Mechanical ventilation-associated lung fibrosis in acute respiratory distress syndrome: a significant contributor to poor outcome

Abstract

One of the most challenging problems in critical care medicine is the management of patients with the acute respiratory distress syndrome. Increasing evidence from experimental and clinical studies suggests that mechanical ventilation, which is necessary for life support in patients with acute respiratory distress syndrome, can cause lung fibrosis, which may significantly contribute to morbidity and mortality. The role of mechanical stress as an inciting factor for lung fibrosis versus its role in lung homeostasis and the restoration of normal pulmonary parenchymal architecture is poorly understood. In this review, the authors explore recent advances in the field of pulmonary fibrosis in the context of acute respiratory distress syndrome, concentrating on its relevance to the practice of mechanical ventilation, as commonly applied by anesthetists and intensivists. The authors focus the discussion on the thesis that mechanical ventilation-or more specifically, that ventilator-induced lung injury-may be a major contributor to lung fibrosis. The authors critically appraise possible mechanisms underlying the mechanical stress-induced lung fibrosis and highlight potential therapeutic strategies to mitigate this fibrosis.

Figure 1

Histologic findings of hematoxylin-eosin staining at open-lung biopsy in a patient with acute respiratory distress syndrome. The photomicrograph shows myxoid fibrosis, fibroblastic and inflammatory cell infiltration of the interstitium, and scattered collapsed alveoli (A) and subintimal deposition of loose myxoid collagen in an arteriole (B). Reproduced, with permission, from the American College of Chest Physicians and adapted from Meduri GU et al. Chest 1994; 105:1516–27

Figure 2

Mechanical stretch impairs alveolar epithelial integrity. The alveolar epithelial tight junction is consists of several constituents of connected proteins. Occludin is a transmembrane protein known to be associated with F-actin, either directly or indirectly modulating the tight junction structure. Mechanical stretch of alveolar epithelial cells can result in loss of tight junction structure and cell–cell attachment associated with decrease in the expression or increase in degradation of occluding and actin perturbations. The actin cytoskeleton remodeling plays an important role in fibrosis formation in the lung. ATI = alveolar type I; ATII = alveolar type II.

Figure 3

Mechanical stretch causes inflammatory responses associated with release of mediators that can worsen lung injury leading to “biotrauma.” Mechanical stretch of alveoli results in increased expression of small fragment hyaluronan (sHA) and activation of cytoplasmic proline-rich tyrosine kinase- 2 (PyK2); polymorphonuclear leukocyte (PMN) infiltration that release soluble mediators such as cytokines and platelet-derived growth factor (PDGF); increased production of extracellular matrix (ECM) proteins including transforming growth factor- β1 (TGF-β1), collagen, elastin, fibronectin laminin, lumican, proteoglycan, and glycosaminoglycans. During the exudative phase of acute respiratory distress syndrome, the influx of T regulatory cells (Treg) may play a critical role in the crosstalk between innate and adaptive immune systems that normally would modulate the transition from injury to repair in resolving lung injury. ATI = alveolar type I; ATII = alveolar type II.

Figure 4

Proposed cell sources of mechanical ventilation– associated lung fibrosis in acute respiratory distress syndrome. Mechanical stretch of alveoli results in (1) increased circulating fibrocytes recruitment into the lung by chemokines, contributing to local fibrosis formation; (2) accelerated fibroproliferation so that resident fibroblasts can proliferate and participate in the lung repair process; and (3) epithelial– mesenchymal transition (EMT) whereby epithelial cells undergo transition to a mesenchymal phenotype in the process of epithelial repair following injury. ECM = extracellular matrix

Figure 5

Potential mechanisms of mesenchymal stromal cells (MSCs) in the lung repair process in acute respiratory distress syndrome. MSCs exert a number of properties to enhance repair and restoration of physiologic function after ventilator- induced lung injury. The effects seem to be paracrine mediated and dependent in part on keratinocyte growth factor produced by the stromal cells. The bone marrow–derived MSC could transfer their mitochondria into lung epithelial cells resulting in increased alveolar adenosine triphosphate concentrations and enhanced cellular bioenergetics and improved lung function. The MSC may also be able to differentiate into alveolar type I (ATI) and type II (ATII) epithelial cells.