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  1. S.-F. Ma1,
  2. D. N. Grigoryev2,
  3. R. B. Easley3,
  4. S. Q. Ye1,
  5. B. A. Simon3,
  6. J. G N. Garcia1
  1. 1Critical Care, The University of Chicago, Chicago, IL;
  2. 2Clinical Immunology and
  3. 3Anesthesiology and Critical Care, Johns Hopkins University, Baltimore, MD


Rationale The unilateral (one lung injured and the contralateral lung intact) model of ventilator-associated lung injury (VALI) allows us to utilize uninjured lung as the systemic VALI effects indicator. We speculated that regulation of genes in uninjured lung will be attributed to blood or lymph carrying effectors produced by an injured lung and the analysis of upstream bioprocesses governed by affected genes will lead to the effectors' discovery.

Methods Dogs (n = 4) were intubated, left lung lavaged, and then both lungs were either independently ventilated (total Vt = 15 mL/kg) for 6 hours (injured and uninjured) or immediately harvested (control). Lung mRNA (n = 16 for all three groups) was hybridized to HG_U133A and analyzed by SAM using interspecies probe adjustment. Genes with the lowest false discovery rate (q = 0.124%) that imposed fold change (FC) range from -3.52 to -1.26 and 1.22 to 6.96 with corresponding FC averages -1.59 and 2.01 were considered affected by VALI. Gene ontology filtering for receptor activity term was conducted by MAPPFinder.

Results Our analyses revealed 22 receptor-related genes, of which 7 were growth factor receptors including EGFR (FC = -1.54), FGFR1 (FC = -1.59), FGFR2 (FC = -1.56), and PDGFR (FC = -1.30). The overall down-regulation of these receptors was concordant with decreased expression of their corresponding ligands in injured lung including EGF (FC = -1.39), FGF2 (FC = -1.39), PDGFA (FC = -1.41), and PDGFB (FC = -2.00). Fibroblast (Z = 6.17) and epidermal (Z = 4.49) growth factor receptor activity were the first and the third significantly (Z > 1.96) affected pathways.

Conclusions Our approaches effectively identify a class of potential biomarkers in VALI. Further investigation of this study may elucidate systemic VALI effects and facilitate the development of new diagnostic tools.

Funded by SCCOR U01 HL-073994.

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