B75-06 MCEMP1 Identifies a Cross-Species Inflammatory Signature Associated With Mortality in Human and Experimental ARDS

Abstract Rationale Acute respiratory distress syndrome (ARDS) is a severe form of respiratory failure characterized by hypoxemia and non-cardiogenic pulmonary edema, often resulting from pneumonia, aspiration, trauma, or transfusion. Despite advances in care, mortality remains high (35–45%, up to 75% in COVID-19–related ARDS). We previously identified mast cell–expressed membrane protein 1 (MCEMP1) as a gene associated with increased mortality in Idiopathic Pulmonary Fibrosis, but its role in ARDS remains unclear. Methods Human gene expression and clinical data were analyzed from three independent COVID-19 cohorts (total N = 309): (1) discovery cohort (N = 100; bulk leukocyte RNA-seq, GEO GSE157103) ; (2) COVID-19 validation cohort (USF/TGH, N = 141; MCEMP1 by qRT-PCR from peripheral mononuclear cells PBMCs) ; and (3) COVID delta variant cohort (USF/TGH, N = 68; whole-blood expression via nCounter Analysis System). qRT-PCR cycle threshold (Ct) values were normalized to reference genes and expressed as transcript units (2^–ΔCt). NanoString data were log-transformed and presented as log2 fold change (FC). Gene expression analysis was performed to assess MCEMP1 regulation in experimental and clinical ARDS. Transcriptomic datasets from lung tissues derived from preclinical ARDS models with rat and porcine exposure to lipopolysaccharide (LPS) and ventilator-induced lung injury (VILI) were analyzed using DEseq2 normalized mRNA counts, defining differential expression by |log2 fold change| ≥ 1 and false discovery rate (FDR) 0. 05. Results In the human discovery cohort, MCEMP1 expression dichotomized by the median revealed markedly different survival outcomes: 96% survival in the low-expression group versus 56% in the high-expression group (P= 3 ×10−6 Fisher’s exact test). These findings were replicated in the USF/TGH validation and COVID delta variant cohorts, where lower MCEMP1 expression was again associated with improved survival (92. 8% vs. 73. 2%; P=0. 003 and 70. 5% vs. 20. 5%; P = 3. 9 × 10−6, respectively). In the rat LPS/VILI ARDS model, MCEMP1 (ENSRNOG00000028259) showed a log2 fold change of 0. 86 (Q = 4. 48 × 10−6). In the porcine model, MCEMP1 was significantly upregulated (log2 fold change=2. 59; Q = 7. 68 × 10−4), ranking among the top 100 differentially expressed genes (FC ≥ 2. 5, FDR0. 005). Conclusions MCEMP1 expression is upregulated in human COVID-19 ARDS is associated with increased mortality across independent cohorts. Consistent with these findings, elevated MCEMP1 lung tissue expression in both rat and porcine ARDS/VILI models, supporting a role for MCEMP1 expression as a robust cross-species biomarker of inflammatory and mechanical ventilation-induced lung injury. MCEMP1 is a novel and potential therapeutic target for mechanistic studies of macrophage-driven pathways contributing to ARDS pathogenesis. This abstract is funded by: Ubben Family Fund