The fibroproliferative response in acute respiratory distress syndrome: mechanisms and clinical significance

Abstract

Acute respiratory distress syndrome (ARDS) continues to be a major healthcare problem, affecting >190,000 people in the USA annually, with a mortality of 27-45%, depending on the severity of the illness and comorbidities. Despite advances in clinical care, particularly lung protective strategies of mechanical ventilation, most survivors experience impaired health-related quality of life for years after the acute illness. While most patients survive the acute illness, a subset of ARDS survivors develops a fibroproliferative response characterised by fibroblast accumulation and deposition of collagen and other extracellular matrix components in the lung. Historically, the development of severe fibroproliferative lung disease has been associated with a poor prognosis with high mortality and/or prolonged ventilator dependence. More recent studies also support a relationship between the magnitude of the fibroproliferative response and long-term health-related quality of life. The factors that determine which patients develop fibroproliferative ARDS and the cellular mechanisms responsible for this pathological response are not well understood. This article reviews our current understanding of the contribution of pulmonary dysfunction to mortality and to quality of life in survivors of ARDS, the mechanisms driving pathological fibroproliferation and potential therapeutic approaches to prevent or attenuate fibroproliferative lung disease.

Conflict of interest statement

Conflict of interest: None declared.

Figures

FIGURE 1

High-resolution computed tomography image of the base of the lungs of an actue respiratory distress syndrome survivor demonstrating persistent reticular changes in the lungs and traction bronchiectasis 18 months after the acute illness.

FIGURE 2

Mechanisms driving fibroproliferation in acute respiratory distress syndrome. Characteristic alterations related to lung injury evolve over time, and may be influenced by a variety of environmental and patient-specific factors. In response to alveolar–capillary injury, a provisional extracellular matrix (ECM) is ultimately formed to promote repair, and proteinaceous pulmonary oedema fluid is cleared from the alveolar space. The provisional ECM largely resolves after restoration of lung architecture; however, a subset of patients will not clear the provisional ECM and exhibit evidence of exuberant fibroproliferation with fibrosis lasting from months to years after the acute event. Bold type represents major “activity” at this time point. AT: angiotensin; TGF: transforming growth factor; IGF: insulin-like growth factor; PDGF: platelet-derived growth factor; FGF: fibroblast growth factor; KGF: keratinocyte growth factor; PGE: prostaglandin E; HGF: hepatocyte growth factor; MMP: matrix metalloproteinases; TIMP: tissue inhibitor of metalloproteinase; PFT: pulmonary function test; HRCT: high-resolution computed tomography.