Acute respiratory distress syndrome (ARDS) continues to be a major healthcare

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. 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 armadillo 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. Diminished quality of life in acute respiratory distress syndrome survivors Since the initial description of the acute respiratory distress syndrome (ARDS) by Ashbaugh in 1967 [1] the overall mortality associated with the disorder has decreased [2 3 Multicentre randomised clinical trials have been a major driver of this improvement fostering advances such as the use of positive end-expiratory pressure (PEEP) [4] low tidal volume ventilation [5] and conservative fluid management [6]. Although these interventions have resulted in improved survival and reduced time spent on mechanical ventilation it is increasingly recognised that a substantial proportion of ARDS survivors continue to suffer from reduced health-related quality of life (HRQoL) that lasts for months to years (24S)-24,25-Dihydroxyvitamin D3 [7-12]. While recent investigations have drawn attention to extrapulmonary complications of ARDS such as depression and neuromuscular weakness residual pulmonary dysfunction has been largely discounted as a significant contributing factor to diminished HRQoL. Indeed the prevailing opinion among ARDS experts in the current era of lung protective (24S)-24,25-Dihydroxyvitamin D3 (24S)-24,25-Dihydroxyvitamin D3 mechanical ventilation is that the prevalence of persistent pulmonary impairment in ARDS survivors has decreased. However perusal of available data suggests that pathological fibroproliferation in the lung (24S)-24,25-Dihydroxyvitamin D3 continues to play a critical role in both short-term and longer-term outcomes in ARDS patients. Understanding the clinical relevance of profibrotic activity in ARDS and predicting which patients are at risk of the development of excessive fibroproliferation will pave the way for the identification of novel therapies that can target specific pathways involved in maintenance and restoration of normal lung architecture. Persistent pulmonary dysfunction in the low tidal volume era The most current data assessing the prevalence of pulmonary dysfunction among ARDS survivors arise from four independent cohorts in which pulmonary function tests (PFTs) were performed 6 months to 5 years after intensive care unit (ICU) discharge [7-13]. These studies each demonstrated median values for forced vital capacity (FVC) forced expiratory volume in 1 s (FEV1) total lung capacity (TLC) and (24S)-24,25-Dihydroxyvitamin D3 diffusion capacity of the lung for carbon monoxide (>80% predicted). However for each parameter values in the lowest quartile were consistently below normal [8 10 12 13 Notably in one study over half of the survivors had impairments in at least one of these parameters [11]. Importantly decrements in lung function changed little after the first year and even 5 years after discharge subjects in the lowest quartile of one study displayed a persistently reduced FEV1 FVC TLC residual volume and standardised questionnaires have been explored [10 12 Heyland [10] observed a modest association between lower FVC and FEV1 and poorer scores on the physical component subtotal (24S)-24,25-Dihydroxyvitamin D3 of the 36-item short form health survey (SF-36) (ρ>0.5 for comparisons) as well as the St George’s Respiratory Questionnaire (SGRQ) (ρ>0.4 for comparisons). Similar associations between FVC FEV1 [12]. However in most ARDS survivor investigations respiratory-specific questionnaires such as the SGRQ [14] have been performed much less frequently than questionnaires that assess global health and wellbeing such as the SF-36 [15] where responses may be influenced by respiratory as well as neuromuscular symptoms. Moreover the fact that a sizable percentage of ARDS survivors have a significantly diminished 6 min walk distance [8 9 11 further suggests that both neuromuscular.