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Impact of Low and High Tidal Volumes on the Rat Alveolar Epithelial Type II Cell Proteome

¹ Cardiovascular Research Institute, ² Department of Anesthesia and Perioperative Care, and ³ Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to Jan Hirsch, M.D., Cardiovascular Research Institute, University of California, San Francisco, 505 Parnassus Avenue, HSW 825, San Francisco, CA 94143-0130. E-mail: jhirsch{at}itsa.ucsf.edu

Rationale: Mechanical ventilation with high tidal volumes leads to increased permeability, generation of inflammatory mediators, and damage to alveolar epithelial cells (ATII).

Objectives: To identify changes in the ATII proteome after two different ventilation strategies in rats.

Methods: Rats (n = 6) were ventilated for 5 hours with high- and low tidal volumes (VTS) (high VT: 20 ml/kg; low VT: 6 ml/kg). Pooled nonventilated rats served as control animals. ATII cells were isolated and lysed, and proteins were tryptically cleaved into peptides. Cellular protein content was evaluated by peptide labeling of the ventilated groups with ¹⁸O. Samples were fractionated by cation exchange chromatography and identified using electrospray tandem mass spectrometry. Proteins identified by 15 or more peptides were statistically compared using t tests corrected for the false discovery rate.

Measurements and Main Results: High VT resulted in a significant increase in airspace neutrophils without an increase in extravascular lung water. Compared with low-VT samples, high-VT samples showed a 32% decrease in the inositol 1,4,5-trisphosphate 3 receptor (p < 0.01), a 34% decrease in Na⁺, K⁺-ATPase (p < 0.01), and a significantly decreased content in ATP synthase chains. Even low-VT samples displayed significant changes, including a 66% decrease in heat shock protein 90- (p < 0.01) and a 67% increase in mitochondrial pyruvate carboxylase (p < 0.01). Significant differences were found in membrane, acute phase, structural, and mitochondrial proteins.

Conclusions: After short-term exposure to high-VT ventilation, significant reductions in membrane receptors, ion channel proteins, enzymes of the mitochondrial energy system, and structural proteins in ATII cells were present. The data supports the two-hit concept that an unfavorable ventilatory strategy may make the lung more vulnerable to an additional insult.

Key Words: acute lung injury • alveolar epithelium • corticosterone

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Mechanical ventilation with high tidal volumes leads to increased permeability, generation of inflammatory mediators, and damage to alveolar epithelial cells that may contribute to ventilator-induced lung injury. What This Study Adds to the Field Using a proteomic approach, significant reductions of key proteins in alveolar type II cells from rats were identified after short-term positive-pressure ventilation.

 

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