Postoperative AE-ILD is a fatal complication, and thus it is important to increase its predictive accuracy before surgery. This study showed that baseline levels of serum HMGB1 in patients with postoperative AE-ILD were significantly higher than those without AE-ILD. Additionally, higher levels of HMGB1 were significantly and independently associated with a higher incidence of this fatal complication. Lastly, HMGB1 had the potential to improve the predictive accuracy of risk scoring system, which had been already reported by Sato et al [8, 14]. These data indicate that HMGB1 can be a promising biomarker to predict the postoperative AE in patients with lung cancer and ILD.
This study firstly showed that higher levels of HMGB1 were significantly associated with a higher incidence of postoperative AE-ILD in patients with lung cancer and ILD. We and others previously reported that HMGB1 levels in serum and BALF in patients with IPF were significantly elevated than those in healthy subjects [5, 16]. Additionally, we previously reported that higher levels of HMGB1 were associated with earlier onset of AE in patients with IPF . HMGB1 itself accelerates pro-inflammatory signaling via interacting with RAGE and TLR4 [3, 4], and intratracheal administration of HMGB1 induces acute lung injury . At the same time, some reports showed that injured alveolar epithelial cells highly expressed HMGB1 , indicating that one of the HMGB1 sources in patients with ILD is injured lung tissue. This study also showed that there was a negative correlation between HMGB1 and VC. These data suggest that higher levels of HMGB1 reflect not only pro-inflammatory conditions in the lung but also pre-existing lung damage. Thus, its higher levels can predict the development of postoperative AE-ILD.
This study showed that the patients, both with higher HMGB1 and longer operative time, had a significantly higher risk of this fatal complication than patients with either higher HMGB1 or longer operative time and patients with neither. When operative time becomes longer, it requires a longer time of artificial ventilation, which increases the expression of HMGB1 in BALF and lung tissue in a tidal volume- and time-dependent manner [9, 10]. Exposure to hyperoxia during artificial ventilation also promotes increasing expression of HMGB1 in a time-dependent manner . This mechanical ventilation- and hyperoxia-induced lung injury is canceled by inhibition of HMGB1 [9, 18]. Additionally, higher bleeding volume, which was correlated with operative time and showed potential association with postoperative AE-ILD in this study, is also reported to increase the expression of HMGB1 in plasma and lung . These data indicate that surgery accelerates inflammatory response via additional HMGB1 secretion, which results in the development of postoperative AE-ILD, especially in patients with HMGB1 higher levels.
This study also showed that HMGB1, especially when combined with operative time, could improve the predictive accuracy of postoperative AE-ILD based on previously reported risk scoring systems in patients with lung cancer and ILD . Surgical resection is generally performed as a standard radical treatment for lung cancer. However, it is associated with higher postoperative morbidity of complications when the patient has concurrent ILD . Preventing this fatal complication is crucial to improve the long-term outcome in patients with lung cancer and ILD who underwent surgical resection. One potential preventive strategy is that patients with higher HMGB1 accompanied with reported risks would be treated with wedge resection, because it generally needs shorter operative time and implies less bleeding volume than segmentectomy/lobectomy. Another potential strategy is to use HMGB1-inhibitory drugs. Some existing drugs are reported to inhibit HMGB1-induced inflammatory signal via decreasing HMGB1 secretion and capturing HMGB1 . Further investigations are needed to elucidate the utility of circulatory HMGB1 as a predictive biomarker and molecular target for preventing postoperative AE-ILD in patients with lung cancer and ILD.
This study has several limitations. It was a single-institution study, and the number of patients with postoperative AE-ILD was relatively small. These may substantially impact the generalizability of the study findings. Multicenter studies with a larger sample size are needed to validate the predictive value and the optimal cut off levels of HMGB1.