Chest
Volume 124, Issue 4, October 2003, Pages 1206-1214
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Clinical Investigations
The Increase in Serum Soluble ST2 Protein Upon Acute Exacerbation of Idiopathic Pulmonary Fibrosis

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Background

The human ST2 gene can be specifically induced by growth stimulation in fibroblastic cells, and the soluble ST2 protein (ST2) is expressed preferentially in T-helper type 2 (Th2) cells. Furthermore, ST2 is induced by proinflammatory stimuli such as tumor necrosis factor-α and interleukin-1β. It has been reported that the inflammatory response in idiopathic pulmonary fibrosis (IPF) is thought to be associated with proinflammatory cytokines and Th2 immune response.

Study objective

The objective of this study was to evaluate the relevance of the serum ST2 levels in the pathogenesis of IPF.

Design

Retrospective study.

Setting

Inpatients in a college hospital.

Participants

Forty-nine patients with IPF admitted to our hospital 64 times: 36 patients were admitted once, 11 patients were admitted twice, and 2 patients were admitted three times. The participants also included 200 healthy control volunteers.

Measurements and results

Among 64 events in 49 patients with IPF, 50 of the events occurred in a stable state, and 14 events occurred during acute exacerbation. An acute exacerbation of IPF was defined as an accelerated phase of IPF. The serum ST2 levels were measured by enzyme-linked immunosorbent assay. The serum levels of ST2 in the stable state group did not differ from those in the healthy control group, while the serum levels of ST2 in the acute exacerbation group were significantly higher than those in the stable state group or the healthy control group (p < 0.001, acute exacerbation group vs stable state group or healthy control group; acute exacerbation group, 2.76 ± 0.56 ng/mL; stable state group, 0.44 ± 0.07 ng/mL; healthy control group, 0.42 ± 0.03 ng/mL). Furthermore, serum ST2 statistically correlated with lactate dehydrogenase (r = 0.344, p = 0.005) and C-reactive protein (r = 0.496, p < 0.001), and inversely correlated with Pao2 (r = − 0.356, p = 0.018) and the percentage of predicted vital capacity (r = − 0.346, p = 0.026).

Conclusions

These results suggest that ST2 protein may increase in the serum, reflecting severity in the inflammatory process and Th2 immune response in the IPF lung.

Section snippets

Subjects

We conducted a retrospective study of 49 patients with IPF who were admitted to Jichi Medical School Hospital. The median age at the time of hospital admission was 66.9 years (range, 44 to 84 years). The diagnosis of IPF was based on an international consensus statement (ICS).1The diagnoses of IPF were obtained by video-assisted thoracoscopic surgery (VATS) in 20 patients, and by autopsy in 4 patients (Table 1). In the remaining 25 patients, IPF was diagnosed clinically on the basis of a

Serum Concentration of ST2 in Patients With IPF

The serum ST2 levels in the 64 events of patients with IPF were elevated compared to those of healthy control subjects (median values of patients with IPF vs healthy control subjects, 0.94 ng/mL vs 0.42 ng/mL, respectively), and there was a significant difference in serum ST2 levels between the two groups (p < 0.0001, Fig 1). We classified 64 subjects into two groups: the 50 subjects whose events occurred in stable IPF, and the 14 subjects whose events occurred on acute exacerbation of IPF.

Discussion

Although little is known about the pathogenesis of IPF, it is hypothesized that several interacting factors that modify the fibrotic response include the genetic background of the patient, environmental inflammatory triggers, and the predominant inflammatory phenotype (Th1 or Th2).32The inflammatory response may modulate tissue injury, fibrosis, or both during the evolution of IPF. It has been reported that the inflammatory response in IPF is thought to be associated with proinflammatory

Conclusion

Our results show that the serum ST2 levels are significantly elevated in patients with acute exacerbation of IPF, and that these levels correlate with the serum levels of LDH and CRP, and inversely correlate with Pao2, Pao2/Fio2, and %VC. These results suggest that ST2 in the serum may increase, possibly reflecting the development of the inflammatory process and the Th2 immune response in the IPF lung. The regulation of ST2 expression, interaction with other cytokines, and local expression of

ACKNOWLEDGMENT

The authors thank Mrs. Tomoko Ikahata.

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    This work was supported by a grant-in-aid for interstitial lung disease from the Japanese Ministry of Health, Labour and Welfare, and a grant-in-aid for scientific research 13670612 from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]).

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