Abstract
This review analyses the mechanisms by which lung fluid balance is strictly controlled in the air-blood barrier (ABB). Relatively large trans-endothelial and trans-epithelial Starling pressure gradients result in a minimal flow across the ABB thanks to low microvascular permeability aided by the macromolecular structure of the interstitial matrix. These edema safety factors are lost when the integrity of the interstitial matrix is damaged. The result is that small Starling pressure gradients, acting on a progressively expanding alveolar barrier with high permeability, generate a high transvascular flow that causes alveolar flooding in minutes. We modeled the trans-endothelial and trans-epithelial Starling pressure gradients under control conditions, as well as under increasing alveolar pressure (Palv) conditions of up to 25 cmH2O. We referred to the wet-to-dry weight (W/D) ratio, a specific index of lung water balance, to be correlated with the functional state of the interstitial structure. W/D averages ∼5 in control and might increase by up to ∼9 in severe edema, corresponding to ∼70% loss in the integrity of the native matrix. Factors buffering edemagenic conditions include: (i) an interstitial capacity for fluid accumulation located in the thick portion of ABB, (ii) the increase in interstitial pressure due to water binding by hyaluronan (the “safety factor” opposing the filtration gradient), and (iii) increased lymphatic flow. Inflammatory factors causing lung tissue damage include those of bacterial/viral and those of sterile nature. Production of reactive oxygen species (ROS) during hypoxia or hyperoxia, or excessive parenchymal stress/strain [lung overdistension caused by patient self-induced lung injury (P-SILI)] can all cause excessive inflammation. We discuss the heterogeneity of intrapulmonary distribution of W/D ratios. A W/D ∼6.5 has been identified as being critical for the transition to severe edema formation. Increasing Palv for W/D > 6.5, both trans-endothelial and trans-epithelial gradients favor filtration leading to alveolar flooding. Neither CT scan nor ultrasound can identify this initial level of lung fluid balance perturbation. A suggestion is put forward to identify a non-invasive tool to detect the earliest stages of perturbation of lung fluid balance before the condition becomes life-threatening.
Highlights
Efficient gas diffusion in the air-blood barrier is only possible by strict control of extravascular water volume to prevent edema-induced tissue swelling and alveolar flooding
The sequence of events leading to severe lung edema have been delineated, at this point, there remains a wide gap in our knowledge of how to prevent the loss of lung fluid balance when W/D > 6 and the critical role of properly set mechanical ventilation
Since the distribution of edema is heterogeneous by nature, in the lung portions where W/D < 6.5, the control of lung fluid balance is only possible when the built-in safety factors, intact matrix, interstitial capacity, and lymphatics not yet saturated, are still functional
Summary
Efficient gas diffusion in the air-blood barrier is only possible by strict control of extravascular water volume to prevent edema-induced tissue swelling and alveolar flooding. Two important functional features of ABB are the following: very strict control of water balance by minimizing fluid exchanges across the endothelial and epithelial barriers, and remarkable mechanical resistance to the increase in tension related to change in lung volumes. These two important features rely on the structure-function relationship between the epithelial and endothelial cells and the macromolecular structure of the interstitial compartment separating the epithelial and endothelial layers. The structure of the interstitial compartment includes a mesh of collagen and elastic fibers whose main role is to provide mechanical support and elasticity (Miserocchi and Rivolta, 2012) These molecules are chemically very stable and resistant to proteolysis. Large molecular weight chondroitin-sulfate proteoglycans (CS-PG > 1,000 kDa) bound to hyaluronan act as link proteins through low energy noncovalent bonds with other molecules and cells providing rigidity to the parenchymal mesh
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