Abstract Rationale The presence of fatal rapidly progressive interstitial lung disease (RP-ILD) is the leading cause of high mortality in patients with anti-melanoma differentiation-associated protein 5 antibody-positive dermatomyositis (MDA5+DM). Its poorly understood etiology and pathogenesis, as well as the limited efficacy of its empirical therapies render MDA5+DM RP-ILD one of the most formidable challenges in clinical practice. This study aimed to define the histopathological hallmarks and molecular mechanisms driving MDA5+DM-associated RP-ILD. Methods We established a prospective cohort of 16 lung transplant recipients with end-stage RP-ILD and a retrospective cohort of 45 RP-ILD patients and 64 non-RP-ILD controls. Pathological examination, transcriptomic profiling, and multi-cytokine analyses were integrated to identify potential underlying pathogenic mechanisms. Functional assays were performed to assess the potential role of chemotactic signaling in the over recruitment of monocytes in vascular injury and inflammation. Results Diffuse alveolar capillary damage (DACD) and diffuse alveolar hemorrhage (DAH) were identified as the most typical and fatal histopathological features of MDA5+DM RP-ILD. Affected lungs exhibited extensive perivascular infiltration of myeloid cells, predominantly monocytes expressing high levels of pro-inflammatory cytokines. In vitro, these monocytes induced endothelial injury. In vivo, monocyte depletion or genetic deletion of CXCR1 or CXCR2 markedly reduced pulmonary monocyte and neutrophil infiltration, mitigated pristane-induced DAH, and restored lung function. These findings identify CXCR signaling-mediated monocyte chemotaxis as a central mechanism of vascular injury in MDA5+DM RP-ILD. Conclusion MDA5+DM-associated RP-ILD is characterized by DACD and DAH as its defining pathological features. Aberrant CXCR-driven monocyte recruitment underlies vascular injury and disease progression, providing mechanistic insight and potential therapeutic targets for this devastating condition. This abstract is funded by: This study was supported by National Natural Science Foundation of China (8240010395); Development Center for Medical Science Shanghai Municipal Health Commission (2023ZZ02025); Natural Science Foundation of Shanghai (24YF2735300); The National Key Research and Development Program of China (2024YFC3044600); Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0529005); Tongji University Cross disciplinary Research Project 2025 (TJ-FK-YXJC010).
Hu et al. (Fri,) studied this question.