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Clinical Investigations: PULMONARY FIBROSIS |

The Increase in Serum Soluble ST2 Protein Upon Acute Exacerbation of Idiopathic Pulmonary Fibrosis* FREE TO VIEW

Shunji Tajima; Katsuhisa Oshikawa; Shin-ichi Tominaga; Yukihiko Sugiyama
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*From the Division of Pulmonary Medicine, Department of Medicine (Drs. Tajima, Oshikawa, and Sugiyama), and Department of Biochemistry (Dr. Tominaga), Jichi Medical School, Tochigi, Japan.

Correspondence to: Katsuhisa Oshikawa, MD, PhD, Division of Pulmonary Medicine, Department of Medicine, Jichi Medical School, Minamikawachi-machi, Kawachi-gun, Tochigi 329-0498, Japan; e-mail: oshikatu@jichi.ac.jp



Chest. 2003;124(4):1206-1214. doi:10.1378/chest.124.4.1206
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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.

Figures in this Article

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with the histologic appearance in a lung biopsy of usual interstitial pneumonia (UIP).1 The etiology is unknown. Examination of affected pulmonary tissue reveals inflammatory infiltrates, composed principally of T lymphocytes and macrophages, with variable numbers of mast cells, neutrophils, and eosinophils and distinct B-lymphocyte aggregates.23

Advances in immune reactions have shown that an imbalance between T-helper type 1 (Th1) cells and T-helper type 2 (Th2) cells plays a pivotal role in the inflammatory response of various diseases.4 Studies have revealed a predominance of the Th2 cytokine pattern in the inflammatory response of IPF. The Th2-like pattern of immune response predominated in the infiltrating interstitial inflammatory cells and hyperplastic type II epithelial cells of patients with IPF.56 A significantly higher level of interleukin (IL)-4 was observed in the co-cultures of T cells with autologous alveolar macrophages from patients with IPF.7 These findings suggest that the Th2-mediated inflammatory response may be involved in the inflammatory and fibroproliferative process of IPF.

It is now well established that there is a strong link between the overexpression of proinflammatory cytokines, including tumor necrosis factor (TNF)-α and IL-1β, in the lower respiratory tract and the development of pulmonary fibrosis.811 IL-1β and TNF-α had a stimulatory effect on fibroblasts to synthesize collagen.8 In patients with IPF, TNF-α and IL-1β expression by alveolar and interstitial macrophages and type II epithelial cells have been reported to increase.911

The ST2 gene, also designated T1, Fit-1, and DER4, was originally detected as one of the primary response genes at the initial stage of cell proliferation in fibroblasts.1216 It is classified in the IL-1 receptor family due to the proximity of its locus to IL-1r1 in both mouse and human chromosomes.1720 Studies2124 have shown that ST2 gene products are predominantly expressed in Th2 cells but not in Th1 cells, suggesting that they may play novel roles in the immunologic response in addition to their roles in cell proliferation. We previously constructed an enzyme-linked immunosorbent assay system to quantify the human ST2 protein (ST2) in sera, and revealed that patients with atopic asthma exhibit significantly higher levels of serum soluble ST2 than healthy control subjects.26 Furthermore, ST2 could be expressed significantly when induced by proinflammatory cytokines such as TNF-α and IL-1β.27 These findings suggest that the ST2 gene may have been related to Th2 immune response as well as to inflammatory response.

We therefore hypothesized that the expression of ST2 may be up-regulated, reflecting an inflammatory response induced by Th2 cytokine and proinflammatory cytokine in IPF. To test this hypothesis, we analyzed the serum levels of ST2 in patients with IPF and evaluated the relationship of ST2 to the pathogenesis of IPF.

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).1 The 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 typical finding of IPF on CT scans of the chest and pulmonary function testing as stated in the ICS. Exclusion criteria consisted of other known causes of interstitial lung disease such as drug toxicities, environmental exposures, and collagen vascular diseases. Forty-nine patients with IPF were admitted to our hospital 64 times: 36 patients were admitted once, 11 patients were admitted twice, and 2 patients were admitted three times. The reasons for hospital admission were further examination (n = 27), acute exacerbation (n = 14), bacterial pneumonia (n = 11), induction of home oxygen therapy (HOT) [n = 9], heart failure (n = 2), and pneumothorax (n = 1) [Table 1] . We analyzed the serum ST2 levels in 64 samples obtained at the time of the hospital admission. An acute exacerbation of IPF is characterized by the histopathologic pattern of diffuse alveolar damage (DAD) with UIP.,2830 An acute exacerbation in patients with IPF was defined as follows: for the accelerated phase of IPF, exacerbation of dyspnea within 1 month, new diffuse pulmonary opacities on chest radiography, a decrease in Pao2 of > 10 mm Hg, and an absence of infection or heart failure.,2930 We defined stable IPF as IPF without acute exacerbation. Among the 64 events for which these patients with IPF were admitted to the hospital, 50 of the events occurred during stable IPF and 14 events occurred during acute exacerbation of IPF (Table 1) . Serum samples in our study were obtained during early phase of acute exacerbation. In turing cases of acute exacerbation of IPF, a histopathologic pattern of DAD with UIP was confirmed at autopsy in four patients. Severity of lung injury was assessed semiquantitatively according to the method described by Murray and coworkers.31 The lung injury scores of the 14 patients with an acute exacerbation of IPF fell into the category of moderate-to-severe lung injury (mean lung injury score ± SD, 2.6 ± 0.8; range, 1.5 to 4.0), and all of these patients died in the hospital despite steroid therapy (mean survival time after hospital admission ± SD, 79 ± 99 days; range, 5 to 274 days). Three patients with stable IPF had bronchial asthma, and two patients with an acute exacerbation of IPF received steroid therapy before hospital admission (Table 1) . As a control group, 200 healthy control volunteers were also included in this study.

Pulmonary Function Tests and Blood Gas Analyses

In 50 stable IPF events, pulmonary function tests were performed for 36 of the events that occurred in patients with IPF admitted to the hospital for further examination (n = 27) or for the induction of HOT (n = 9). Pulmonary function tests included FEV1, the ratio of FEV1 to forced expiratory vital capacity (FEV1%), vital capacity (VC), the percentage of predicted VC (%VC), and the percentage of predicted carbon monoxide diffusing capacity (%Dlco).

In all 64 events, blood gas samples were obtained at hospital admission. Blood gas samples were obtained at room air in 43 events, during the inhalation of oxygen in 19 events, and during controlled ventilation in 2 events. Since we could not determine the fraction of inspired oxygen (Fio2) in 19 events, we evaluated the Pao2 and Paco2 at room air in 43 events, and the ratio of the Paco2 to Fio2 in 45 events.

Blood Samples

Sixty-four peripheral venous blood samples with and without ethylenediaminetetra-acetic acid were obtained at the time of the hospital admission. After centrifugation at 3,000g for 10 min at 4°C, the serum was frozen and stored at − 80°C until assayed.

Measurement of ST2 and Several Variables

Peripheral blood samples were measured for a full blood count. The serum samples were analyzed for ST2, lactate dehydrogenase (LDH), C-reactive protein (CRP), and total IgE. ST2 concentration was determined by sandwich enzyme-linked immunosorbent assay as previously described.2526 In brief, to calibrate the purified recombinant human ST2 assay of various concentrations in phosphate-buffered saline solution + 0.1% (weight/volume) bovine serum antigen, sera from healthy volunteers and patients were added to a 96-well plate coated with FB9, an antihuman ST2 monoclonal antibody. After 1 h, the plate was washed three times with phosphate-buffered saline solution + 0.05% (weight/volume) Tween 20. Then, 50 μL of 500 ng/mL of biotinylated 2A5 monoclonal antibody was added to each well and reacted for 1 h. After being washed three times, streptavidine-horseradish peroxidase conjugate was added and allowed to react for 30 min. After being washed five times, the plate was reacted with 100 μL of 10 mmol/L o-phenylenediamine-0.01% (volume/volume) H2O2 in 50 mmol/L sodium acetate buffer (pH 5.0) for 20 min. The optical density at 450 nm was measured. All of the samples were assayed in duplicate.

Statistical Analysis

Data were expressed as mean ± SEM. Differences between two variables were assessed with the Mann-Whitney U test. Multiple comparison was carried out by the Fisher protected least-significant differences method followed by the post hoc test. Positive quantitative differences between groups were tested by χ2 test or the Fisher exact probability test. Analysis of correlation was done with the Pearson coefficient of correlation. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were calculated for the serum ST2 level to analyze the optimal criteria for discriminating cases between acute exacerbation and stable state of IPF; p < 0.05 was considered statistically significant.

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. Although the serum levels of ST2 in stable IPF statistically did not differ from those in healthy control subjects, the serum levels of ST2 in acute exacerbation of IPF were significantly higher than those in stable IPF (p < 0.0001, acute exacerbation of IPF vs stable IPF or healthy control subjects, 2.76 ± 0.56 ng/mL vs 0.44 ± 0.07 ng/mL or 0.42 ± 0.03 ng/mL, respectively, as shown in Fig 2 ). In 11 events of bacterial pneumonia with stable IPF, the serum ST2 levels were not elevated (data not shown).

Positive Rate of Serum ST2

The cutoff values of serum ST2 were set at 1.33 ng/mL on the basis of the 95% specificity level for the healthy control group. The positive rate of serum ST2 in acute exacerbation of IPF was 71.4% and was significantly higher than that in stable IPF or healthy control subjects (Fig 3 ). The serum levels of ST2 were below the cutoff values in 92% of the patients with stable IPF.

Evolution of Serum ST2

In six patients with IPF, serum samples at two points, before acute exacerbation and in acute exacerbation, could be obtained and compared. The ST2 levels in these six patients did not increase before acute exacerbation. The levels of serum ST2 on acute exacerbation were, however, significantly elevated in comparison with those before acute exacerbation of IPF in each case (p < 0.05; before acute exacerbation vs on acute exacerbation, 0.29 ± 0.09 ng/mL vs 1.92 ± 0.67 ng/mL, respectively; Fig 4 ).

Correlation of Serum ST2 Levels to Several Variables

Various clinical parameters of the patients with IPF are shown in Table 2 . Physiologic parameters were consistent with a restrictive disorder (reduced %VC). In addition, gas exchange abnormalities were evident with a reduction in the %Dlco, Pao2, and Pao2/Fio2. Although the serum LDH and CRP were increased, the total serum IgE, WBC count, and eosinophils were not elevated. Factors associated with the serum ST2 levels in patients with IPF were analyzed using the Pearson correlation coefficient test (Table 3 ). The serum levels of ST2 statistically correlated with serum LDH (r = 0.344, p = 0.005) and CRP (r = 0.496, p < 0.001). Furthermore, the serum levels of ST2 were inversely correlated with Pao2 (r = − 0.356, p = 0.018), Pao2/Fio2 (r = − 0.559, p < 0.001), and %VC (r = −0.346, p = 0.026). Other factors, such as age, blood eosinophil count, total serum IgE, Paco2, WBC count, VC, FEV1, FEV1%, and %Dlco did not correlate with the serum ST2 levels.

Serum ST2 Levels in the Diagnosis of Acute Exacerbation of IPF

We evaluated serum ST2 as a marker for acute exacerbation of IPF. The cutoff values of serum ST2 were set at 1.33 ng/mL on the basis of the 95% specificity level for the healthy control group. Cutoff levels of other markers were set at 8,000/μL for WBC count, 0.5 mg/dL for CRP, and 410 IU/L for LDH. Using these cutoff levels, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy in the diagnosis of acute exacerbation of IPF for each marker are shown in Table 4 . Overall, measurement of serum ST2 levels in the diagnosis of acute exacerbation of IPF gave the highest diagnostic accuracy.

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).32 The 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 cytokines and Th2 immune response.511 Reports2123,27 have demonstrated that ST2 gene products are predominantly expressed in Th2 cells, and that their expression is also significantly induced by proinflammatory cytokines; therefore, we hypothesized that ST2 gene expression may be up-regulated, reflecting an inflammatory response induced by Th2 cytokine or proinflammatory cytokine in IPF. The results of the present study demonstrated that the serum ST2 levels in patients with stable IPF did not differ from those in healthy control subjects, while the serum levels of ST2 in patients with acute exacerbation of IPF were significantly elevated. Furthermore, the serum level of ST2 was statistically correlated with LDH and CRP. These findings suggest that the serum ST2 level may reflect progress in the inflammatory process in the lung in IPF.

Most patients with IPF show a slowly progressive deterioration characterized by progressive parenchymal lung injury and fibrosis leading to restrictive lung function, decreased diffusing capacity and, ultimately, cor pulmonale. However, Kondoh et al30 reported that an accelerated phase occurs at some point during the chronic course of the disease. Furthermore, open-lung biopsy performed within 2 weeks after the exacerbation confirmed an acute DAD pattern together with a chronic interstitial pneumonia of the UIP type.30 Although it remains uncertain what causes acute exacerbation, the pathologic findings of lung autopsy specimens with respect to acute exacerbation of IPF demonstrated that IL-1β and TNF-α were strongly positive in the alveolar macrophages and proliferating type II pneumocytes.28 It has been reported that both IL-1β and TNF-α lead to acute/subacute and chronic inflammation that evolve into pulmonary fibrosis, and that the transient overexpression of IL-1β or TNF-α has a great effect in promoting fibrosis.3334 These findings suggest that IL-1β and TNF-α may be involved in the pathogenesis of the acute exacerbation of IPF; however, an in vitro study,27 demonstrated that the expression of ST2 was enhanced by proinflammatory cytokines, such as IL-1α, IL-1β, and TNF-α. The results of the present study demonstrated that the levels of serum ST2 were significantly elevated on acute exacerbation of IPF; therefore, proinflammatory cytokines such as IL-1β and TNF-α may enhance the expression of ST2 on acute exacerbation of IPF. The elevated levels of soluble ST2 protein may be related to the inflammatory process of the accelerated phase of IPF, and reflect the severity of lung inflammation.

The inflammatory response in pulmonary fibrosis has been thought to be closely associated with a Th2 immune response. Interferon (IFN)-γ inhibits fibroblast proliferation and the production of collagen and other noncollagenous extracellular matrix proteins by these cells, while IL-4 promotes it.3537In vivo studies3839 using a bleomycin-induced pulmonary fibrosis model have also supported this concept by demonstrating that IL-4 messenger RNA expression is up-regulated in lung fibrosis lesions and that IL-12 attenuates pulmonary fibrosis via the modulation of IFN-γ production. Furthermore, in the clinical study, IFN-γ treatment of patients with IPF was seen to improve pulmonary function and gas exchange.40 These findings suggest that the persistent imbalance in the expression of Th1 and Th2 cytokines in the lung may be one of the important underlying factors in the progression of pulmonary fibrosis. There have been several reports2526,41 demonstrating that serum ST2 protein increases in Th2-mediated disease, such as acute eosinophilic pneumonia and bronchial asthma; therefore, if Th2-mediated inflammation is related to the fibroproliferative process, we expect that the serum ST2 level may increase in IPF, reflecting the activity of IPF. The results of the present study, however, demonstrated that the serum levels of ST2 were not elevated in stable IPF; however, the possibility that ST2 expression may be implicated in the fibroproliferative process cannot be denied, because serum levels of ST2 may not reflect the local expression of ST2 in the lung tissue. Previous reports56 regarding Th2 cytokine expression in IPF have demonstrated that Th2 cytokines, such as IL-4 or IL-5, are overexpressed in the lung tissue, but not in the serum. Further analysis is required to investigate the correlation of the local expression of ST2 and Th2 cytokines in the IPF lung.

Although the origin of the elevated serum ST2 in patients with IPF is unknown, several investigators have reported on the cellular source of ST2. Li et al20 showed that the messenger RNA of human ST2 was highly expressed in the tissues of the lung, kidney, placenta, and stomach. Kumar et al27 showed that the messenger RNA of ST2 was expressed in mast cells, fibroblasts, and vascular endothelial cells. We also observed ST2 messenger RNA expression in human bronchial epithelial cells, type II pneumocytes, alveolar macrophages, pulmonary smooth-muscle cells, pulmonary artery endothelial cells, and lung fibroblasts.42 Parenchymal inflammation in IPF involves T lymphocytes, macrophages, mast cells, neutrophils, eosinophils, hyperplastic type II epithelial cells, fibroblast proliferation, and distinct B-lymphocyte aggregates.23 These findings suggest that ST2 in acute exacerbation of IPF may be produced by lung structural cells or infiltrating interstitial inflammatory cells. Further analysis such as in situ hybridization or immunohistochemistry is needed to determine which cells produce ST2 protein in IPF.

To evaluate the clinical role of the serum ST2, we analyzed the correlation between ST2 and various clinical parameters. Interestingly, the present study demonstrated that the serum levels of ST2 inversely correlated with Pao2, Pao2/Fio2, and %VC. Furthermore, the serum levels of ST2 statistically correlated with those of LDH, which could reflect the cellular destruction of lung cells in diffuse interstitial pneumonitis.43 These findings suggest that soluble ST2 in sera may increase, possibly reflecting the severity of respiratory insufficiency and restrictive pulmonary dysfunction caused by progressing fibrosis in the IPF lung. Moreover, our results demonstrated that measurement of serum ST2 levels in the diagnosis of acute exacerbation of IPF gave the higher diagnostic accuracy than other markers, suggesting that elevated serum ST2 levels might predict an acute exacerbation of IPF. However, given the small number of patients, a larger confirmatory study is necessary to ascertain how applicable these results are to patients with IPF in general.

Although the biological function of elevated ST2 in the patients with IPF is still uncertain, there have been several reports suggesting the function of soluble ST2 protein in murine models. In murine asthma models, the administration of recombinant ST2 fusion protein or IV soluble ST2 gene transfer attenuates eosinophilic inflammation of the airway and suppresses IL-4 and IL-5 production, and these data suggest that soluble forms of ST2 can inhibit the interaction of membrane-bound ST2 by competing with its putative ligand, resulting in down-regulation of the Th2 effector function.23,4445 Furthermore, Sweet et al46 showed that the administration of a recombinant ST2 fusion protein suppresses TNF-α production and results in a significantly enhanced survival rate in murine lipopolysaccharide-induced shock models. These findings suggest that soluble forms of ST2 may have the capability to inhibit the production of proinflammatory cytokines and Th2 cytokines. Although protective roles of ST2 have been reported in animal models, it is difficult to extrapolate these results of animal study to human pathologic conditions, such as IPF; however, we can speculate that the elevation in endogenous ST2 in the lung was too late or too low to prevent acute lung injury or pulmonary fibrosis. An experimental study utilizing a model of bleomycin-induced pulmonary fibrosis is underway to determine the role and function of ST2 gene products in pulmonary fibrosis.

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 ST2 in the lung should be further analyzed.

Abbreviations: CRP = C-reactive protein; DAD = diffuse alveolar damage; %Dlco = percentage of the predicted carbon monoxide diffusing capacity; FEV1% = ratio of FEV1 to forced expiratory vital capacity; Fio2 = fraction of inspired oxygen; HOT = home oxygen therapy; ICS = international consensus statement; LDH = lactate dehydrogenase; IFN = interferon; IL = interleukin; IPF = idiopathic pulmonary fibrosis; ST2 = soluble ST2 protein; Th1 = T-helper type 1; Th2 = T-helper type 2; TNF = tumor necrosis factor; UIP = usual interstitial pneumonia; VATS = video-assisted thoracoscopic surgery; VC = vital capacity; %VC = percentage of predicted vital capacity

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.

Table Graphic Jump Location
Table 1. Characteristics of Patients With IPF
Figure Jump LinkFigure 1. The serum concentration of ST2 in patients with IPF. The bar indicates the mean value in each group. The horizontal line indicates the cutoff levels of serum ST2 (1.33 ng/mL). The serum ST2 levels in the 64 events of IPF were elevated compared to those of healthy control (HC) subjects (n = 200) [median values ± SEM of IPF vs healthy control subjects, 0.94 ± 0.18 ng/mL vs 0.42 ± 0.03 ng/mL, respectively], and there was a significant difference in serum ST2 levels between the two groups (p < 0.0001).Grahic Jump Location
Figure Jump LinkFigure 2. The serum concentration of ST2 in patients with acute exacerbation of IPF. The serum levels of ST2 in acute exacerbation of IPF (n = 14) were significantly higher than those in stable IPF (n = 50) [p < 0.0001, acute exacerbation of IPF vs stable IPF; 2.76 ± 0.56 ng/mL vs 0.44 ± 0.07 ng/mL, respectively].Grahic Jump Location
Figure Jump LinkFigure 3. Positive rate of serum ST2. The cutoff values are set at 1.33 ng/mL on the basis of the 95% specificity level for the healthy control group. The positive rate in acute exacerbation of IPF is significantly higher than that in stable IPF (p < 0.0001, acute exacerbation of IPF vs stable IPF; acute exacerbation of IPF, 10 of 14 = 71.4%; stable IPF, 4 of 50 = 8.0%, respectively). There was no significant difference between stable IPF and healthy control subjects. NS = not significant.Grahic Jump Location
Figure Jump LinkFigure 4. Evolution of serum ST2 levels in patients with IPF before acute exacerbation and in acute exacerbation (n = 6). Each bar represents the mean ± SEM. The horizontal line indicates the cutoff levels for serum ST2. Significant differences between ST2 levels before acute exacerbation and those on acute exacerbation were observed (p < 0.05 by a Mann-Whitney U test, before acute exacerbation vs on acute exacerbation; 0.29 ± 0.09 ng/mL vs 1.92 ± 0.67 ng/mL, respectively).Grahic Jump Location
Table Graphic Jump Location
Table 2. Various Clinical Parameters of the Patients With IPF
Table Graphic Jump Location
Table 3. Correlation of Serum ST2 Levels to Several Variables
* 

Analysis of correlation was done with the Pearson coefficient of correlation.

Table Graphic Jump Location
Table 4. Diagnostic Values of Measurement of Serum ST2 and Several Variables in Acute Exacerbation of IPF*
* 

Data are presented as %. Cutoff levels were set on 1.33 ng/mL for ST2, 8,000/μL for WBC count, 0.5 mg/dL for CRP, and 410 IU/L for LDH.

The authors thank Mrs. Tomoko Ikahata.

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Akira, M, Hamada, H, Sakatani, M, et al CT findings during phase of accelerated deterioration in patients with idiopathic pulmonary fibrosis.AJR Am J Roentgenol1997;168,79-83. [PubMed]
 
Kondoh, Y, Taniguchi, H, Kawabata, Y, et al Acute exacerbation in idiopathic pulmonary fibrosis: analysis of clinical and pathologic findings in three cases.Chest1993;103,1808-1812. [CrossRef] [PubMed]
 
Murray, JF, Matthay, MA, Luce, JM, et al An expanded definition of the adult respiratory distress syndrome.Am Rev Respir Dis1988;138,720-723. [PubMed]
 
Gross, TJ, Hunninghake, GW Idiopathic pulmonary fibrosis.N Engl J Med2001;345,517-525. [CrossRef] [PubMed]
 
Kolb, M, Margetts, PJ, Anthony, DC, et al Transient expression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis.J Clin Invest2001;107,1529-1536. [CrossRef] [PubMed]
 
Sime, PJ, Marr, RA, Gauldie, D, et al Transfer of tumor necrosis factor-α to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-beta1 and myofibroblasts.Am J Pathol1998;153,825-832. [CrossRef] [PubMed]
 
Pfeffer, LM, Murphy, JS, Tamm, I Interferon effects on the growth and division of human fibroblasts.Exp Cell Res1979;121,111-120. [CrossRef] [PubMed]
 
Duncan, MR, Berman, B Gamma interferon is the lymphokine and β interferon the monokine responsible for inhibition of fibroblast collagen production and late but not early fibroblast proliferation.J Exp Med1985;162,516-527. [CrossRef] [PubMed]
 
Lawrence, DA Transforming growth factor-β: a general review.Eur Cytokine Netw1996;7,363-374. [PubMed]
 
Gharaee-Kermani, M, Nozaki, Y, Hatano, K, et al Lung interleukin-4 gene expression in a murine model of bleomycin-induced pulmonary fibrosis.Cytokine2001;15,138-147. [CrossRef] [PubMed]
 
Keane, MP, Belperio, JA, Burdick, MD, et al IL-12 attenuates bleomycin-induced pulmonary fibrosis.Am J Physiol Lung Cell Mol Physiol2001;281,L92-L97. [PubMed]
 
Ziesche, R, Hofbauer, E, Wittmann, K, et al A preliminary study of long-term treatment with interferon-γ-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis.N Engl J Med1999;341,1264-1269. [CrossRef] [PubMed]
 
Oshikawa, K, Kuroiwa, K, Tokunaga, T, et al Acute eosinophilic pneumonia with increased soluble ST2 in serum and bronchoalveolar lavage fluid.Respir Med2001;95,532-533. [CrossRef] [PubMed]
 
Oshikawa, K, Yanagisawa, K, Tominaga, S, et al ST2 protein induced by inflammatory stimuli can modulate acute lung inflammation.Biochem Biophys Res Commun2002;299,18-24. [CrossRef] [PubMed]
 
DeRemee, RA Serum lactic dehydrogenase activity and diffuse interstitial pneumonitis.JAMA1968;204,1193-1195. [CrossRef] [PubMed]
 
Coyle, AJ, Lloyd, C, Tian, J, et al Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses.J Exp Med1999;190,895-902. [CrossRef] [PubMed]
 
Oshikawa, K, Yanagisawa, K, Tominaga, S, et al Expression and function of the ST2 gene in a murine model of allergic airway inflammation.Clin Exp Allergy2002;32,1520-1526. [CrossRef] [PubMed]
 
Sweet, MJ, Leung, BP, Kang, D, et al A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression.J Immunol2001;166,6633-6639. [PubMed]
 

Figures

Figure Jump LinkFigure 1. The serum concentration of ST2 in patients with IPF. The bar indicates the mean value in each group. The horizontal line indicates the cutoff levels of serum ST2 (1.33 ng/mL). The serum ST2 levels in the 64 events of IPF were elevated compared to those of healthy control (HC) subjects (n = 200) [median values ± SEM of IPF vs healthy control subjects, 0.94 ± 0.18 ng/mL vs 0.42 ± 0.03 ng/mL, respectively], and there was a significant difference in serum ST2 levels between the two groups (p < 0.0001).Grahic Jump Location
Figure Jump LinkFigure 2. The serum concentration of ST2 in patients with acute exacerbation of IPF. The serum levels of ST2 in acute exacerbation of IPF (n = 14) were significantly higher than those in stable IPF (n = 50) [p < 0.0001, acute exacerbation of IPF vs stable IPF; 2.76 ± 0.56 ng/mL vs 0.44 ± 0.07 ng/mL, respectively].Grahic Jump Location
Figure Jump LinkFigure 3. Positive rate of serum ST2. The cutoff values are set at 1.33 ng/mL on the basis of the 95% specificity level for the healthy control group. The positive rate in acute exacerbation of IPF is significantly higher than that in stable IPF (p < 0.0001, acute exacerbation of IPF vs stable IPF; acute exacerbation of IPF, 10 of 14 = 71.4%; stable IPF, 4 of 50 = 8.0%, respectively). There was no significant difference between stable IPF and healthy control subjects. NS = not significant.Grahic Jump Location
Figure Jump LinkFigure 4. Evolution of serum ST2 levels in patients with IPF before acute exacerbation and in acute exacerbation (n = 6). Each bar represents the mean ± SEM. The horizontal line indicates the cutoff levels for serum ST2. Significant differences between ST2 levels before acute exacerbation and those on acute exacerbation were observed (p < 0.05 by a Mann-Whitney U test, before acute exacerbation vs on acute exacerbation; 0.29 ± 0.09 ng/mL vs 1.92 ± 0.67 ng/mL, respectively).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Characteristics of Patients With IPF
Table Graphic Jump Location
Table 2. Various Clinical Parameters of the Patients With IPF
Table Graphic Jump Location
Table 3. Correlation of Serum ST2 Levels to Several Variables
* 

Analysis of correlation was done with the Pearson coefficient of correlation.

Table Graphic Jump Location
Table 4. Diagnostic Values of Measurement of Serum ST2 and Several Variables in Acute Exacerbation of IPF*
* 

Data are presented as %. Cutoff levels were set on 1.33 ng/mL for ST2, 8,000/μL for WBC count, 0.5 mg/dL for CRP, and 410 IU/L for LDH.

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Pan, LH, Ohtani, H, Yamauchi, K, et al Co-expression of TNF-α and IL-1β in human acute pulmonary fibrotic diseases: an immunohistochemical analysis.Pathol Int1996;46,91-99. [CrossRef] [PubMed]
 
Akira, M, Hamada, H, Sakatani, M, et al CT findings during phase of accelerated deterioration in patients with idiopathic pulmonary fibrosis.AJR Am J Roentgenol1997;168,79-83. [PubMed]
 
Kondoh, Y, Taniguchi, H, Kawabata, Y, et al Acute exacerbation in idiopathic pulmonary fibrosis: analysis of clinical and pathologic findings in three cases.Chest1993;103,1808-1812. [CrossRef] [PubMed]
 
Murray, JF, Matthay, MA, Luce, JM, et al An expanded definition of the adult respiratory distress syndrome.Am Rev Respir Dis1988;138,720-723. [PubMed]
 
Gross, TJ, Hunninghake, GW Idiopathic pulmonary fibrosis.N Engl J Med2001;345,517-525. [CrossRef] [PubMed]
 
Kolb, M, Margetts, PJ, Anthony, DC, et al Transient expression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis.J Clin Invest2001;107,1529-1536. [CrossRef] [PubMed]
 
Sime, PJ, Marr, RA, Gauldie, D, et al Transfer of tumor necrosis factor-α to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-beta1 and myofibroblasts.Am J Pathol1998;153,825-832. [CrossRef] [PubMed]
 
Pfeffer, LM, Murphy, JS, Tamm, I Interferon effects on the growth and division of human fibroblasts.Exp Cell Res1979;121,111-120. [CrossRef] [PubMed]
 
Duncan, MR, Berman, B Gamma interferon is the lymphokine and β interferon the monokine responsible for inhibition of fibroblast collagen production and late but not early fibroblast proliferation.J Exp Med1985;162,516-527. [CrossRef] [PubMed]
 
Lawrence, DA Transforming growth factor-β: a general review.Eur Cytokine Netw1996;7,363-374. [PubMed]
 
Gharaee-Kermani, M, Nozaki, Y, Hatano, K, et al Lung interleukin-4 gene expression in a murine model of bleomycin-induced pulmonary fibrosis.Cytokine2001;15,138-147. [CrossRef] [PubMed]
 
Keane, MP, Belperio, JA, Burdick, MD, et al IL-12 attenuates bleomycin-induced pulmonary fibrosis.Am J Physiol Lung Cell Mol Physiol2001;281,L92-L97. [PubMed]
 
Ziesche, R, Hofbauer, E, Wittmann, K, et al A preliminary study of long-term treatment with interferon-γ-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis.N Engl J Med1999;341,1264-1269. [CrossRef] [PubMed]
 
Oshikawa, K, Kuroiwa, K, Tokunaga, T, et al Acute eosinophilic pneumonia with increased soluble ST2 in serum and bronchoalveolar lavage fluid.Respir Med2001;95,532-533. [CrossRef] [PubMed]
 
Oshikawa, K, Yanagisawa, K, Tominaga, S, et al ST2 protein induced by inflammatory stimuli can modulate acute lung inflammation.Biochem Biophys Res Commun2002;299,18-24. [CrossRef] [PubMed]
 
DeRemee, RA Serum lactic dehydrogenase activity and diffuse interstitial pneumonitis.JAMA1968;204,1193-1195. [CrossRef] [PubMed]
 
Coyle, AJ, Lloyd, C, Tian, J, et al Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses.J Exp Med1999;190,895-902. [CrossRef] [PubMed]
 
Oshikawa, K, Yanagisawa, K, Tominaga, S, et al Expression and function of the ST2 gene in a murine model of allergic airway inflammation.Clin Exp Allergy2002;32,1520-1526. [CrossRef] [PubMed]
 
Sweet, MJ, Leung, BP, Kang, D, et al A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression.J Immunol2001;166,6633-6639. [PubMed]
 
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