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DNA‐Dependent Protein Kinase Inhibition Prevents Manifestation of Acute Lung Injury in Mice, a Novel Target Associated with Th1 Type Disease
Author(s) -
Pyakurel Kusma,
Ghonim Mohamed,
Ibba Salome,
Tarhuni Abdelmetalab,
Wang Jeffery,
Boulares Hamid
Publication year - 2016
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.30.1_supplement.1202.4
Subject(s) - myeloperoxidase , pulmonary edema , medicine , lung , ards , diffuse alveolar damage , immunology , cytokine , pathology , pharmacology , inflammation , acute respiratory distress
Background The acute respiratory distress syndrome (ARDS), a clinical complication of severe acute lung injury (ALI) in humans, is a leading cause of morbidity and mortality in critically ill patients. ALI is characterized by disruption of the lung alveolar‐capillary membrane barrier and resultant pulmonary edema associated with a proteinaceous alveolar exudates which is explained by injury to both the vascular endothelium and alveolar epithelium. We previously reported that DNA‐dependent Protein Kinase (DNA‐PK) inhibition prevents in‐vitro differentiation of T‐helper 1(Th1) cells and Th1 specific cytokine production under Th1 skewing condition. Materials and methods LPS‐induced ALI, Th1 type, murine disease model was used. Wild‐type or DNA‐PK heterzygous animals were anesthetized using i.p administration of xylazine/ketamine after which 10mg/kg LPS was intratracheally administered. Some group of mice received 5mg/kg of DNA‐PK inhibitor, NU 7441, 30 min after LPS administration. Cytospin and subsequent diff‐quick staining, myeloperoxidase assay, cytokine analysis and recording of dry and wet lung weights were performed. Results Administration of DNA‐PK inhibitor, NU 7441, reduced production of inflammatory cytokines in the broncheoalveolar lavage fluid (BALF). Such effects correlated with a marked reduction in inflammatory cells such macrophages, neutrophils and lymphocytes in the lungs. Reduction in myeloperoxidase expression in lung homogenates in NU 7441 treated groups further confirmed the inhibition of neutrophils recruitment in the lungs. Furthermore, administration of NU 7441 reduced pulmonary edema in the mice, as measured by lung water retention volume (wet to dry weight ratio). DNA‐PK heterozygosity also prevented manifestation of ALI symptoms similar to those observed in NU 7441 treated animals. Conclusion DNA‐PK plays a critical role in ALI and, therefore, may constitute a novel therapeutic target for the treatment of the disease. Support or Funding InformationSupport: NIH; AHA; LCRC funds