Abstract
BackgroundDiaphragmatic dysfunction found in the patients with acute lung injury required prolonged mechanical ventilation. Mechanical ventilation can induce production of inflammatory cytokines and excess deposition of extracellular matrix proteins via up-regulation of transforming growth factor (TGF)-β1. Lumican is known to participate in TGF-β1 signaling during wound healing. The mechanisms regulating interactions between mechanical ventilation and diaphragmatic injury are unclear. We hypothesized that diaphragmatic damage by short duration of mechanical stretch caused up-regulation of lumican that modulated TGF-β1 signaling.MethodsMale C57BL/6 mice, either wild-type or lumican-null, aged 3 months, weighing between 25 and 30 g, were exposed to normal tidal volume (10 ml/kg) or high tidal volume (30 ml/kg) mechanical ventilation with room air for 2 to 8 hours. Nonventilated mice served as control groups.ResultsHigh tidal volume mechanical ventilation induced interfibrillar disassembly of diaphragmatic collagen fiber, lumican activation, type I and III procollagen, fibronectin, and α-smooth muscle actin (α-SMA) mRNA, production of free radical and TGF-β1 protein, and positive staining of lumican in diaphragmatic fiber. Mechanical ventilation of lumican deficient mice attenuated diaphragmatic injury, type I and III procollagen, fibronectin, and α-SMA mRNA, and production of free radical and TGF-β1 protein. No significant diaphragmatic injury was found in mice subjected to normal tidal volume mechanical ventilation.ConclusionOur data showed that high tidal volume mechanical ventilation induced TGF-β1 production, TGF-β1-inducible genes, e.g., collagen, and diaphragmatic dysfunction through activation of the lumican.
Highlights
Acute lung injury (ALI) and its most severe manifestation, acute respiratory distress syndrome (ARDS), are inhomogeneous lung diseases characterized by the initial diffuse inflammatory reactions, neutrophil influx into the lungs, loss of epithelial and endothelial integrity, the development of noncardiogenic pulmonary edema and is followed by fibroblast proliferation and extracellular matrix accumulation [1,2,3]
In high tidal volume ventilation-induced diaphragmatic injury model in mice, we examined the relationships between different tidal volume of mechanical ventilation, transforming growth factor (TGF)-b1-inducible genes, and TGF-b1 production using the lumican deficient mice
Disruptions of diaphragmatic collagen fiber and increase of interfibrillar spacing were observed in mice subjected to high tidal volume mechanical ventilation for 8 hours as compared to that of control, nonventilated mice (Figure 1)
Summary
Acute lung injury (ALI) and its most severe manifestation, acute respiratory distress syndrome (ARDS), are inhomogeneous lung diseases characterized by the initial diffuse inflammatory reactions, neutrophil influx into the lungs, loss of epithelial and endothelial integrity, the development of noncardiogenic pulmonary edema and is followed by fibroblast proliferation and extracellular matrix accumulation [1,2,3]. Mechanical ventilation has been shown to increase diaphragmatic injury (VIDD: ventilator-induced diaphragmatic dysfunction) associated with the increase of protein oxidation and inflammatory cytokines such as macrophage inflammatory protein-2 (MIP-2), interferon (IFN) c-inducible protein of 10 kD (IP-10), and transforming growth factor (TGF)-b1 [5,6,7]. Diaphragmatic dysfunction found in the patients with acute lung injury required prolonged mechanical ventilation. Mechanical ventilation can induce production of inflammatory cytokines and excess deposition of extracellular matrix proteins via up-regulation of transforming growth factor (TGF)-b1. The mechanisms regulating interactions between mechanical ventilation and diaphragmatic injury are unclear. We hypothesized that diaphragmatic damage by short duration of mechanical stretch caused up-regulation of lumican that modulated TGF-b1 signaling
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