Pathogenesis of indirect (secondary) acute lung injury

Abstract

At present, therapeutic interventions to treat acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) remain largely limited to lung-protective strategies, as no real molecular-pathophysiologic-driven therapeutic intervention has yet become available. This is in part the result of the heterogeneous nature of the etiological processes that contribute to the state of ALI/ARDS. This article sets out to understand the development of ALI resulting from indirect pulmonary insults, such as extrapulmonary sepsis and trauma, shock, burn injury or mass transfusion, as opposed to direct pulmonary challenges, such as pneumonia, aspiration or lung contusion. Here, we consider not only the experimental and clinical data concerning the roles of various immune (neutrophil, macrophage, lymphocyte and dendritic) as well as nonimmune (epithelial and endothelial) cells in orchestrating the development of ALI resulting from indirect pulmonary stimuli, but also how these cell populations might be targeted therapeutically.

Figure 1. Proposed mechanisms of acute lung injury through hemorrhage ‘priming’ for inflammation (inflamed Epi. [red])/apoptosis (Ao Epi. [grey])/injury and ‘triggered’ by a subsequent infectious insult (see facing page)

The resting lung (A) is primed by divergent inflammatory mediators released during an initial event (e.g., shock and inflammation) that acts on a number of cells in the blood and lung (B). These cells in turn stimulate either separately or concomitantly the proinflammatory response and/or the Ao of a small number of Epi., both through Fas FasL activation. The release of chemokines primes the AMO, when, at a later time, a subsequent inflammatory/infectious (trigger) event takes place (note this be antagonized [dashed lines] by the anti-inflammatory actions of pulmonary Treg cells and/or (C) The local EC, pDC). AMO and/or become activated, release chemokines and activating agents that recruit the primed and now activated leukocytes lung (D). These activated leukocytes then transmigrate across the endothelium (which actively/passively retracts in response to such cell–leukocyte interactions) (E) into the interstitium and alveoli where they perform their effector roles (in the absence of infection the effector response may be solely injurious). In addition they may propel the inflammatory/apoptotic response into a vicious cycle by further activating Fas through FasL on their cell surface (F). AMØ: Alveolar macrophage; Ao: Apoptosis; EC: Endothelial cell; Epi.: Epithelial cell; MØ: Monocyte; MCP: Monocyte protein; pDC: Plasmacytoid dendritic cell; PMN: Polymorphonuclear cell; Treg: T-regulatory cell.