Disease Focus

Acute Respiratory Distress Syndrome

Acute Lung Injury/Acute Respiratory Distress Syndrome:

  Acute lung injury (ALI), a devastating inflammatory lung syndrome characterized by diffuse alveolar infiltration, hypoxemia, and respiratory failure, develops via a variety of local and systemic insults such as sepsis, pneumonia, and trauma from mechanical ventilation, an intervention strategy commonly used in the ICU to treat ALI, but potentially exacerbating ALI.  The hallmarks for ALI are profound inflammation, deranged alveolar capillary permeability, leukocyte extravasation, and spatial heterogeneity lung edema which are contributing factors for death due to multi-organ dysfunction.  ALI, and its most severe form, acute respiratory distress syndrome (ARDS), accounts for approximately 190,000 cases per year in the United States and an incidence of 17–34 cases/100,000 people per year in Europe, Australia, and other developed countries.  Thus, ALI and ARDS constitute a major healthcare burden due to the intensive and often prolonged intensive care unit (ICU) hospitalizations. Only a subset of individuals exposed to potential ALI-inciting insults develop the disorder, but with a mortality rate of 34–58%, the severity of the disease varies from complete resolution to death.  In addition, ALI susceptibility and severity are also affected by ethnicity as evident by the higher mortality rate in African-American ALI patients than those belonging to other ethnic groups in the United States.

Genetics and Genomics of ALI/ARDS:

  A lingering issue of concern for critical care physicians has been the enormous heterogeneity in the outcomes observed in the care of the ALI/ARDS patient, in which some ventilated ARDS patients recover quickly with rapid extubation, whereas other ARDS patients progress to multiorgan failure and death. Recent genetic associations strongly suggest that genetic variations, or gene polymorphisms, contribute to ALI susceptibility and severity in a racial- and ethnic-specific manner in which African-Americans are particularly susceptible.  One particular important challenge in the search for susceptibility genes on ALI and ventilation-associated lung injury (VALI), is that ALI does not affect families and/or pedigrees are not available.  Linkage mapping, a strategy involving the scanning of entire family genomes and a method proven useful in asthma and chronic obstructive pulmonary disease (COPD) genetic epidemiology studies, has the advantage of not requiring prior knowledge of the biology underlying an illness; this is a feature especially important in complex disorders such as sepsis and ALI.  However, this approach has the disadvantage of requiring large families with both affected and unaffected individuals. Thus the use of linkage studies for identifying those genetic variants (alleles) that are shared by affected family members more frequently than would be expected based on chance are significantly limited in human ALI populations.

Table 1. Acute Lung Injury Candidate Gene List

ABL1

Fra1

MIF

S1P Lyase

ACE

GADD45a

MYLK

SphK 1

AKT

GST1

MYPT

SphK 2

AQP1

HSP70

NRF2

SPB

C5AR

IL1RA

PAI1

SPC

CD14

IL-6

PBEF

TLR4

COX

ITB4

Rac

TNFa

EMS1

LBP

S1P1

TSP1

FCGR2A

c-Met

S1P3

VEGFR2

Approach for Identifying Disease-Modifying Genes:

  For the reasons cited above, we chose to utilize a candidate gene approach, a strategy that can be performed using unrelated cases and controls, to identify ALI disease-modifying genes. Complementing the linkage studies described above, the candidate gene approach generates a disease-specific candidate gene list via extensive microarray gene profiling as well as by the analysis of relevant pathophysiological pathways.  We have focused our studies on unraveling the genetic underpinnings of this syndrome utilizing a candidate gene approach to identify novel genes for ALI susceptibility (Table 1).  Additional translational bench to bedside genomic and genetic strategies approaches combined with dissection of basic mechanisms of endothelial structure/function during inflammation, will lead to greater specificity in advancing clinical trials of agents for the treatment of inflammatory lung injury in a manner which represents personalized medicine for critically ill individuals.

Prognostic Indicators and Biomarkers of ALI/ARDS:

  Various molecules participating in the activation of inflammation in ALI serve as indicators for the progression of normal to pathological biological processes, providing important tools to detect disease and support diagnostic and therapeutic decisions.  Ideally, vascular biomarkers have strong correlation between their presence/absence of a disease state and clinical outcome and provide predictive points of intervention to slow or reverse the disease.  Furthermore, the indication of specific biomarker may allow for customized therapies that are more effective in different phase of the disease.  New research and novel understanding of the molecular mechanisms of ALI have revealed an abundance of exciting new biomarkers such as S1P, tyrosine nitrated S1P3R, and PBEF, which have high potential value as prognostic tools in the management of patient therapy.

Therapeutic Strategies to Limit Pulmonary Edema:

  Despite decades of frustration in the pursuit of potent barrier-regulatory therapies, progress has now been made for alleviation of the human suffering associated with uncontrolled lung vascular leakage and alveolar flooding.  Leveraging new insights into the mechanisms which govern the integrity of the vascular endothelium, particularly the role of cytoskeletal linkages to junctional proteins, novel biologically compatible agents have now been identified which can preserve or restore vascular integrity.  The newly revised scientific armamentarium offers promise for the future management of pulmonary edema associated with increased vascular leak in the critically ill as well as other lung conditions which exhibit strongly dysregulated barrier function such as radiation pneumonitis, acute chest syndrome in sickle cell patients and in subacute inflammatory disorders such as asthma.  Nearly each barrier regulatory agent has been successfully evaluated in preclinical models of ALI and one agent, FTY720, is in Phase III trials, while three other agents, statins, activated protein C and methylnaltrexone, are currently approved by the FDA for other medical conditions.  Thus, the prospects for the rapid translation of these lung vascular barrier-protective strategies to clinical practice are high.