The response to recruitment worsens with progression of lung injury and fibrin accumulation in a mouse model of acid aspiration

Abstract

Reopening the injured lung with deep inflation (DI) and positive end-expiratory pressure (PEEP) likely depends on the duration and severity of acute lung injury (ALI), key features of which include increased alveolar permeability and fibrin accumulation. We hypothesized that the response to DI and PEEP would worsen as ALI evolves and that this would correspond with increasing accumulation of alveolar fibrin. C57BL/6 mice were anesthetized and aspirated 75 microl of HCl (pH 1.8) or buffered normal saline. Subgroups were reanesthetized 4, 14, 24, and 48 h later. Following DI, tissue damping (G) and elastance (H) were measured periodically at PEEP of 1, 3, and 6 cmH(2)O, and air within the lung (thoracic gas volume) was quantified by microcomputed tomography. Following DI, G and H increased with time during progressive lung derecruitment, the latter confirmed by microcomputed tomography. The rise in H was greater in acid-injured mice than in controls (P < 0.05) and also increased from 4 to 48 h after acid aspiration, reflecting progressively worsening injury. The rise in H was reduced by PEEP, but this effect was significantly blunted by 48 h (P < 0.05), also confirmed by thoracic gas volume. Lung permeability and alveolar fibrin also increased over the 48-h study period, accompanied by increasing levels and transcription of the fibrinolysis inhibitor plasminogen activator inhibitor-1. Lung injury worsens progressively in mice during the 48 h following acid aspiration. This injury manifests as progressively increasing alveolar instability, likely due to surfactant dysfunction caused by increasing levels of alveolar protein and fibrin.

Neither fibrin nor plasminogen activator inhibitor-1 deficiency protects lung function in a mouse model of acute lung injury

“…The importance of PAI-1 in ALI is further underscored by the finding that elevated plasma and edema fluid levels of PAI-1 are associated with higher mortality in ALI patients (45,61). In agreement with the widely speculated role for PAI-1 and fibrin in the impairment of lung function in ALI, we demonstrated that progressive derangement in lung mechanics over 48 h in mice with acid aspiration injury corresponds with an increase in air space PAI-1 and fibrin (5). Although implied by our findings, the direct roles of fibrin accumulation and its clearance, as governed by PAI-1, in the derangement of in vivo lung mechanical function has yet to be firmly established.…”

“…Immediately before anesthesia, mice received a tail vein injection with a 2.5 mg/ml solution of FITC-labeled dextran (4,000 Da; Sigma Chemical, St. Louis, MO) at a dose of 25 mg/kg, according to a protocol previously described (5,24). Fifty microliters of BALF was later loaded on a microwell plate, excited at 485 nm, read at 528 nm, and the concentration determined from a linear dilution standard curve.…”

“…Fibrin formation and clearance in the lung are governed by the relative quantity and activity of fibrinolysis promoters such as plasminogen activators and fibrinolysis inhibitors such as plasminogen activator inhibitor-1 (PAI-1) (28). The importance of PAI-1 in ALI pathogenesis is suggested by its upregulation in various ALI models (5,7) and by the finding that PAI-1-deficient mice fail to accumulate alveolar fibrin and die less quickly in response to injury (8). The importance of PAI-1 in ALI is further underscored by the finding that elevated plasma and edema fluid levels of PAI-1 are associated with higher mortality in ALI patients (45,61).…”

High Tidal Volume Ventilation Is Not Deleterious in Infant Rats Exposed to Severe Hemorrhage

“…The linear increase in H is compatible with a progressive loss of lung volume as a result of progressive airway closure [22][23][24] that was not prevented by a PEEP of 5 cmH 2 O. In rats ventilated with low V T neither V T nor peak P ao was probably high enough to reopen atelectatic lung units and reverse the increase in H over time.…”

Lung volume recruitment maneuvers and respiratory system mechanics in mechanically ventilated mice

“…It is essential to provide information on ventilator settings in order to facilitate future studies. However, apart from specific "recruitment maneuver studies" (Allen et al, 2002;Allen et al, 2004;Frank et al, 2005;Koh et al, 2005;Farias et al, 2005;Allen et al, 2006;Allen et al, 2007;Ko et al, 2008;Jonasson et al, 2008) few experimental studies using mechanical ventilation protocols provide detailed information on application, frequency, and type of lung volume recruitment maneuvers (RMs). Given that the mechanical properties of the respiratory system are specific to the lung volume at which their measurements are made (Sly et al, 2003) and to the lung volume history , it is surprising that details of RMs are not always reported.…”