–216. doi: 10.1016/s0022-3476(76)80984-5. [DOI] [PubMed] [Google Scholar]
- Nakamura H., Yoshimura K., McElvaney N. G., Crystal R. G. Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. J Clin Invest. 1992 May;89(5):1478–1484. doi: 10.1172/JCI115738. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Noah T. L., Black H. R., Cheng P. W., Wood R. E., Leigh M. W. Nasal and bronchoalveolar lavage fluid cytokines in early cystic fibrosis. J Infect Dis. 1997 Mar;175(3):638–647. doi: 10.1093/infdis/175.3.638. [DOI] [PubMed] [Google Scholar]
- O'Mahony S., Arranz E., Barton J. R., Ferguson A. Dissociation between systemic and mucosal humoral immune responses in coeliac disease. Gut. 1991 Jan;32(1):29–35. doi: 10.1136/gut.32.1.29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- O'Mahony S., Barton J. R., Crichton S., Ferguson A. Appraisal of gut lavage in the study of intestinal humoral immunity. Gut. 1990 Dec;31(12):1341–1344. doi: 10.1136/gut.31.12.1341. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rayner R. J., Wiseman M. S., Cordon S. M., Norman D., Hiller E. J., Shale D. J. Inflammatory markers in cystic fibrosis. Respir Med. 1991 Mar;85(2):139–145. doi: 10.1016/s0954-6111(06)80292-1. [DOI] [PubMed] [Google Scholar]
- Smyth R. L., Ashby D., O'Hea U., Burrows E., Lewis P., van Velzen D., Dodge J. A. Fibrosing colonopathy in cystic fibrosis: results of a case-control study. Lancet. 1995 Nov 11;346(8985):1247–1251. doi: 10.1016/s0140-6736(95)91860-4. [DOI] [PubMed] [Google Scholar]
- Strong T. V., Boehm K., Collins F. S. Localization of cystic fibrosis transmembrane conductance regulator mRNA in the human gastrointestinal tract by in situ hybridization. J Clin Invest. 1994 Jan;93(1):347–354. doi: 10.1172/JCI116966. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Suter S., Schaad U. B., Roux-Lombard P., Girardin E., Grau G., Dayer J. M. Relation between tumor necrosis factor-alpha and granulocyte elastase-alpha 1-proteinase inhibitor complexes in the plasma of patients with cystic fibrosis. Am Rev Respir Dis. 1989 Dec;140(6):1640–1644. doi: 10.1164/ajrccm/140.6.1640. [DOI] [PubMed] [Google Scholar]
- Troncone R., Caputo N., Campanozzi A., Cucciardi M., Esposito V., Russo R., De Vizia B., Greco L., Cucchiara S. Gut lavage IgG and interleukin 1 receptor antagonist:interleukin 1 beta ratio as markers of intestinal inflammation in children with inflammatory bowel disease. Gut. 1997 Jul;41(1):60–65. doi: 10.1136/gut.41.1.60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Troncone R., Caputo N., Esposito V., Campanozzi A., Campanozzi F., Auricchio R., Greco L., Cucchiara S. Increased concentrations of eosinophilic cationic protein in whole-gut lavage fluid from children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1999 Feb;28(2):164–168. doi: 10.1097/00005176-199902000-00014. [DOI] [PubMed] [Google Scholar]
- Wilmott R. W., Kassab J. T., Kilian P. L., Benjamin W. R., Douglas S. D., Wood R. E. Increased levels of interleukin-1 in bronchoalveolar washings from children with bacterial pulmonary infections. Am Rev Respir Dis. 1990 Aug;142(2):365–368. doi: 10.1164/ajrccm/142.2.365. [DOI] [PubMed] [Google Scholar]
- Zahm J. M., Gaillard D., Dupuit F., Hinnrasky J., Porteous D., Dorin J. R., Puchelle E. Early alterations in airway mucociliary clearance and inflammation of the lamina propria in CF mice. Am J Physiol. 1997 Mar;272(3 Pt 1):C853–C859. doi: 10.1152/ajpcell.1997.272.3.C853. [DOI] [PubMed] [Google Scholar]