Dimethyl Malonate Protects the Lung in a Murine Model of Acute Respiratory Distress Syndrome

Details

• Alternative Title:
  J Trauma Acute Care Surg
• Personal Author:
  Taghavi, Sharven ; Campbell, Alexandra ; Engelhardt, David ; Duchesne, Juan ; Shaheen, Farhana ; Pociask, Derek ; Kolls, Jay ; Jackson-Weaver, Olan
• Description:
  Introduction:
  
  Succinate is a pro-inflammatory citric acid cycle metabolite that accumulates in tissues during pathophysiological states. Oxidation of succinate after ischemia-reperfusion leads to reversal of the electron transport chain and generation of reactive oxygen species. Dimethyl malonate (DMM) is a competitive inhibitor of succinate dehydrogenase, which has been shown to reduce succinate accumulation. We hypothesized that DMM would protect against inflammation in a murine model of ARDS.
  
  Methods:
  
  C57BL/6 mice were given ARDS via 67.7 ug of intra-tracheally administered lipopolysaccharide (LPS). DMM (50 mg/kg) was administered via tail vein injection 30 minutes after injury, then daily for 3 days. The animals were sacrificed on day 4 after bronchoalveolar lavage (BAL). BAL cell counts were performed to examine cellular influx. Supernatant protein was quantified via Bradford protein assay. Animals receiving DMM (n=8) were compared to those receiving sham injection (n=8). Cells were fixed and stained with FITC-labelled wheat germ agglutinin to quantify the endothelial glycocalyx (EGX).
  
  Results:
  
  Total cell counts in BAL was less for animals receiving DMM (6.93 × 106 vs. 2.46 × 106, p=0.04). The DMM group had less BAL macrophages (168.6 vs. 85.1, p=0.04) and lymphocytes (527.7 vs. 248.3; p=0.04). DMM treated animals had less protein leak in BAL than sham treated (1.48 vs. 1.15 ug/ul, p=0.03). Treatment with DMM resulted in greater staining intensity of the EGX in the lung when compared to sham (12,016 vs. 15,186 Arbitrary Units, p=0.03). Untreated animals had a greater degree of weight loss than treated animals (3.7% vs. 1.1%, p=0.04). DMM prevented the upregulation of MCP-1 (1.66 vs. 0.92 RE, p=0.02) and ICAM-1 (1.40 vs. 1.01 RE, p=0.05).
  
  Conclusions:
  
  DMM reduces lung inflammation and capillary leak in ARDS. This may be mediated by protection of the EGX and inhibition of MCP-1 and ICAM-1. DMM may be a novel therapeutic for ARDS.
  
  
• Subjects:
  Animals Chemokine CCL2 Disease Models, Animal Intercellular Adhesion Molecule-1 Lung Malonates Mice Mice, Inbred C57BL Respiratory Distress Syndrome Succinates
• Source:
  J Trauma Acute Care Surg. 96(3):386-393
• Pubmed ID:
  37934622
• Pubmed Central ID:
  PMC10922501
• Document Type:
  Journal Article
• Funding:
  R35 HL139930/HL/NHLBI NIH HHSUnited States/ ; U01 CE003384/CE/NCIPC CDC HHSUnited States/
• Volume:
  96
• Issue:
  3
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:3386b73be3c0e890f65fc539d330919f6b60c144aa418e26d60513cf44700010ae453eaa1a609dfe8d35b54a59d42e399d07582b30647bd61c01aceb7a189fc3
• Download URL:
  https://stacks.cdc.gov/view/cdc/151628/cdc_151628_DS1.pdf
• File Type:
  [PDF - 1.24 MB ]