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(Chest. 2001;120:S71.)
© 2001 American College of Chest Physicians

Influence of Hyperglycemia to the Severity of Pulmonary Fibrosis*

Jiro Usuki, MD; Tatsuji Enomoto, MD; Arata Azuma, MD; Kuniko Matsuda, BS; Akinori Aoyama, PhD and Shoji Kudoh, MD

Several investigators1 have reported the frequent association of diabetes mellitus (DM) and idiopathic interstitial pneumonia (IIP). One hundred four cases of IIP in our hospital were studied retrospectively. Glucose tolerance could be reviewed in 37 cases. Twelve cases (32.4%) of IIP met the criteria for DM. As the prevalence of DM is reported at approximately 9.4% of those > 40 years old in Japan, it appeared that IIP patients tended to have accompanying DM. However, the correlation between IIP and DM is still unclear. We focused on advanced glycation end products (AGEs), the late-stage products of Maillard reaction, because AGEs have been shown to play an important role in fibrotic changes in many organs, including kidneys2 and arteries3 in patients with DM. Immunoreactivity for AGEs has been demonstrated in lung tissues from patients with pulmonary fibrosis.4 Serum AGEs level (/creatinine) of patients with IIP in our hospital was higher than that of normal volunteers. To investigate the role of AGEs in the pathogenesis of pulmonary fibrosis, we used bleomycin-induced pulmonary fibrosis in mice with or without hyperglycemia.

Hyperglycemia was induced with streptozotocin treatment in ICR mice. Bleomycin was injected into mice with or without streptozotocin treatment. The mice were killed 4 weeks after bleomycin treatment. To evaluate the extent of pulmonary fibrosis, we measured the hydroxyproline content in the lung and graded the pathologic features. We also did immunohistochemical analysis with an anti-AGE antibody (6D12).

Hyperglycemia was induced with streptozotocin treatment. The morphologic grade of fibrosis in diabetic mice was more severe than that in mice treated with bleomycin alone. The hydroxyproline content in lungs of diabetic mice was also higher, but it was not statistically significant. Immunohistochemical analysis showed a positive reaction for AGEs in type II pneumocytes and alveolar macrophages in normal lungs. In bleomycin-treated lungs, fibrotic lesions including extracellular matrix and macrophages showed moderate-to-intense staining for AGEs in mice both with and without DM. In conclusion, the present study suggests that hyperglycemia influences the severity of pulmonary fibrosis. AGEs may be one of important factors accelerating pulmonary fibrosis in patients with hyperglycemia.

Footnotes

Abbreviations: AGE = advanced glycation end product; DM = diabetes mellitus; IIP = idiopathic interstitial pneumonia

References

  1. Abramowitz, S, Leiner, GC, Small, MJ (1969) Chronic respiratory diseases and diabetes. Rev Allergy 23,972-977[Medline]
  2. Makino, H, Shikata, K, Hironaka, K, et al (1995) Ultrastructure of nonenzymatically glycated mesangial matrix in diabetic nephropathy. Kidney Int 48,517-526[ISI][Medline]
  3. Rumble, JR, Cooper, ME, Soulis, T, et al (1997) Vascular hypertrophy in experimental diabetes: role of advanced glycation end products. J Clin Invest 99,1016-1027[ISI][Medline]
  4. Matsuse, T, Ohga, E, Teramoto, S, et al (1998) Immunohistochemical localization of advanced glycation end products in pulmonary fibrosis. J Clin Pathol 51,515-519[Abstract]




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