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Nitrated Fatty Acids Reduce Inflammatory Cell Recruitment in Bleomycin‐Induced Lung Injury
Author(s) -
Krishnan Anirudh,
Wilkinson Melissa L.,
Gow Andrew J.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04221
Subject(s) - inflammation , bleomycin , integrin alpha m , infiltration (hvac) , chemistry , lung , cellular infiltration , pathology , medicine , immune system , endocrinology , immunology , chemotherapy , physics , thermodynamics
Acute lung injury (ALI) leads to infiltration of inflammatory cells and impaired lung function. Matrix Metalloproteinase 9 (MMP9) is a zinc‐dependent endopeptidase that degrades the extra cellular matrix and increases the porosity of the lung. CD11b is a marker for macrophage activation and migration. Nitro‐oleic fatty acid (OANO 2 ), an electrophile that reduces cardiovascular inflammation has not been examined in lung injury. OANO 2 modifies cysteine residues via Michael addition altering protein function. The goal of this study were to determine if OANO 2 administration would reduce MMP9 expression and cellular infiltration following ALI. An intratracheal bleomycin (ITB) ALI model was used. Two groups of 6 C57BL/6‐J mice were treated intratracheally with bleomycin (3U/kg) or PBS (50uL). Half of the animals received OANO 2 (50μg) in the same instillation and 72 hours later. The lungs were collected 7 days post ITB treatment. As previously seen, mice treated with ITB lost a significant amount of body weight; however, the addition of OANO 2 mitigated this loss (−2.3 +/− 0.94 vs −0.4 +/− 0.83 g). Histology revealed cellular infiltration, deposition of proteinaceous debris, and airway epithelial damage in ITB mice that was reduced with OANO 2 administration. The number of CD11b+ cells (marker for migratory macrophages) and MMP9+ cells was determined by immunohistochemistry. ITB increased number of CD11b+ (69 +/− 17.1 vs 195 +/− 17.1 #cells/HPF). OANO 2 treatment reduced CD11b+ cells most in ITB animals (121 +/− 17.1#cells/HPF). ITB increased MMP9+ cell numbers compared to controls (71 +/− 15.7 vs 124 +/− 15.7 #cells/HPF). However, MMP9 expression was increased with OANO 2 administration in PBS animals (304 +/− 15.7; 166 +/− 15.7 #cells/HPF), though this increase was not significant in ITB mice. Increased MMP9 expression was confirmed by western blot of whole lung tissue, where both ITB OANO 2 and control OANO 2 animals displayed high expression. Increased MMP9 expression may result from reduced self‐degradation as a consequence of OANO 2 mediated enzyme inhibition. Overall, OANO 2 increased MMP9+ cells and decreased CD11b+ cell populations. These findings suggest that treatment with OANO 2 may oppose ITB‐mediated pro‐inflammatory cellular activation possibly by inhibition of extracellular peptidases, making it a potential therapeutic agent for acute lung injury. Support or Funding Information Supported by the Summer Undergraduate Research Fellowship and NIH Grants: 5R25ES020721‐09 (MPI)