Linking genetics to ARDS pathogenesis: the role of the platelet.

ARDS is a complex syndrome, characterized by damage to the alveolar-capillary barrier resulting in increased permeability in the setting of an amplified inflammatory response. The role of the activation of clotting pathways in this process has been increasingly recognized, including the significant impact of platelets on ARDS pathogenesis.1-3 In a steady state, inactive platelets circulate in blood and promote endothelial barrier integrity.4 However, in the setting of critical illnesses (eg, sepsis), several overlapping mechanisms activate platelets, resulting in platelet aggregation, platelet-leukocyte complex formation, and release of the granule contents of the platelet cell, including molecules that enhance inflammation and cell adhesion. While platelet-mediated thrombosis in the lungs has been implicated in ARDS pathogenesis, the activation of circulating platelets results in a host of other inflammatory effects contributing to ARDS development, including augmented neutrophil migration and increased endothelial barrier permeability.3 Given the accumulating evidence for the role of platelets in ARDS, significant interest has recently developed in therapeutically targeting platelet activation and function. In mouse models of ARDS, inhibiting P-selectin-mediated platelet-neutrophil interactions protect from lung injury.2 In humans, preexisting antiplatelet drugs, such as aspirin or clopidogrel, are associated with decreased risk of ARDS as well as decreased mortality among the critically ill.5,6 Several ongoing studies are investigating the role of antiplatelet therapy in ARDS, including the Lung Injury Prevention Study with Aspirin (LIPS-A),7 a multicentered randomized controlled clinical trial evaluating aspirin for the prevention of ARDS in patients at risk. While current antiplatelet agents have the potential to have therapeutic benefit in the critically ill, further enhancing our understanding of the mechanisms by which platelets contribute to ARDS may identify novel therapeutic targets or select patient subgroups most likely to respond to antiplatelet therapy. In this issue of CHEST (see page 607), Wei and colleagues8 use an innovative approach to identify a novel genetic variant linked to platelets, which is associated with ARDS risk. Several investigators have identified genetic variants in genes implicated in alveolar-capillary barrier integrity,9 inflammation,10 and coagulation as risk factors for ARDS11; however, variants resulting in platelet heterogeneity have not previously been linked to ARDS. Working with the knowledge that thrombocytopenia during critical illness is associated with poor outcomes,12 and that genome-wide association studies have identified several genetic variants linked to platelet count in the noncritically ill,13 Wei and colleagues8 set out to answer several questions. First, they determined the association of single nucleotide polymorphisms (SNPs) in candidate genes with platelet count in a cohort of critically ill patients at risk for ARDS. They selected candidate genes based on previous associations with platelet count in relatively healthy populations and identified an intronic SNP in LRRC16A as also associated with platelet count among the critically ill. Next, the same SNP in LRRC16A was determined to be associated with altered risk of ARDS. Lastly, they used sophisticated statistical methods to determine whether platelet count was a causal mediator linking the LRRC16A genotype to ARDS risk. Decreased platelet count, measured at ICU admission, was associated with increased ARDS risk in their cohort and functioned as a partial mediator of the association between LRRC16A genotype and ARDS. While not proving causation, this approach not only identified a novel genetic risk factor for ARDS, but also provided evidence for a potential mechanism resulting in the altered risk. The most significant limitation to the study conducted by Wei and colleagues8 is that the only causal mediator evaluated was a single measure of platelet count at ICU admission. Based on these data, it is difficult to determine whether the effects of platelet count on ARDS risk are a result of decreased platelet production or increased platelet activation, lung sequestration, and consumption. Additionally, platelet function may be equally as important in mediating ARDS risk as platelet count and may explain why count was only a partial causal mediator of the LRRC16A and ARDS association. In addition to validating their findings in an independent population, future research should evaluate the effects of LRRC16A on measures of platelet consumption and production, such as serial platelet counts or immature platelet fractions, as well as measures of platelet function, aggregation, and neutrophil adhesion. Despite these limitations, Wei and colleagues8 have successfully identified a variant in LRRC16A associated with altered ARDS risk, at least partially mediated via effects on platelet count. LRRC16A encodes the protein, capping protein ARP2/3 and myosin-I linker (CARMIL), important in actin-based cellular processes.14 This protein has not previously been implicated in ARDS, and the mechanisms underlying its effects on platelet count are not completely understood. Furthering our understanding of the role of LRRC16A and CARMIL protein in platelet development and/or function as well as ARDS pathogenesis may identify novel therapeutic targets within platelet cellular processes with relevance to ARDS. Likewise, LRRC16A variation may represent a key focus for pharmacogenetic interaction in ongoing trials of aspirin therapy. Therefore, the study by Wei and colleagues8 provides key data to focus our near-term research efforts on the role of platelets in ARDS.