Cytokine-mediated inflammation in acute lung injury

doi:10.1016/S1359-6101(03)00059-5

Cytokine & Growth Factor Reviews

Volume 14, Issue 6, December 2003, Pages 523-535

https://doi.org/10.1016/S1359-6101(03)00059-5 Get rights and content

Abstract

Clinical acute lung injury (ALI) is a major cause of acute respiratory failure in critically ill patients. There is considerable experimental and clinical evidence that pro- and anti-inflammatory cytokines play a major role in the pathogenesis of inflammatory-induced lung injury from sepsis, pneumonia, aspiration, and shock. A recent multi-center clinical trial found that a lung-protective ventilatory strategy reduces mortality by 22% in patients with ALI. Interestingly, this protective ventilatory strategy was associated with a marked reduction in the number of neutrophils and the concentration of pro-inflammatory cytokines released into the airspaces of the injured lung. Further research is needed to establish the contribution of cytokines to both the pathogenesis and resolution of ALI.

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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^☆: Supported in part by grants HL69955, HL30542, HL70178, HL51856, HL051854 and HR46059 from the National Institutes of Health; and the Medical Research Service of the Department of Veterans’ Affairs.

¹: Tel.: +1-206-764-2504; fax: +1-206-764-2659.

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Cytokine-mediated inflammation in acute lung injury☆

Abstract

Introduction

Section snippets

Interleukin-1β (IL-1β) and its counter-regulatory ligands and receptors

Neutrophils (PMN)

Corticosteroid effects in ARDS

Mechanical ventilator-induced lung injury (VILI)

Conclusions

J. Biol. Chem.

Adv. Immunol.

Curr. Opin. Immunol.

Chest

Lancet

Blood

Gastroenterology

Chest

J. Biol. Chem.

J. Biol. Chem.

Cytokine

J. Biol. Chem.

J. Biol. Chem.

Surgery

J. Biol. Chem.

Blood

Am. J. Pathol.

Blood

Kidney Int.

The acute respiratory distress syndrome

N. Engl. J. Med.

Neutrophil-activating peptide-1/interleukin-8: a novel cytokine that activates neutrophils

J. Clin. Invest.

Structure and neutrophil-activating properties of a novel inflammatory peptide (ENA-78) with homology to interleukin-8

J. Exp. Med.

Macrophage inflammatory protein-1: expression in interstitial lung disease

J. Immunol.

High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interkeukin-1, interferon, and elastase, in patients with respiratory distress syndrome after trauma, shock, or sepsis

Am. Rev. Respir. Dis.

Immunoreactive interleukin-1 in bronchoalveolar lavage fluid of high-risk patients and patients with the adult respiratory distress syndrome

Exp. Lung Res.

Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome

Am. J. Respir. Crit. Care Med.

Cytokine balance in the lungs of patients with acute respiratory distress syndrome

Am. J. Respir. Crit. Care Med.

The association between mortality rates and decreased concentrations of interleukin-10 and interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome

Ann. Intern. Med.

An IL-1 inhibitor from human monocytes: production and characterization of biologic properties

J. Immunol.

The inhibitory activity of human interleukin-1 receptor antagonist is enhanced by type II interleukin-1 soluble receptor and hindered by type I interleukin-1 soluble receptor

J. Clin. Invest.

IL-1 signaling cascade in liver cells and the involvement of a soluble form of the IL-1 receptor accessory protein

J. Immunol.

Pro-inflammatory activity in bronchoalveolar lavage fluids from patients with ARDS, a prominent role for interleukin-1β

Am. J. Respir. Crit. Care Med.

The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of ARDS

Crit. Care Med.

Interleukin-1beta augments in vitro alveolar epithelial repair

Am. J. Physiol. Lung Cell Mol. Physiol.

Pulmonary edema fluid from patients with acute lung injury augments in vitro alveolar epithelial repair by an IL-1beta-dependent mechanism

Am. J. Respir. Crit. Care Med.

Cachectin/TNF-alpha in septic shock and septic adult respiratory distress syndrome

Am. Rev. Respir. Dis.

The role of tumor necrosis factor in increased airspace epithelial permeability

Am. J. Respir. Cell Mol. Biol.

Plasma tumor necrosis factor in patients with septic shock: mortality rate, incidence of adult respiratory distress syndrome, and effects of methylprednisolone administration

Am. Rev. Respir. Dis.

Tumor necrosis factor levels in serum and bronchoalveolar lavage fluid of patients with the adult respiratory distress syndrome

Am. Rev. Respir. Dis.

Increased release of soluble tumor necrosis factor receptors into blood during clinical sepsis

Arch. Surg.

Early prediction of outcome in score-identified, postcardiac surgical patients at high risk for sepsis, using soluble tumor necrosis factor receptor-p55 concentrations

Crit. Care Med.

Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome

JAMA

Release of soluble receptors for tumor necrosis factor in clinical sepsis and experimental endotoxemia

J. Infect. Dis.

P55 tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock: a randomized controlled multi-center trial

JAMA

Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones

J. Exp. Med.