Proteoglycan fragmentation and respiratory mechanics in mechanically ventilated healthy rats

Abstract

This research investigated whether stretching of lung tissue due to increased positive alveolar pressure swings during mechanical ventilation (MV) at various tidal volumes (V(T)) might affect the composition and/or structure of the glycosaminoglycan (GAG) components of pulmonary extracellular proteoglycans. Experiments were performed in 30 healthy rats: 1) anesthetized and immediately killed (controls, C-0); 2) anesthetized and spontaneously breathing for 4 h (C-4h); and 3) anesthetized, paralyzed, and mechanically ventilated for 4 h with air at 0-cmH(2)O end-expiratory pressure and V(T) of 8 ml/kg (MV-1), 16 ml/kg (MV-2), 24 ml/kg (MV-3), or 32 ml/kg (MV-4), adjusting respiratory rates at a minute ventilation of 270 ml/min. Compared with C-0 and C-4h, a significant reduction of dynamic and static compliance of the respiratory system and of the lung was observed only in MV-4, while extravascular lung water significantly increased in MV-3 and MV-4, but not in MV-1 and MV-2. However, even in MV-1, MV induced a significant fragmentation of pulmonary GAGs. Extraction of covalently bound GAGs and wash out of loosely bound or fragmented GAGs progressively increased with increasing V(T) and was associated with increased expression of local (matrix metalloproteinase-2) and systemic (matrix metalloproteinase-9) activated metalloproteases. We conclude that 1) MV, even at "physiological" low V(T), severely affects the pulmonary extracellular architecture, exposing the lung parenchyma to development of ventilator-induced lung injury; and 2) respiratory mechanics is not a reliable clinical tool for early detection of lung injury.

Oxygen Increases Lung Inflammatory Response in Spontaneous One-Lung Ventilation in Rabbits: A Prospective Randomized Experimental Study

“…This fact confirms the tendency of OLV is prone to the occurrence of acute lung injury in spontaneous breathing subjects [14], reinforced by evidence that near physiologic tidal volumes may also be somehow harmful [17].…”

Role of the extracellular matrix in the genesis of ventilator-induced lung injury

“…Some authors have shown that ventilation under physiologic tidal volumes (6-8 ml/kg) for a few hours induces proteoglycan fragmentation from the alveolar septa, which is not associated with activation of systemic or tissue MMPs, lung edema, inflammation, or collagen fiber deposition [2,6].…”

“…On the other hand, Al Jamal et al showed that extremely high VT (30 ml/kg) and high respiratory rate (90 breaths/minute) induce the expression of versican (CS-PG), basement membrane HS-proteoglycan (HS-PG), and biglycan in lung tissue [16]. Moriondo et al also observed CS and HS fragmentation at high VT [6] and showed that the fluid overload associated with high-VT mechanical ventilation worsened GAG fragmentation, mainly in the ventral lung regions [13].…”

“…MV with physiologi-cal VT induces increased expression and activity of MMP-2 and MMP-9 over time [13], while high VT induces increased expression and release of MMPs by macrophages and epithelial and endothelial cells in response to mechanical stress [6]. Moreover, Foda et al observed that MMPs play an important role in the development of VILI in an in vivo rat model of high-volume ventilation [19].…”

“…Ventilation with high VT and airway pressure, as well as transpleural gradients, initiates ECM remodeling [6]. Berg et al found that high lung inflation due to high PEEP levels increased mRNA expression of procollagen, fibronectin, and profibrogenic growth factors [24].…”