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This is the first study to describe the daytime evolution of respiratory parameters in mechanically ventilated COVID-19 patients. The data base refers to patients hospitalised in the intensive care unit (ICU) at Arequipa Hospital (Peru, 2335 m) in 2021. In both survivors (S) and non-survivors (NS) patients, a remarkable decrease in respiratory compliance was observed, revealing a proportional decrease in inflatable alveolar units. The S and NS patients were all hyperventilated and their SatO2 was maintained at >90%. However, while S remained normocapnic, NS developed progressive hypercapnia. We compared the efficiency of O2 uptake and CO2 removal in the air blood barrier relying on a model allowing to partition between diffusion and perfusion limitations to gas exchange. The decrease in O2 uptake was interpreted as diffusion limitation, while the impairment in CO2 removal was modelled by progressive perfusion limitation. The latter correlated with the increase in positive end-expiratory pressure (PEEP) and plateau pressure (Pplat), leading to capillary compression, increased blood velocity, and considerable shortening of the air-blood contact time. [ABSTRACT FROM AUTHOR]

We evaluated the changes in plasma membrane composition, biophysical properties, and morphology of pulmonary endothelial cells in anesthetized rabbits receiving 0.5 ml*[kg.sup.-1]*[min.sup.-1] saline infusion for 180 min, causing mild interstitial edema. Plasma membrane fractions were obtained from lung homogenates with gradient centrifugation, allowing a sixfold enrichment in caveolin-1. In edematous lungs, cholesterol content and phospholipidic phosphorus increased by 15 and 40%, respectively. These data correlated with morphometric analysis of lungs fixed in situ by vascular perfusion with 2.5% glutaraldehyde, suggesting a relative increase in surface of luminal to interstitial front of the capillary endothelial cells, due to a convoluted luminal profile. In edematous lungs, the fraction of double-bound fatty acids increased in membrane lipids; moreover, the phosphatidylcholine/phosphatidylethanolamine and the cholesterol/phospholipid ratios decreased. These changes were consistent with the increase in fluorescence anisotropy of plasma membrane, indicating an increase in its fluidity. Data suggest that mechanical stimuli elicited by a modest (~4%) increase in extravascular water cause marked changes in plasma membranes that may be of relevance in signal transduction and endothelial cell activation. rabbit; air-blood barrier; endothelial cells; membrane composition and fluidity

Mild pulmonary interstitial edema was shown to cause fragmentation of interstitial matrix proteoglycans. We therefore studied compartmental fluid accumulation by light and electron microscopy on lungs of anesthetized rabbits fixed in situ by vascular perfusion after 0.5 ml*[kg.sup.-1]*[min.sup.-1] iv saline infusion for 180 min causing ~6% increase in lung weight. Morphometry showed that a relevant portion (44%) of extravascular fluid is detected early in the alveolar septa, 85% of this fluid accumulating in the thick portion of the air-blood barrier. The arithmetic mean thickness of the barrier increased in interstitial edema from 1.06 [+ or -] 0.05 (SE) to 1.33 [+ or -] 0.06 [micro]m. The harmonic mean thickness increased from 0.6 [+ or -] 0.03 to 0.86 [+ or -] 0.07 [micro]m, mostly due to thickening of the thin portion causing an increase in gas diffusion resistance. Despite some structural damage, the air-blood barrier displays a relatively high structural resistance providing a safety factor against the development of severe edema. It is suggested that the increase in extra-alveolar perivascular space occurs as a consequence of fluid accumulation in the air-blood barrier. thin and thick portions of the air-blood barrier; extracellular matrix; fibrillar collagen; basement membranes; gas diffusion; fluid accumulation; proteoglycans; top and bottom lung regions

Negrini, Daniela, Anna Candiani, Federica Boschetti, Beatrice Crisafulli, Massimo Del Fabbro, Dario Bettinelli, and Giuseppe Miserocchi. Pulmonary microvascular and perivascular interstitial geometry during development of mild hydraulic edema. Am J Physiol Lung Cell Mol Physiol 281: L1464-L1471, 2001.--To study pulmonary arteriolar vasomotion in control conditions and in the transition to hydraulic edema, changes in subpleural pulmonary arteriolar diameter and perivascular interstitial volume were evaluated in anesthetized spontaneously breathing rabbits. Images of subpleural pulmonary microvessels were recorded in control conditions and for up to 180 min during a 0.5 ml.kg-1.min-1 intravenous saline infusion through an intact parietal pleural window. Images were digitized and analyzed with a semiautomatic procedure to determine vessel diameter and perivascular interstitial thickness from which interstitial fluid volume was derived. In control yessels, the diameter of-30-, -50-, and -80-[mu]m arterioles and the perivascular interstitial thickness were fairly stable. During infusion, the diameter increased maximally by 20% in -30-[mu]m vessels, was unchanged in -50-[mu]m vessels, and decreased by 25% in -80-[mu]m arterioles; the perivascular interstitial volume increased by 54% only around 30-[mu]m microvessels. In papaverine-treated rabbits, all arterioles dilated and a larger increase in perivascular interstitial thickness was observed. The data suggest that the opposite vasomotor behavior of 30- and 80-[mu]m arterioles during development of mild edema may represent a local specific response of the pulmonary microcirculation to reduce capillary pressure in the face of an increased transendothelial fluid filtration, thus counteracting progression toward severe edema. pulmonary arteriolar vasomotion; perivascular interstitial volume; mild interstitial edema

Proteoglycans from lung tissue samples obtained from three groups of anesthesized rabbits were extracted, isolated and analyzed. Results suggested that elastase treatment produces a major degree of damage to the organization of basement membrane, while saline loading affects the architecture of interstitial extracellular matrix. Qualitative zymography on the lung extracts provided evidences that the activation of tissue proteinases may play a role in acute lung injury.

Intravenous injection of pancreatic elastase followed by lung compliance measurement in situ was undertaken to determine the effect of elastase on the mechanical properties of rabbit lung. Results reveal that there is an increase in tissue compliance after elastase injection owing to a destruction of the proteoglycans in the extracellular matrix. An analysis of the degradation products confirmed this conclusion.

The breakdown of the intestitial matrix structure leading to severe lung edema can be identified through changes in pulmonary perivascular interstitial pressure (P(sub ip)) in rabbits. The P(sub ip) reduces to atmospheric pressure with edema development. The extractibility of pulmonary interstitial proteoglycans (PG) increases as the wet-to-dry lung weight ratio increases. Edema development is related to enhanced PG extractibility in both 0.4 and 4 M guanidinium chloride extracts, and reduction of the strength of PG interactions with other extracellular matrix components.

Abstract Background Pulmonary edema induces changes in airway and lung tissues mechanical properties that can be measured by low-frequency forced oscillation technique (FOT). It is preceded by interstitial edema which is characterized by the accumulation of extravascular fluid in the interstitial space of the air-blood barrier. Our aim was to investigate the impact of the early stages of the development of interstitial edema on the mechanical properties of the respiratory system. Methods We studied 17 paralysed and mechanically ventilated closed-chest rats (325–375 g). Total input respiratory system impedance (Zrs) was derived from tracheal flow and pressure signals by applying forced oscillations with frequency components from 0.16 to 18.44 Hz distributed in two forcing signals. In 8 animals interstitial lung edema was induced by intravenous infusion of saline solution (0.75 ml/kg/min) for 4 hours; 9 control animals were studied with the same protocol but without infusion. Zrs was measured at the beginning and every 15 min until the end of the experiment. Results In the treated group the lung wet-to-dry weight ratio increased from 4.3 ± 0.72 to 5.23 ± 0.59, with no histological signs of alveolar flooding. Resistance (Rrs) increased in both groups over time, but to a greater extent in the treated group. Reactance (Xrs) did not change in the control group, while it decreased significantly at all frequencies but one in the treated. Significant changes in Rrs and Xrs were observed starting after ~135 min from the beginning of the infusion. By applying a constant phase model to partition airways and tissue mechanical properties, we observed a mild increase in airways resistance in both groups. A greater and significant increase in tissue damping (from 603.5 ± 100.3 to 714.5 ± 81.9 cmH2O/L) and elastance (from 4160.2 ± 462.6 to 5018.2 ± 622.5 cmH2O/L) was found only in the treated group. Conclusion These results suggest that interstitial edema has a small but significant impact on the mechanical features of lung tissues and that these changes begin at very early stages, before the beginning of accumulation of extravascular fluid into the alveoli.

Abstract Background A correlation between interstial pulmonary matrix disorganization and lung cellular response was recently documented in cardiogenic interstitial edema as changes in the signal-cellular transduction platforms (lipid microdomains: caveoale and lipid rafts). These findings led to hypothesize a specific "sensing" function by lung cells resulting from a perturbation in cell-matrix interaction. We reason that the cell-matrix interaction may differ between the cardiogenic and the hypoxic type of lung edema due to the observed difference in the sequential degradation of matrix proteoglycans (PGs) family. In cardiogenic edema a major fragmentation of high molecular weight PGs of the interfibrillar matrix was found, while in hypoxia the fragmentation process mostly involved the PGs of the basement membrane controlling microvascular permeability. Based on these considerations, we aim to describe potential differences in the lung cellular response to the two types of edema. Methods We analysed the composition of plasma membrane and of lipid microdomains in lung tissue samples from anesthetized rabbits exposed to mild hypoxia (12 % O2 for 3–5 h) causing interstitial lung edema. Lipid analysis was performed by chromatographic techniques, while protein analysis by electrophoresis and Western blotting. Lipid peroxidation was assessed on total plasma membranes by a colorimetric assay (Bioxytech LPO-586, OxisResearch). Plasma membrane fluidity was also assessed by fluorescence. Lipid microdomains were isolated by discontinuous sucrose gradient. We also performed a morphometric analysis on lung cell shape on TEM images from lung tissue specimen. Results After hypoxia, phospholipids content in plasma membranes remained unchanged while the cholesterol/phospholipids ratio increased significantly by about 9% causing a decrease in membrane fluidity. No significant increase in lipid peroxidation was detected. Analysis of lipid microdomains showed a decrease of caveolin-1 and AQP1 (markers of caveolae), and an increase in CD55 (marker of lipid rafts). Morphometry showed a significant decrease in endothelial cell volume, a marked increase in the cell surface/volume ratio and a decrease in caveolar density; epithelial cells did not show morphological changes. Conclusion The biochemical, signaling and morphological changes observed in lung endothelial cell exposed to hypoxia are opposite to those previously described in cardiogenic edema, suggesting a differential cellular response to either type of edema.