Evaluating the fibroproliferative response to ventilator-induced lung injury

Introduction

Acute lung injury (ALI), and its more severe subset acute respiratory distress syndrome (ARDS), are a major cause of mortality in the ICU [1]. Mechanical ventilation, a supportive therapy necessary to sustain life in many cases, may contribute to and worsen ALI, termed ventilator-induced lung injury (VILI). Fibroproliferation is an early response to lung injury [2]. Indeed, dysregulated repair resulting in pulmonary fibrosis may be at the heart of ventilator dependence in ARDS. Characterising the role of excessive lung stretch in contributing to aberrant repair mechanisms would assist in developing strategies to hasten recovery from ARDS.

Methods

Male Sprague-Dawley rats were anaesthetized, orotracheally intubated and subjected to injurious ventilation until a defined worsening of compliance was noted. The rats were then recovered and extubated. The level of ongoing injury/repair was characterised at time periods of 6, 24 and 48 hours and at 4, 7 and 14 days. Systemic oxygenation, lung compliance, wet/dry ratio, BAL total protein, cytokines and cell count and histological analysis was carried out at each time point.

Results

The results demonstrated a time-course-dependent improvement in compliance and oxygenation, together with clearance of neutro philic infiltration at 96 hours. TNFα, and IL-1β, IL-6 and IL-10 were significantly elevated in BAL fluid early post injury. Although total lung collagen remained similar at all time points, evidence of an early fibroproliferative response was present in the form of transforming growth factor-β activation and pro-collagen I and III peptide mRNA levels. Matrix metalloproteinase 3 and 9 zymography demonstrated increased levels of these matrikines. Histologic assessment of injury revealed increased alveolar tissue fraction up to and including 96 hours post injury. Myofibroblasts were present in α-smooth muscle actin stained sections in significantly increased numbers post injury.

Conclusions

This rat model of repair of VILI demonstrates some of the mechanisms by which excessive lung stretch can contribute to fibroproliferation in ARDS and will serve to improve our knowledge of aberrant lung tissue remodelling as well as provide a useful paradigm for testing strategies to hasten recovery in ALI.