Oxidative/nitrosative stress caused by an imbalance between cellular production of reactive oxygen species/reactive nitrogen species and endogenous antioxidants such as stress response protein including HO-1 and classic antioxidant enzymes including superoxide dismutases, catalase, and glutathione peroxidase might play a major role in the progression of various lung diseases such as IPF, chronic obstructive pulmonary disease, and DAD18,19,20,21,22. On the other hand, macrophages play key roles in all phases of adult wound healing, which are inflammation, proliferation, and remodeling. Human peripheral monocytes are differentiated uncommitted macrophages (M0), and they are broadly polarized to pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages23. The interaction between M1 and M2 macrophages is reported to be closely correlated with disease progression in patients with IP, including AEs24,25,26. In patients with AEs of IP, HO-1 is strongly and exclusively induced on M2 macrophages, which differentiate in response to IL-4, IL-10, and IL-13 and produce large amounts of TGF-β1, resulting in extracellular matrix deposition, epithelial-mesenchymal transition, fibroblast activation, and cell death, depending on M1 macrophage activation4,5,24,25. Consistent with this previous research, we have demonstrated that serum HO-1 is useful for distinguishing between AE and stable IP, and serum HO-1 levels were positively correlated with serum levels of SP-D and the GGO score9. However, because this research included a very small number of cases, the clinical utility of serum HO-1 measurement has not been examined for each IP subtype (for each IIP and SIP); therefore, the ability of serum HO-1 to detect AEs in patients with each IP subtype was evaluated for the purpose of validation and to compare with the detectability to other biomarkers commonly used in clinical practice.
IP is characterized by alveolar inflammation leading to progressive fibrosis27. In the presence of alveolitis, surfactant apoproteins such as SP-A and SP-D are secreted by type II pneumocytes, and these apoproteins can be detected in the serum27,28. SP-A and SP-D concentrations are reported to correlate with the extent of alveolitis (denoted by HRCT findings of GGO), but not with the progression of fibrosis29. The serum LDH level is a non-specific biomarker that is elevated in various inflammatory diseases and reflects inflammation and cellular injury in the lungs of IP patients and has been mentioned as a prognostic factor in AE patients with IPF30,31. Consistent with this observation, it was found that the serum HO-1 level was positively correlated with the serum LDH and SP-D levels and the GGO score (especially in IIPs) in the present study. Therefore, we hypothesize that serum HO-1 as an M2 macrophage activation marker could provide a highly specific marker of alveolitis in patients having an AE. The points that serum HO-1 did not correlate with SP-D level or GGO score in SIPs were that the number of cases diagnosed with AE was much smaller than that of IIPs and that the included cases seemed to be more heterogeneous than those of IIPs. It was considered essential to verify only the SIPs, which increased the number of cases in the future.
AEs can occur in both groups of IIPs and SIPs, presenting with rapid respiratory failure, and the primary treatment is steroid pulse therapy15,16,32. AE diagnosis is often difficult, because the clinical manifestations of pulmonary infections, congestion, and thromboembolism are sometimes similar to those of AEs. In cases where a diagnosis is difficult, various drugs such as steroids, antibacterial drugs, and diuretics are administered in combination, resulting in unnecessary drug administration. Therefore, it is essential to improve the AE diagnosis rate. We have reported that, in 28 patients with IP, serum HO-1 levels helped predict the severity of the disease and hospital mortality and were higher in patients who developed AE than in those who did not9. In the present study involving a larger number of patients, the serum HO-1 level had a favorable AUC value similar with other biochemical biomarkers such as serum LDH in AE diagnosis, and a composite parameter consisting of serum HO-1 and the GGO score provided high AUC values in both IIP and SIP groups. Furthermore, although the number of cases was small, it was shown that serum HO-1 was significantly higher in AE than ARW due to infection, lung edema, and pneumothorax. Therefore, serum HO-1 measurement could contribute to providing an accurate diagnosis of patients with AEs, leading to rapid decision-making related to treatment, including steroid pulse therapy or other options such as antibiotics. Regarding the validation of the discrimination performance between AE and ARW, it was considered that a larger-scale prospective research was necessary.
Although the serum HO-1 level might have been shown to be a useful biomarker in patients with AE, there are several limitations in the present research. First, the number of patients was still small and from a single institution. The clinical diagnoses of the patients enrolled with SIPs were much smaller than those of IIPs and heterogeneous and no similar trends to IIPs could be found. The reproducibility of the findings of this study needs to be confirmed through validation cohorts which increased the number of cases in the future. Second, after the onset of AEs, a certain number of patients did not undergo histopathological evaluation because of severe respiratory failure. Therefore, the evaluation of serum HO-1 related to the degree of DAD and organizing pneumonia in affected lesions of the lung has not been investigated. Third, we have not evaluated the clinical utility of measuring serum HO-1 over time for the purpose of the tracking disease activity in patients with AE, although we reported the AE of IPF case that the serial changes of serum HO-1 seemed to reflect disease activity of AE33. Fourth, as shown in the Supplement Fig. 1, although the number of cases was small, we demonstrated that serum HO-1 was significantly higher in AE than ARW due to infection, lung edema, and pneumothorax which was sometimes difficult to discriminate from AE. This result also needs further verification with more cases.
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