Inter-alpha-trypsin inhibitor heavy chain 4: a novel biomarker for environmental exposure to particulate air pollution in patients with chronic obstructive pulmonary disease

Figures & data

Table 1 Baseline characteristics of healthy control subjects, smokers, and patients with COPD

Categorical variables	Healthy controls (n=10)	Healthy smokers (n=5)	Patients with COPD (n=50)
Age, years	67.8±6.2	59.8±14.6	70.7±8.4
Men, %	75.0	75.0	95.5
BMI, kg/m^2	22.5±2.9	24.8±4.0	23.8±3.7
Current smoking, %	0	100	9.1
FEV1, % predicted	88.0±11.5	85.5±14.9	42.6±12.4
8-Isoprostane, pg/mL	ND	ND	13.4±3.0
CRP, mg/L	ND	ND	5.6±6.4

Note: Data is presented as mean ± SD.

Abbreviations: BMI, body mass index; FEV₁, forced expiratory volume in 1 second; CRP, C-reactive protein; ND, no data.

Table 2 Environmental exposure to PM₁₀ over the previous 1 year, 2 years, and 3 years in the study subjects with COPD

	PM10, μg/m^3 (Mean ± SD)
1-year average	46.0±8.4
2-year average	48.5±7.2
3-year average	50.8±7.0

Abbreviations: PM₁₀, particulate matter ≤10 μm; SD, standard deviation.

Figure 1 Protein expression and biological process and molecular functions determined by PANTHER.

Notes: (A) Venn diagram of proteins that are common among or unique to patients with COPD exposed to low ambient particles (LAP; range: 35.4–43.9 μg/m³) and high ambient particles (HAP; range: 63.2–64.5 μg/m³) compared with healthy controls exposed to either LAP or HAP. Six proteins were commonly expressed in the serum samples: proteoglycan 4 (PRG4), inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), apolipoprotein F (APOF), Ig kappa chain V-I region DEE, type I cytoskeletal 16 keratin, and type II cytoskeletal 6A keratin. (B) The biological processes and molecular functions of the unique proteins identified in the LAP and HAP groups. Immune system process and binding are the important biological process and molecular function, respectively, in response to PM₁₀ in COPD.
Abbreviation: COPD, chronic obstructive pulmonary disease.

Figure 2 Serum PRG4, ITIH4, and APOF levels in healthy controls, smokers, and subjects with COPD.

Notes: The PRG4 levels in subjects with COPD were significantly higher than in healthy controls and smokers, whereas the ITIH4 level in COPD was lower than in healthy controls (*P<0.05).
Abbreviations: APOF, apolipoprotein F; COPD, chronic obstructive pulmonary disease; ITIH4, inter-alpha-trypsin inhibitor heavy chain 4; PRG4, proteoglycan 4.

Figure 3 The relationship of serum PRG4, ITIH4, and APOF levels to 1-year, 2-year, and 3-year changes in PM₁₀ levels.

Notes: Study subjects were divided equally based on quintiles of PM₁₀. The values in parentheses along the X-axis represent the mean PM₁₀ values for each quintile group. Spearman’s rank correlation coefficient was used to examine the correlation of quintiles of PM₁₀ with PRG4, ITIH4, and APOF. PRG4 levels were correlated with the 2-year (r=0.278, P=0.033) and 3-year PM₁₀ averages (r=0.349, P=0.007), whereas the ITIH4 levels were correlated with the 1-year (r=−0.325, P=0.012), 2-year (r=−0.401, P=0.002), and 3-year (r=−0.342, P=0.008) PM₁₀ averages.
Abbreviations: APOF, apolipoprotein F; ITIH4, inter-alpha-trypsin inhibitor heavy chain 4; PM₁₀, particulate matter ≤10 μm; PRG4, proteoglycan 4.

Figure 4 Diagnostic performance of serum 8-isoprostane, CRP, PRG4, ITIH4, and APOF in receiver operating characteristic (ROC) curve analyses.

Notes: ROC curve of the sensitivity and specificity of PRG4, ITIH4, and APOF levels for discriminating between the ≥50 μg/m³ and <50 μg/m³ average 3-year PM₁₀ value in COPD. The area under the curve value was 0.563 (95% CI: 0.413–0.713, P=0.405) for 8-isoprostane, 0.634 (95% CI: 0.486–0.782, P=0.086) for CRP, 0.636 (95% CI: 0.492–0.780, P=0.083) for PRG4, 0.690 (95% CI: 0.545–0.836, P=0.015) for ITIH4, and 0.523 (95% CI: 0.376–0.671, P=0.766) for APOF.
Abbreviations: APOF, apolipoprotein F; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; ITIH4, inter-alpha-trypsin inhibitor heavy chain 4; PM₁₀, particulate matter ≤10 μm; PRG4, proteoglycan 4.

Figure 5 Correlation of 8-isoprostane and CRP to PRG4, ITIH4, and APOF in subjects with COPD.

Notes: The Spearman’s rank correlation coefficient for CRP and ITIH4 was r=0.353 (P=0.005).
Abbreviations: APOF, apolipoprotein F; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; ITIH4, inter-alpha-trypsin inhibitor heavy chain 4; PM₁₀, particulate matter ≤10 μm; PRG4, proteoglycan 4.