Pulmonary surfactant and COVID-19: A new synthesis.

Chapter 1: COVID-19 pathogenesis poses paradoxes difficult to explain with traditional physiology. For instance, since type II pneumocytes are considered the primary cellular target of SARS-CoV-2; as these produce pulmonary surfactant (PS), the possibility that insufficient PS plays a role in COVID-19 pathogenesis has been raised. However, the opposite of predicted high alveolar surface tension is found in many early COVID-19 patients: paradoxically normal lung volumes and high compliance occur, with profound hypoxemia. That 'COVID anomaly' was quickly rationalised by invoking traditional vascular mechanisms-mainly because of surprisingly preserved alveolar surface in early hypoxemic cases. However, that quick rejection of alveolar damage only occurred because the actual mechanism of gas exchange has long been presumed to be non-problematic, due to diffusion through the alveolar surface. On the contrary, we provide physical chemical evidence that gas exchange occurs by an process of expansion and contraction of the three-dimensional structures of PS and its associated proteins. This view explains anomalous observations from the level of cryo-TEM to whole individuals. It encompasses results from premature infants to the deepest diving seals. Once understood, the COVID anomaly dissolves and is straightforwardly explained as covert viral damage to the 3D structure of PS, with direct treatment implications. As a natural experiment, the SARS-CoV-2 virus itself has helped us to simplify and clarify not only the nature of dyspnea and its relationship to pulmonary compliance, but also the fine detail of the PS including such features as water channels which had heretofore been entirely unexpected. Chapter 2: For a long time, physical, colloid and surface chemistry have not intersected with physiology and cell biology as much as we might have hoped. The reasons are starting to become clear. The discipline of physical chemistry suffered from serious unrecognised omissions that rendered it ineffective. These foundational defects included omission of specific ion molecular forces and hydration effects. The discipline lacked a predictive theory of self-assembly of lipids and proteins. Worse, theory omitted any role for dissolved gases, O2, N2, CO2, and their existence as stable nanobubbles above physiological salt concentration. Recent developments have gone some way to explaining the foam-like lung surfactant structures and function. It delivers O2/N2 as nanobubbles, and efflux of CO2, and H2O nanobubbles at the alveolar surface. Knowledge of pulmonary surfactant structure allows an explanation of the mechanism of corona virus entry, and differences in infectivity of different variants. CO2 nanobubbles, resulting from metabolism passing through the molecular frit provided by the glycocalyx of venous tissue, forms the previously unexplained foam which is the endothelial surface layer. CO2 nanobubbles turn out to be lethal to viruses, providing a plausible explanation for the origin of 'Long COVID'. Circulating nanobubbles, stable above physiological 0.17 M salt drive various enzyme-like activities and chemical reactions. Awareness of the microstructure of Pulmonary Surfactant and that nanobubbles of (O2/N2) and CO2 are integral to respiratory and circulatory physiology provides new insights to the COVID-19 and other pathogen activity.

Structure and function of the endothelial surface layer: unraveling the nanoarchitecture of biological surfaces.

Among the unsolved mysteries of modern biology is the nature of a lining of blood vessels called the 'endothelial surface layer' or ESL. In venous micro-vessels, it is half a micron in thickness. The ESL is 10 times thicker than the endothelial glycocalyx (eGC) at its base, has been presumed to be comprised mainly of water, yet is rigid enough to exclude red blood cells. How is this possible? Developments in physical chemistry suggest that the venous ESL is actually comprised of nanobubbles of CO2, generated from tissue metabolism, in a foam nucleated in the eGC. For arteries, the ESL is dominated by nanobubbles of O2 and N2 from inspired air. The bubbles of the foam are separated and stabilized by thin layers of serum electrolyte and proteins, and a palisade of charged polymer strands of the eGC. The ESL seems to be a respiratory organ contiguous with the flowing blood, an extension of, and a 'lung' in miniature. This interpretation may have far-reaching consequences for physiology.

Resurrecting FUS: Adrenal Androgens as an Ultimate Cause of Hematuria, Periuria, Pollakuria, Stranguria, Urolithiasis and Obstruction in Neutered Cats.

Although many authors have doubted that "feline urological syndrome" (FUS) describes a real pathogenetic entity, because it subsumes such a large variety of signs, Sumner's recent finding that urethral obstruction occurs most frequently in springtime adds to a large body of evidence that lower urinary tract problems occur most commonly in late winter and spring. This suggests that FUS may be a unitary disorder, with a hormonal basis, driven by increasing day length. We argue that rising adrenal androgens (AA) in neutered cats induce stress, and other more concrete manifestations of FUS through androgen-driven mechanisms.

The effect of source animal age upon extracellular matrix scaffold properties.

Biologic scaffold materials composed of mammalian extracellular matrix (ECM) are commonly used for the repair and reconstruction of injured tissues. An important, but unexplored variable of biologic scaffolds is the age of the animal from which the ECM is prepared. The objective of the present study was to compare the structural, mechanical, and compositional properties of small intestinal submucosa (SIS)-ECM harvested from pigs that differed only in age. Degradation product bioactivity of these ECM materials was also examined. Results showed that there are distinct differences in each of these variables among the various age source ECM scaffolds. The strength and growth factors content of ECM from 3-week-old animals is less than that of ECM harvested from 12, 26 or >52-week-old animals. The elastic modulus of SIS-ECM for 3 week and >52-week-old source was less than that of the 12 and 26 week source. Degradation products from all age source ECMs were chemotactic for perivascular stem cells, with the 12 week source the most potent, while the oldest source caused the greatest increase in proliferation. In summary, distinct differences exist in the mechanical, structural, and biologic properties of SIS-ECM harvested from different aged animals.

Distinct early inflammatory events during ear tissue regeneration in mice selected for high inflammation bearing Slc11a1 R and S alleles.

High inflammatory AIRmax mice homozygous for Slc11a1 R and S alleles were produced. AIRmax(SS) mice showed faster ear tissue regeneration than AIRmax(RR) mice, suggesting that the S allele favored tissue restoration. Here, we investigated the gene expression profiles and the inflammatory reactions of AIRmax(RR) and AIRmax(SS) mice during the initial phase of ear tissue regeneration. We observed superior levels of analysis of wound myeloperoxidase and edema in AIRmax(SS) mice, although similar cell influx was verified in both lines. Of the genes, 794 were up- and 674 down-regulated in AIRmax(RR), while 735 genes were found to be up- and 1616 down-regulated in AIRmax(SS) mice 48 h after punch. Both mouse lines showed significant over-represented genes related to cell proliferation; however AIRmax(SS) displayed up-regulation of inflammatory response genes. Quantitative PCR experiments showed higher expressions of Tgfb1, Dap12 and Trem1 genes in AIRmax(SS) mice. These results indicate that Slc11a1 gene modulated the early inflammatory events of ear tissue regeneration.

Unexpected regeneration in middle-aged mice.

Complete regeneration of damaged extremities, including both the epithelium and the underlying tissues, is thought to occur mainly in embryos, fetuses, and juvenile mammals, but only very rarely in adult mammals. Surprisingly, we found that common strains of mice are able to regenerate all of the tissues necessary to completely fill experimentally punched ear holes, but only if punched at middle age. Although young postweaning mice regrew the epithelium without typical pre-scar granulation tissue, they showed only minimal regeneration of connective tissues. In contrast, mice punched at 5-11 months of age showed true amphibian-like blastema formation and regrowth of cartilage, fat, and dermis, with blood vessels, sebaceous glands, hair follicles, and, in black mice, melanocytes. These data suggest that at least partial appendage regeneration may be more common in adult mammals than previously thought and call into question the common view that regenerative ability is lost with age. The data suggest that the age at which various inbred mouse strains become capable of epimorphic regeneration may be correlated with adult body weight.

Is rheumatoid arthritis premature osteoarthritis with fetal-like healing?

Rheumatoid arthritis is now known to share many pathogenetic features with osteoarthritis including synovial activation with release of pro-inflammatory cytokines into the synovial fluid. As premature chondrocyte aging and dedifferentiation is increasingly accepted as integral to OA pathogenesis, premature aging of chondrocytes and perhaps subchondral bone may underlie RA. This hypothesis explains many otherwise enigmatic features of RA joint pathology such as the homing of pannus to cartilage. In addition, the surprising finding of mesenchymal precursor cells in RA joints has led to speculation that some aspect of RA pathogenesis involves an attempt to recapitulate the embryonic limb development program. In its totality, RA seems to consist of an attempt to regenerate damaged cartilage and subchondral bone in an adult organism. Since this is impossible, the best the pannus can do is to crawl through empty cartilage lacunae and replace the cartilage and subchondral bone with scar tissue. As opposed to fetal healing, inflammation is necessary to sustain and control the fibroproliferation. Two recently-discovered blood cell types seem to maintain and regulate fibroplastic states in humans: (1) CD34+ and/or monocytoid stem-cell precursors replace aging mesenchymal cells, and (2) regulatory-type adherent CD4+CD28-T cells control growth of those increasingly apoptosis-resistant mesenchymal cells. Such cells occur at multiple sites in AID patients.