Review
The role of apoptosis in the pathophysiology of Acute Respiratory Distress Syndrome (ARDS): An up-to-date cell-specific review

https://doi.org/10.1016/j.prp.2009.12.002Get rights and content

Abstract

ARDS pathophysiology is characterized by complex mechanisms that involve cells of inflammation, lung tissue cells, cytokines, chemokines, as well as apoptosis activators and inhibitors. There are two important theories that link apoptosis with ARDS and suggest that epithelial cell apoptosis, as well as the accumulation of neutrophils in the lung, may contribute to a cascade of events and, finally, ARDS. The activation of the Fas/FasL pathway is an important mechanism of alveolar epithelial injury in the lungs of patients with ALI. In addition, neutrophilic inflammation in the alveolar spaces is characteristic of ALI in humans and in most animal models of ALI. The enhanced phagocytosis of apoptotic neutrophils could lead to resolution of inflammation and repair during ARDS. In this review, we will focus on elucidating the role of apoptosis in the pathophysiology of ARDS and the contribution of Fas-mediated inflammation in ARDS. Furthermore, we will give evidence that TNF-alpha, IL-1beta and IL-13 attenuate the pro-cell death effects of Fas/CD95 on A549 epithelial cells, at least partially, by the NF-kB and PI3-K pathways, suggesting that induction of the expression of antiapoptotic genes protects the epithelial cells from cell death.

Introduction

Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is a syndrome characterized by proteinaceous pulmonary edema and acute inflammation. It is associated with increased permeability of the alveolar-capillary barrier [1]. Recent studies suggest a lethality of around 40% for ALI or ARDS [2], [3]. According to the risk factor, ARDS is classified into direct (e.g., from pneumonia or aspiration of gastric contents) and indirect (e.g., due to extra-pulmonary sepsis or severe trauma with shock and multiple transfusions), while according to timing, it is classified into an early and a late phase [4]. Clinically, ARDS is characterized by severe pulmonary gas exchange disorders and diffuse bilateral infiltrates of the lung [4].

The normal alveolar epithelium includes two types of cells: the flattened type I cells, which are more vulnerable to injury and cover 90% of the alveolar surface, and the cuboidal type II cells, which are more resistant. Type II cells produce pulmonary surfactant and transport ions. They proliferate and differentiate into type I cells after damage [4]. The alveolar epithelium and the microvascular endothelium form the alveolar-capillary barrier [4]. The epithelial barrier, under physiological conditions, is much less permeable than the endothelial one [5]. The loss of integrity of epithelium in ALI/ARDS has multiple consequences: it disturbs the removal of fluid from the alveolar space [4], decreases the production of surfactant [6], and contributes to the development of septic shock [7]. The degree of epithelial damage constitutes an important prognostic marker of ARDS [4]. The endothelial damage has also an important role in the development and the resolution of ARDS [4]. The pathophysiology of ARDS is characterized by complex mechanisms that involve cells of inflammation, lung tissue cells, cytokines, chemokines, as well as apoptosis activators and inhibitors [4]. Histologically, ARDS is characterized by lung epithelial and endothelial cell injury, neutrophil influx, hyaline membrane formation and alveolar edema and hemorrhage [4], [8].

Recent studies have shown that apoptosis contributes to ARDS pathogenesis [4], [8], [9], [10], [11], [12], [13]. There are two important theories that link apoptosis with the pathogenesis of ALI and ARDS in humans, including epithelial cell apoptosis and the accumulation of neutrophils.

The aim of this review is to elucidate the role of apoptosis in the pathophysiology of ARDS.

Section snippets

Pathways leading to apoptosis

Before we analyze the role of apoptosis in ALI/ARDS we present a brief introduction of the basic pathways of apoptosis. Apoptosis is morphologically defined by alterations, including cell shrinkage, nuclear fragmentation and chromatin condensation. Apoptosis can be initiated by two alternative convergent pathways: the extrinsic pathway, which is mediated by cell surface death receptors, and the intrinsic pathway, which is mediated by mitochondria. In both pathways, cysteine aspartyl-specific

Epithelial cell apoptosis in ARDS

As mentioned before, damage of the alveolar-capillary barrier is important in the development of ARDS, as it leads to flooding of the alveolar spaces with protein-rich exudates [4].

Apoptosis of lung epithelial cells represents a potentially important mechanism contributing to the loss of this cell type in the development of acute lung injury. Morphological changes occur early in human ARDS, and type I pneumocytes exhibit decreased size and condensation of the chromatin [19]. Subsequent studies

Neutrophil apoptosis in ARDS

Neutrophilic inflammation in the alveolar spaces is characteristic of ALI in humans and in most animal models of ALI [43]. Neutrophil accumulation has been observed early in lung tissue [19], [58], as well as in BALF of ARDS patients [59]. The degree of neutrophilia in BALF has been correlated with poor prognosis in septic ARDS [60]. However, neutrophils can migrate into the lungs of humans without causing injury [61] (e.g., uncomplicated pneumonia [62]). Neutrophil emigration into the lungs is

Alveolar macrophages in ARDS

Clearance of apoptotic cells by phagocytes also plays a role in survival and persistence of inflammation during acute lung injury [74]. The apoptotic cells are recognized by macrophages at inflammation sites via several cell surface molecules. One of these membrane molecules is the hyaluronan receptor CD44. CD44 appears to play an important role in the clearance of apoptotic neutrophils in vivo and in vitro[76], [77]. Failure to clear apoptotic neutrophils was associated with worsened

Endothelial cell apoptosis in ARDS

Endothelial cells form a monolayer lining the vasculature. Due to its positioning, endothelium is exposed to multiple stresses, such as LPS, endotoxin, TNF-alpha, and oxidative stresses. One pathological consequence of stresses in the blood vessel is the induction of endothelial cell apoptosis.

BAL fluid from patients at risk or with early and late phase ARDS is cytotoxic to human lung microvascular endothelial cells. Endothelial cell injury and apoptosis in ARDS patients are caused by TNF-alpha

Conclusion

The pathophysiology of ARDS includes a complexity of mechanisms. The increased alveolar epithelial cell apoptosis, as well as the delay of neutrophil apoptosis early in ARDS, seems to play a central role in the development and progression of this clinical entity. Neutrophil apoptosis returns to normal in the resolution of ARDS. Thus, modulation of apoptosis in a cell-, time-, and location-specific manner, in addition to new therapeutic strategies, such as prone ventilation, could decrease ARDS

Conflict of interest

All authors contributed equally to this review and declared no conflict of competing interests

References (85)

  • G.P. Downey et al.

    Regulation of neutrophil activation in acute lung injury

    Chest

    (1999)
  • A. Dunican et al.

    Neutrophils regulate their own apoptosis via preservation of CXC receptors

    J. Surg. Res.

    (2000)
  • P.C. Glynn et al.

    The selective CXCR2 antagonist SB272844 blocks interleukin-8 and growth-related oncogenealpha-mediated inhibition of spontaneous neutrophil apoptosis

    Pulm. Pharmacol. Ther.

    (2002)
  • EI. Kitsiouli et al.

    Differential determination of phospholipase A(2) and PAF-acetylhydrolase in biological fluids using fluorescent substrates

    J. Lipid Res.

    (1999)
  • J. Pugin et al.

    The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome

    Crit. Care Med.

    (1999)
  • G.D. Rubenfeld et al.

    Incidence and outcomes of acute lung injury

    N. Engl. J. Med.

    (2005)
  • L.B. Ware et al.

    The acute respiratory distress syndrome

    N. Engl. J. Med.

    (2000)
  • J.P. Wiener-Kronish et al.

    Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin

    J. Clin. Invest.

    (1991)
  • K.E. Greene et al.

    Serial changes in surfactant-associated proteins in lung and serum before and after onset of ARDS

    Am. J. Respir. Crit. Care Med.

    (1999)
  • K. Kurahashi et al.

    Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia

    J. Clin. Invest.

    (1999)
  • S. Hashimoto et al.

    Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome

    Am. J. Respir. Crit. Care Med.

    (2000)
  • W.L. Lee et al.

    Neutrophil activation and acute lung injury

    Curr. Opin. Crit. Care

    (2001)
  • G. Matute-Bello et al.

    Neutrophil apoptosis in the acute respiratory distress syndrome

    Am. J. Respir. Crit. Care Med.

    (1997)
  • G. Matute-Bello et al.

    Soluble Fas ligand induces epithelial cell apoptosis in humans with acute lung injury (ARDS)

    J. Immunol.

    (1999)
  • Y. Kitamura et al.

    Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice

    Am. J. Respir. Crit. Care Med.

    (2001)
  • A. Ashkenazi et al.

    Death receptors: Signaling and modulation

    Science

    (1998)
  • D.R. Green et al.

    Mitochondria and apoptosis

    Science

    (1998)
  • K.L. Serrao et al.

    Neutrophils induce apoptosis of lung epithelial cells via release of soluble Fas ligand

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

    (2001)
  • M. Bachofen et al.

    Structural alterations of lung parenchyma in the adult respiratory distress syndrome

    Clin. Chest Med.

    (1982)
  • R.H. Bardales et al.

    Apoptosis is a major pathway responsible for the resolution of type II pneumocytes in acute lung injury

    Am. J. Pathol.

    (1996)
  • D.J. Guinee et al.

    The potential role of BAX and BCL-2 expression in diffuse alveolar damage

    Am. J. Pathol.

    (1997)
  • R.A. Bem et al.

    Lung epithelial cell apoptosis during acute lung injury in infancy

    Pediatr. Crit. Care Med.

    (2007)
  • K.S. Lee et al.

    Evaluation of bronchoalveolar lavage fluid from ARDS patients with regard to apoptosis

    Respir. Med.

    (2007)
  • R.M. Pitti et al.

    Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer

    Nature

    (1998)
  • J. Cheng et al.

    Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule

    Science

    (1994)
  • M. Tanaka et al.

    Downregulation of Fas ligand by shedding

    Nat. Med.

    (1998)
  • M. Tanaka et al.

    Expression of the functional soluble form of human fas ligand in activated lymphocytes

    EMBO J.

    (1995)
  • D. Kagi et al.

    Fas and perforin pathways as major mechanisms of T-cell mediated cytotoxicity

    Science

    (1994)
  • W.C. Liles et al.

    Regulation of apoptosis in neutrophils: Fas track to death?

    J. Immunol.

    (1995)
  • W.C. Liles et al.

    Differential expression of Fas (CD95) and Fas ligand on normal human phagocytes: implications for the regulation of apoptosis in neutrophils

    J. Exp. Med.

    (1996)
  • Q. Lu et al.

    Apoptosis and lung injury

    Keio J. Med.

    (2005)
  • T. Suda et al.

    Expression of the Fas ligand in cells of T cell lineage

    J. Immunol.

    (1995)
  • Cited by (178)

    • Phospholipases A2 as biomarkers in acute respiratory distress syndrome

      2021, Biomedical Journal
      Citation Excerpt :

      The suppression of LPS-induced sPLA2IIA expression in various cell types treated with dexamethasone, or the antibiotic azithromycin, supports the idea of sPLA2IIA utilization as a biomarker [81,82]. Immunoparalysis is a common complication in septic severely ill patients characterized by downregulated innate and adaptive immune responses and is accompanied by decreased pro-inflammatory cytokines release from defense cells, significant apoptosis rates and increased mortality rates [83]. Immunoparalysis is defined as the reduced (<30%) HLA-DR expression in MC.

    View all citing articles on Scopus
    View full text