Pathogenesis of Acute Respiratory Distress Syndrome

Abstract

Acute respiratory distress syndrome (ARDS) is a syndrome of acute respiratory failure caused by noncardiogenic pulmonary edema. Despite five decades of basic and clinical research, there is still no effective pharmacotherapy for this condition and the treatment remains primarily supportive. It is critical to study the molecular and physiologic mechanisms that cause ARDS to improve our understanding of this syndrome and reduce mortality. The goal of this review is to describe our current understanding of the pathogenesis and pathophysiology of ARDS. First, we will describe how pulmonary edema fluid accumulates in ARDS due to lung inflammation and increased alveolar endothelial and epithelial permeabilities. Next, we will review how pulmonary edema fluid is normally cleared in the uninjured lung, and describe how these pathways are disrupted in ARDS. Finally, we will explain how clinical trials and preclinical studies of novel therapeutic agents have further refined our understanding of this condition, highlighting, in particular, the study of mesenchymal stromal cells in the treatment of ARDS.

Figure 1:. Increased alveolar endothelial permeability in ARDS

(A). In ARDS, inflammatory molecules disrupt alveolar barrier function, resulting in the accumulation of alveolar edema fluid. (B). Specifically, disruption of VE-Cadherin bonds causes increased endothelial permeability, and subsequent leakage of water, solutes, leukocytes, platelets, and other inflammatory molecules into the alveolar space.

Figure 2:. Alveolar fluid clearance pathways in the uninjured lung vs. the lung affected by ARDS

(A). In the uninjured lung, fluid is effectively cleared from the alveolar space by vectorial ion transport. Shown are the interstitial, capillary, and alveolar compartments of the lung, with pulmonary edema fluid in the alveolus. Both type I and type II alveolar cells are involved in transepithelial ion transport. Sodium (Na+) is transported across the apical side of the type I and type II cells through the epithelial sodium channel (ENaC), and then across the basolateral side via the sodium/potassium ATPase pump (Na/K-ATPase). Chloride (Cl-) is transported via the CFTR channel or by a paracellular route. Additional cation channels also transport ions across the alveolar epithelium (not shown). This vectorial ion transport creates an osmotic gradient that drives the clearance of fluid. Specifically, water (H₂0) moves down the osmotic gradient through aquaporin channels, such as aquaporin 5 (AQP5) or via an intracellular route (not shown). In the uninjured lung, this vectorial ion transport helps achieve effective alveolar fluid clearance. (B). In lungs affected by ARDS, fluid is less effectively cleared from the lungs. First, hypoxia/hypercapnia result in downregulation of ENaC transcription and trafficking and less efficient function of the Na/K-ATPase. Second, high tidal volumes and elevated airway pressures injure the alveolar epithelium, inducing inflammation and cell death. Third, ARDS results in the formation of pro-inflammatory cytokines, which induce alveolar injury and cause reduced alveolar fluid clearance.

Figure 3.. Potential Mechanisms for the Therapeutic Effects of Mesenchymal Stromal Cells (MSCs) in ARDS

To date, multiple pre-clinical studies have demonstrated the therapeutic benefit of MSCs in the treatment of ARDS, and this diagram depicts our current mechanistic understanding of this therapeutic effect. First, MSCs secrete paracrine factors that modulate tissue repair through four mechanisms: (1) anti-inflammatory effects on host cells, (2) reduction of alveolar epithelial permeability in the lung, (3) increased rate of alveolar fluid clearance and (4) enhancement of host mononuclear cell phagocytic activity. Second, data suggests that MSCs directly transfer mitochondrial DNA to host cells, which also contributes to tissue repair and recovery. Third, MSCs secrete microvesicles that deliver micro RNA, RNA, proteins, and lipids to host cells.