The fat and the skinny on acute lung injury

In this issue of Blood, Ortiz-Muñoz et al take a critical step in evaluating an advanced model of acute lung injury (ALI) pathology, implicating the accumulation of leukocyte-platelet aggregates (LPAs) in alveolar spaces, a central role of bioactive lipids in this process, and a particular identification of 15-epi-lipoxin A₄ (LXA₄) as a central player in the efficacy of aspirin-regulated protection from ALI.¹  These events have been previously described in isolation,^2-4  but this report synthesizes them together into a central model that sheds new light on the multifactorial landscape of ALI pathogenesis.

Emerging paradigms of inflammation-based pathologies, including the critical issue of ALI, are increasingly evoking the coordinate activity of multiple cellular species in initiating, promoting, and propagating disease. In retrospect, the concept that different circulating blood cell types have biological cross talk and interactions seems obvious and perhaps even inevitable. However, this notion nevertheless represents a progressive conceptual evolution, as traditional models have focused more on the singular contributions of cell types in isolation. An added layer of complexity is evoked with the attempt to identify signaling mediators of disease and/or targets of therapeutic intervention. The generation of a comprehensive and holistic understanding will require the integration of each of these components into a generalized schema.

Ortiz-Muñoz et al report significant and provocative data linking specific bioactive lipids to formation of neutrophil-platelet aggregates, followed by an association of the latter with pulmonary pathology in 2 separate in vivo models of ALI, involving either intratracheal lipopolysaccharide (LPS) or a 2-hit LPS/anti–major histocompatibility complex model of transfusion-related acute lung injury (TRALI). Aspirin has known efficacy in these model systems,⁴  and the authors present compelling evidence implicating a causal role for diversion of arachidonic acid metabolism away from eicosanoids, which would normally exacerbate ALI, toward 15-epi-LXA₄, which has protective properties. The authors make use of sophisticated interventional experiments, including either animals treated with pharmacological inhibitors of or animals with targeted deletions of known receptors for 15-epi-LXA₄. Of great importance, aspirin simultaneously attenuated ALI and increased both plasma and bronchiolar 15-epi-LXA₄ in these models, whereas blockade of 15-epi-LXA₄ by the above approaches attenuated aspirin's therapeutic effects.

An additional intellectual connection can be found in models of antibody-independent TRALI, where the direct infusion of biologically active lipid mediators is proposed to directly induce ALI through pathways related and analogous to those elucidated in the current studies.^5-7  This form of TRALI remains of central interest in the ongoing effort to improve the safety of blood products, because antibody-independent TRALI is not remedied by the prophylactic measure of preferentially using male blood products to avoid women who have been alloimmunized to HLA antigens as a result of pregnancy.

As the authors readily point out, ongoing studies are required to refine the interpretation of the observed phenomena, and there are legitimate concerns regarding dose requirements of experimentally administered 15-epi-LXA4. Nevertheless, this report integrates multiple biological players into an integrated model of bioactive lipid generation, LPA formation, and trafficking to alveoli and aspirin efficacy. Perhaps more importantly, this study identifies the potential for using bioactive lipids (or modified chemical agonists of such pathways) as novel interventions. Current available therapies may not allow safe utilization of the identified pathways. Thus, in aggregate, the reported findings represent a conceptual advance of high potential in both general understanding and therapeutic development for ALI prevention and mitigation.