Pathophysiology of acute respiratory distress syndrome. Glucocorticoid receptor-mediated regulation of inflammation and response to prolonged glucocorticoid treatment

Abstract

Based on molecular mechanisms and physiologic data, a strong association has been established between dysregulated systemic inflammation and progression of ARDS. In ARDS patients, glucocorticoid receptor-mediated down-regulation of systemic inflammation is essential to restore homeostasis, decrease morbidity and improve survival and can be significantly enhanced with prolonged low-to-moderate dose glucocorticoid treatment. A large body of evidence supports a strong association between prolonged glucocorticoid treatment-induced down-regulation of the inflammatory response and improvement in pulmonary and extrapulmonary physiology. The balance of the available data from controlled trials provides consistent strong level of evidence (grade 1B) for improving patient-centered outcomes. The sizable increase in mechanical ventilation-free days (weighted mean difference, 6.58 days; 95% CI, 2.93 -10.23; P<0.001) and ICU-free days (weighted mean difference, 7.02 days; 95% CI, 3.20-10.85; P<0.001) by day 28 is superior to any investigated intervention in ARDS. The largest meta-analysis on the subject concluded that treatment was associated with a significant risk reduction (RR=0.62, 95% CI: 0.43-0.91; P=0.01) in mortality and that the in-hospital number needed to treat to save one life was 4 (95% CI 2.4-10). The balance of the available data, however, originates from small controlled trials with a moderate degree of heterogeneity and provides weak evidence (grade 2B) for a survival benefit. Treatment decisions involve a tradeoff between benefits and risks, as well as costs. This low cost highly effective therapy is familiar to every physician and has a low risk profile when secondary prevention measures are implemented.

Figure 1

Inflammatory cytokines and chemokines plasma levels in patients with unresolving and resolving acute respiratory distress syndrome (ARDS) Plasma inflammatory cytokine levels over time in survivors and non-survivors. Plasma TNF-α, IL-1β, IL-6 and IL-8 levels from days 1 to 10 of sepsis-induced ARDS. On day 1 of ARDS, non-survivors (n = 17) had significantly higher (P < 0.001) TNF-α, IL-1β, IL 6 and IL-8 levels. Over time, non-survivors had persistent elevation, whereas survivors (n = 17) had a rapid decline. Receiver operating curve analysis revealed that at the onset of ARDS, plasma IL-1β (Endogen, Boston, MA), TNF-α, IL-6, (Genzyme, Cambridge, MA) and IL-8 (R & D Systems, Minneapolis, MN) greater than 400 pg/mL were prognostic of death. When IL-1β values on day 1 of ARDS were categorized as either greater or lower than 400 pg/mL, high values of IL-1β were prognostic of death (relative risk = 3.75; 95% CI = 1.08–13.07) and independent of the presence of sepsis or shock, APACHE II score, cause of ARDS and MODS score. These findings indicate that loss of autoregulation is an early phenomenon.

Figure 2

Pathophysiological manifestations of dysregulated systemic inflammation in acute respiratory distress syndrome (ARDS) Dysregulated systemic inflammation leads to changes at the pulmonary and systemic levels . In the lungs, persistent elevation of inflammatory mediators sustains inflammation with resulting tissue injury, alveolar-capillary membrane permeability, intra- and extravascular coagulation in previously spared lobules and proliferation of mesenchymal cells with deposition of extracellular matrix in previously affected lobules, resulting in maladaptive lung repair. This manifests clinically with failure to improve gas exchange and lung mechanics and persistent BAL neutrophilia. Systemic manifestations include: systemic inflammatory response syndrome (SIRS) in the absence of infection, progression of MODS, positive fluid balance and increased rate of nosocomial infections. Additional morbidity attributed to elevated cytokinemia includes hyperglycemia , short- and long-term neurological dysfunction (delirium , neuromuscular weakness and posttraumatic stress disorder and sudden cardiac events in those with underlying atherosclerosis , .

Figure 3

Evolution of acute respiratory distress syndrome (ARDS): adaptive vs. maladaptive response Top: progression of the host defense response (HDR) in patients with adaptive and maladaptive repair. In the first group, the HDR is initially less severe and diminish over time allowing for restoration of anatomy and function. In the second group, the HDR is initially more severe and continues unrestrained over time leading to repeated inflammatory insults and amplification of intra- and extravascular coagulation and fibroproliferation resulting in maladaptive lung repair. Maladaptive lung repair manifest clinically, with persistent hypoxemia, failure to improve lung mechanics and prolonged mechanical ventilation. Bottom: in patients with adaptive response, with progressive reduction in NF-κB-driven TNF–α and IL–1β levels, previously spared lobules are not subjected to new insults, while previously affected lobules undergo an adaptive repair leading to restoration of anatomy and function. In patients with maladaptive response, with persistent elevation in NF-κB-driven TNF–α and IL–1β levels, previously spared lobules are now subjected to new insults and previously affected lobules undergo a maladaptive repair (unrestrained coagulation and fibroproliferation) leading to fibrosis.

Figure 4

Longitudinal relation on natural logarithmic scales between mean levels of nuclear NF-κB and nuclear GRα: resolving vs. unresolving Acute respiratory distress syndrome (ARDS) (right) and after randomization to methylprednisolone vs. placebo Left: plasma samples from patients with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GRκ-mediated activity (P = 0.04) and a progressive significant (P = 0.0001) increase in NF-κB nuclear binding over time (dysregulated, NF-κB-driven response). In contrast, in patients with regulated inflammation an inverse relationship was observed between these two transcription factors, with the longitudinal direction of the interaction shifting to the left (decreased NF-κB) and upward (increased GC-GRα). The first interaction is defined as NF-κB–driven (progressive increase in NF-κB-DNA binding and transcription of TNF-α and IL-1β) and the second interaction as GRα-driven response (progressive increase in GRα-DNA binding and transcription of IL-10). Right: longitudinal relation on natural logarithmic scales between mean levels of nuclear NF-αB and nuclear GRα observed by exposing naive PBL to plasma samples collected at randomization (rand) and after 3, 5, 7 and 10 days in the methylprednisolone (open squares) and placebo (open triangles) groups. With methylprednisolone, contrary to placebo, the intracellular relationship between the NF-κB and GRα signaling pathways changed from an initial NF-κB-driven and GR-resistant state to a GRα-driven and GR-sensitive one. It is important to compare the two figures to appreciate how methylprednisolone supplementation restored the equilibrium between activation and suppression of inflammation that is distinctive of a regulated inflammatory response.

Figure 5

Effects of prolonged glucocorticoid treatment on mechanical ventilation (top) and intensive care unit (bottom) -free days to day 28

Figure 6

Effects of prolonged glucocorticoid treatment on acute respiratory distress syndrome (ARDS) survival