The pathophysiology of this condition is challenging to pinpoint as the etiology is multifactorial. In the early research describing the pathophysiology of ARDS, a direct pulmonary or indirect extrapulmonary insult was implicated in the proliferation of inflammatory mediators promoting neutrophil accumulation in the microcirculation of the lung. With the current research on this condition, etiologies that trigger this syndrome have been grouped into direct and indirect causes. Direct causes trigger primary injuries to the lung epithelium and include pneumonia, aspiration, drowning, and toxic inhalation. Indirect causes, however, trigger diffuse damage to the lung's vascular endothelium and cause systemic lung inflammation. These triggers include:
- Extrapulmonary sepsis
- Non-cardiogenic shock
- Adverse drug reactions
The histological hallmark of ARDS appears to be diffuse alveolar damage (DAD). These etiologies provoke a systemic inflammatory response in the lung.
Various pathways, mediators, and molecular systems contribute to altered alveolar endothelial and epithelium porosity. An adherens junctional protein, the vascular endothelial cadherin (VE-cadherin, has been identified to perfume critical physiological functions in maintaining barrier integrity in the lung microvessels. Disruption of the homophilic bonds on the VE-cadherin destabilizes lung barrier integrity. Antibodies against VE-cadherin and other destabilizing agonists such as thrombin, TNF, VEGF, and leucocyte signals have disrupted VE-cadherin bonds, prompting lung edema (Lupu et al., 2020). In sharp contrast, factors that stabilize VE-cadherin bonds, including genetic manipulation of VE-cadherin-catenin interactions or preventing the dissociation of a phosphatase group from VE-cadherin, reduce the influx of leucocytes and fluids into the alveolar space. The interaction has been proven in clinical studies exploring potential treatment options for ARDS in mice (Jones et al., 2022).
Recent studies on a new pathway implicated in alveolar epithelium damage focus on the role of a neutrophil-platelet complex. Neurons in the intravascular and extravascular compartments often form a complex with platelets. These platelets have intricate thrombo-inflammatory activities and, most importantly, the ability to deploy neutrophil extracellular traps (NETs). Histological researchers describe NETs as filamentous chromatin fiber complexed with neutrophil-derived antimicrobial proteins. These traps reportedly evolved as an innate mechanism for pathogen containment and clearance. However, they are also involved in inflammatory insults to major organs, including the lung (Lefrancais et al., 2018). In experimental models, NETs correlate with alveolar-capillary and epithelial disruptions causing alveolar edema and damage. Research observations have also suggested an early intravascular interaction of platelets with monocytes in an aggregation mechanism similar to the neutrophil-platelet association. These aggregations involving monocytes also reportedly drive the development of ARDS in patients at risk. The pathway involved in recruiting neutrophils and monocytes to the lung is influenced by intra-alveolar macrophages releasing chemotactic factors. These factors, including CC-Chemokine ligand 2 and IL-8, enhance neutrophil recruitment as a physiological response to acute pulmonary infections (Abdulnour et al., 2018).
Studies have shown that the balance between the protective and harmful innate and adaptive immune responses may also determine the severity of alveolar injuries. Acute inflammatory responses to pathogens and toxins in disease cycles of lung infections can precipitate ALI. These inflammatory responses release leucocyte protease, synthesis of chemokines and cytokines, toll-like receptor engagement, and generation of reactive oxygen species (Xie et al., 2021). Research submissions have also highlighted how molecular events governing the balance between angiotensin-converting enzymes 1 and 2 (ACE I and II) may also contribute to inflammatory lung injuries as a direct consequence of viral infection, acute injury, and sepsis (Wu et al., 2022). Injuries cause airspace and interstitium edema by developing a protein-rich neutrophilic exudate. The development of exudate compromises gas exchange and reduces the integrity of the normal respiratory cycle. Understanding the pathophysiology of ARDS regarding alveolar integrity involves studying the normal gas transfer flow of the lung.
A healthy lung is physiologically designed to exchange carbon dioxide and oxygen across the distal alveoli-capillary unit. The selectively-permeable barrier establishing a gaseous exchange in the lung is formed by a single layer of the endothelial lining, aggregated together by tight junctions and plasma membrane structures such as adherens (Chen et al., 2021). The surface of this expansive boundary is lined by fat alveolar type 1 cells (ATI) and cuboid-shaped alveolar type 2 cells (ATII), forming a barrier restricting the free flow of solutes but allowing the diffusion of oxygen and carbon dioxide. Surfactants secreted by the Alveolar cells serve critical functions in the reduction of surface tension and in maintaining active gas exchange by keeping the alveoli complex open. Sodium channels and basolateral Na+/K+ -ATPase pumps on the alveolar cells help absorb excess fluid from the airspaces by vectorial ion support (Esquivel-Ruiz et al., 2021).
With this mechanism, there is the reabsorption of edematous fluid in the event of alveolar edema. Fluids reabsorption through this mechanism into the lung is primarily transported and removed by lung microcirculation and the lymphatic network. In addition to the tight barrier structure, the cellular makeup of a normal, healthy alveolus also includes alveolar macrophages ready for rapid deployment into the lung microcirculation. These macrophages and a cellular population of platelets, monocytes, and neutrophils control the defensive response of the healthy alveolus and have a critical function in the pathophysiology of ALI.
Image 1: Structure of an Alveolus
In ARDS, the lung epithelium and the selective barrier on the alveoli surface are compromised, forcing liquid and protein across the endothelium. The absorption of protein and fluids across this barrier precipitate edema in the lung interstitium (Meyer et al., 2021). From the lung interstitium, fluid flows to the alveoli, taking advantage of damage to the alveolar epithelium. Increased alveolar-capillary permeability to protein, neutrophils, and blood cells results in the accumulation of fluids in the alveoli (Doig et al., 2022). Research studies have identified the impaired excretion of carbon dioxide due to alveolar-capillary compromise as the root component of respiratory failure in ARDS. Impaired carbon dioxide excretion results in elevated ventilation associated with a greater volume of breath participating in carbon dioxide excretion (an increase in pulmonary dead space). In addition to increased pulmonary dead space, a decrease in respiratory compliance is another independent predictor of mortality in ARDS (Patel et al., 2022).