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