DIAGNOSTIC VALUE OF T-CELL DEATH-ASSOCIATED GENE 8 IN HYPOXIA-INDUCED PULMONARY HYPERTENSION

Hui Wang^#, Pengfei Xuan^#, Narengeril Li, Baoying Bu, Shumei Wang, Wurina, Xiyuan Xu^*, Jingping Yang^*

Department of Respiratory and Critical Medicine, The Third Affiliated Hospital of Inner Mongolia Medical University, Baotou, Inner Mongolia Autonomous Region, China 

Objective: Due to the  unspecific symptoms and the invasive testing method of pulmonary hypertension (PH), serum markers of PH would  be of great clinical value. We constructed a hypoxia induced pulmonary hypertension (HPH) rat model to explore the diagnostic value of T-cell death-associated gene 8 (TDAG8) and its underlying mechanism in PH.

Methods: Sprague-Dawley rats were placed into normobaric hypoxia chambers for 28 days. The pulmonary artery pressure (PAP) and right ventricular hypertrophy index (RVHI) were measured and small pulmonary arterial morphological alterations were analyzed with hematoxylin and eosin (H&E) staining. mRNA levels of TDAG8 in lung tissues, pulmonary vessels and peripheral blood were separately determined by real-time polymerase chain reaction (PCR). Enzyme-linked immunosorbent assay (ELISA) was performed to detected levels of the C-C motif chemokine ligand 22 (CCL2), tumor necrosis factor-α (TNF-α) and interleukin (IL)-25.

Results: TDAG8 levels in lung tissues, pulmonary vessels and the peripheral blood of the HPH group were 229.34±95.60, 884.03±689.06 and 9.95±2.58, higher than controls (p=0.009, 0.024 and p<0.001, respectively). The levels of cytokines, CCL22, TNF-α and IL-25, were (412.36±70.43) ng/mL, (120.00±68.95) ng/mL and (102.60±116.60) ng/mL in the blood, and significantly increased in HPH rats. TDAG8 levels had high expression consistency in lung tissues, pulmonary vessels and peripheral blood (lung & vessels: r²=0.808, p<0.001, vessels & blood: r2=0.840, p=0.004). The value of PAP was correlated with TDAG8 in the lung tissues (r²=0.592, p=0.001). And the TDAG8 level was separately associated with levels of CCL22, TNF-α and IL-25 in HPH rats (CCL2: r²= 0.779, p=0.001, TNF-α: r²=0.574, p=0.032; and IL-25: r²=0.579, p=0.029, respectively). TDAG8 (cut-off 7.02 ×103) demonstrated a sensitivity of 92.9% and a specificity of 92.3% in predicting HPH. 

Conclusions: TDAG8 plays a role in the HPH development by activating CCL22, TNF-α and IL-25 and represents a promising candidate for diagnosis in HPH.