Oxidative stress plays an important role in the development and progression of lung injuries including ARDS and AE-ILDs (7, 8). HO-1, a rate-limiting enzyme in heme catabolism, has antioxidative activities in patients with diffuse parenchymal lung disease (17-19). We previously investigated whether evaluating the degree of oxidative stress by measuring serum HO-1 using the sandwich ELISA method is useful for assessing disease activities and predicting prognosis in patients with ARDS and AE-ILDs (12, 13). The present study was an integrated analysis of these. We analyzed the clinical usefulness of serum HO-1 in lung injury patients, and compared the baseline serum HO-1 and its variation during intensive treatment between ARDS and AE-ILDs.
As a protective reaction against oxidative stress, HO-1 protein has been reported to increase in lung tissue including alveolar macrophages, alveolar and bronchial epithelium, interstitium, and endothelium taken from patients with ARDS or AE-ILDs, contributing to the changes in iron mobilization, signalling, and regulation seen in these conditions (11, 13). We found that in the patient with AE of idiopathic pulmonary fibrosis (IPF), high HO-1 expression was observed mainly in alveolar macrophages, while HO-1 expression in fibrotic lesions or alveolar macrophages was not conspicuous in stable IPF (20). In our present case report, autopsy findings of patients with drug-induced ARDS (serum HO-1 = 76 ng/mL at baseline) showed no obvious HO-1 expression in the fibrotic DAD lesion. However, in the active DAD lesion, HO-1 expression was prominent in alveolar macrophages (Fig. S1, Supplementary Information). In addition, serum HO-1 significantly correlated with serum T-bil as the downstream product of active heme metabolism and serum LDH as a marker of cellular damage (21-23). Therefore, we speculate that the mechanism of HO-1 increase in the blood is as follows. High HO-1 expression in the lung, which converts heme to CO, iron, and bilirubin, is introduced into the bloodstream due to its relatively small molecular size (32 kDa), destruction of alveolar structures and enhancement of vascular permeability (24). In the present study, ARDS patients had significantly higher serum HO-1 levels at baseline compared with AE-ILD patients. Furthermore, plasma levels of oxidative stress factors including superoxide dismutase, malondialdehyde, and nitric oxide in patients with sepsis have been reported to significantly increase, which is closely related to organ damage and poor prognosis (25). Taken together, we consider that oxidative stress in ARDS is stronger than that in AE-ILDs, and the oxidative stress intensity could correlate with disease prognosis.
Ongoing and persistent oxidative stress leads to poor prognosis (22, 26). HO-1 is encoded by HMOX1, the transcription of which can be induced by a variety of signal transduction pathways that activate different transcription factors. Of these transcription factors, nuclear factor erythroid 2-related factor 2 (Nrf2) is possibly one of the most important regulators of the cellular stress response. Cancer cells with persistent Nrf2 activation often develop Nrf2 addiction and show malignant phenotypes, leading to poor prognoses (26). In patients with ILDs, persistently high ethane levels, a product of lipid peroxidation that has been proposed as a biomarker of oxidative stress, may correlate with poor prognosis (23). In the present study, serum HO-1 levels tended to decrease 2 weeks after the start of treatment in both ARDS and AE-ILD patients. However, HO-1 levels remained persistently elevated. Furthermore, while intravenous corticosteroid therapy is widely used in severe ARDS and AE-ILDs, serum HO-1 levels remained high even in patients treated with intravenous corticosteroids (Fig. S2, Supplementary Information) (27-30). These data suggest that corticosteroid therapy does not effectively reduce oxidative stress in patients with ARDS and AE-ILDs and specific treatments aimed at reducing oxidative stress are important for improving the prognosis of ARDS and AE-ILDs (31, 32).
Composite approaches have been developed using peripheral blood biomarkers and physiological and radiographic measurements to provide more accurate prognostic information (33-35). The acute physiology and chronic health evaluation (APACHE) II score is frequently used to measure disease severity in intensive care unit patients with ARDS (33). The composite scoring system, which is based on serum LDH, Krebs von den Lungen-6, P/F ratio, and extent of abnormal high resolution computed tomography findings, is useful for predicting 3-month mortality in AE-IPF patients (34). We previously demonstrated that the Charlson comorbidity index score, sex, and serum LDH are important for predicting 3-month mortality in AE-ILD patients (35). In the present study, we found that composite parameters including serum HO-1, ARDS diagnosis, P/F ratio, and sex had acceptable AUC for prediction of 1-month mortality in ARDS and AE-ILD patients. In addition, in ARDS patients only, these composite parameters were more accurate for predicting 1-month mortality than the APACHE II score (Fig. S3, Supplementary Information). However, this finding must be confirmed in a multi-centre prospective study.
There are several limitations to this study. First, the study enrolled only a small number of patients from a few institutions. Therefore, our findings need to be confirmed in a multi-centre, prospective study. Second, clinical diagnoses among ARDS and AE-ILD patients were heterogeneous. Future investigation to evaluate the clinical utility of serum HO-1 measurement in patients with each of the clinical diagnoses is needed.