Cytokine-mediated inflammation in acute lung injury☆
Introduction
Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are characterized by an acute inflammatory process in the airspaces and lung parenchyma. These clinical syndromes are manifestations of the loss of barrier function of the alveolar epithelial and pulmonary capillary endothelial cells resulting in respiratory failure in critically ill patients [1]. Evidence from several clinical studies indicates that a complex network of inflammatory cytokines and chemokines play a major role in mediating, amplifying, and perpetuating the lung injury process. Simultaneous production of anti-inflammatory cytokines can potentially counteract pro-inflammatory cytokine effects and modify the intensity of the inflammatory process. The pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) have been identified in bronchoalveolar lavage fluids (BALF) from ARDS patients, but measurements of their specific antagonists IL-1RA and soluble TNF receptors (sTNFR I and II) demonstrate their simultaneous presence. Similarly, biologically significant concentrations of neutrophil chemotactic cytokines such as IL-8, growth-related oncogene (GRO)-α, ENA-78, and GCP-2 are present in ARDS BALF, but are balanced by the presence of counter-ligands such as α-2-macroglobulin, the Duffy antigen chemokine binding protein, natural neutralizing antibodies, and the anti-inflammatory cytokine IL-10 in the lung milieu. Molar concentration ratios of pro- and anti-inflammatory molecular pairs in BALF provide insight into the inflammatory balance in individual patients, and measurement of the net inflammatory activity specific to each cytokine in cellular assays is a key step in validating these calculated ratios. Finally, relating these measurements to clinical measures of lung function and clinical outcomes underscore the relevance of these investigations. Understanding the balance of pro- and anti-inflammatory cytokines in the lungs of patients with ARDS is an important step in unraveling the pathogenesis of this devastating clinical syndrome.
Section snippets
Interleukin-1β (IL-1β) and its counter-regulatory ligands and receptors
Because it can stimulate the production of a variety of chemotactic cytokines such as interleukin-8 (IL-8) [2], epithelial cell neutrophil activator (ENA-78) [3], monocyte chemotactic peptide (MCP-1) [4], and macrophage inflammatory peptide-1α (MIP-1α) [5], IL-1β has earned a position of prominence at the head of the inflammatory cytokine cascade. Several investigators have identified the presence of this pro-inflammatory cytokine in BALF from patients with ARDS [6], [7], [8], [9]. Its
Neutrophils (PMN)
Several bronchoalveolar lavage studies in patients with ARDS identify the acute inflammatory cell populations, their evolution over time, and their importance with respect to clinical outcomes [54], [55], [56], [57], [58], [59]. Neutrophils (PMN) are abundant in BALF from patients with ARDS, and PMN products in BALF correlate with the physiological abnormalities that occur [56], [60]. Moreover, persistence of high numbers of PMN in BALF after the first week of ARDS is associated with mortality,
Corticosteroid effects in ARDS
After an initial report characterizing the lung histology of persistent ARDS as similar to idiopathic pulmonary fibrosis and suggesting its responsiveness to corticosteroids [135], several small clinical studies further developed the concept that corticosteroids might improve lung function and mortality in patients with persistence of ARDS (reviewed in [136]). Meduri et al. reported a phase II randomized controlled trial in 24 patients with persistent ARDS [137]. They reported that
Mechanical ventilator-induced lung injury (VILI)
Dunn and Pugin developed an innovative plastic lung model to study the effects of mechanical stress of lung cells in vitro [140]. Primary human lung cells or cells lines were cultured on collagen I-coated silastic membranes that formed the bottom of wells of a 12-well plate; a Plexiglas lid was bolted down in an airtight manner, and connected to a mechanical ventilator. They examined primary alveolar macrophages, monocyte-derived macrophages, THP-1 cells, type II-like A549 and bronchial BET-1A
Conclusions
Although a variety of injurious events and mediators can lead to ALI and ARDS depending on the clinical risk group, cytokine-mediated inflammation is shared in all of these patients. This inflammatory process contributes to the severe dysfunction of the lungs and to the injury of resident epithelial and endothelial cells. Understanding the basic cellular and mechanisms and the balance of pro- and anti-inflammatory cytokines and chemokines in the lungs of patients with ARDS is an important step
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