Epithelial Membrane Research Articles

Topical Losartan Decreases Myofibroblast Generation But Not Corneal Opacity After Surface Blast-Simulating Irregular PTK in Rabbits.

To evaluate the efficacy of topical losartan after blast injury-simulating irregular phototherapeutic keratectomy (PTK) in rabbits. Twelve NZW rabbits underwent 100 pulse 6.5mm diameter PTK over a metal screen to generate severe surface irregularity and inhibit epithelial basement membrane regeneration. Corneas were treated with 0.8mg/mL losartan in balanced salt solution (BSS) or BSS 50 µL six times per day for six weeks after PTK. All corneas had slit lamp photography, with and without 1% fluorescein at two, four, and six weeks after PTK, and were analyzed using immunohistochemistry for the myofibroblast marker α-smooth muscle actin (α-SMA), keratocyte marker keratocan, mesenchymal cell marker vimentin, transforming growth factor (TGF)-β1, and collagen type IV. Topical 0.8mg/mL losartan six times a day significantly decreased anterior stromal α-SMA intensity units compared to BSS at six weeks after anterior stromal irregularity-inducing screened PTK (P = 0.009). Central corneal opacity, however, was not significantly different between the two groups. Keratocan, vimentin, TGF-β1, or collagen type IV levels in the anterior stroma were not significantly different between the two groups. Topical losartan effectively decreased myofibroblast generation after surface blast simulation irregular PTK. However, these results suggest initial masking-smoothing PTK, along with adjuvant topical losartan therapy, may be needed to decrease corneal stromal opacity after traumatic injuries that produce severe surface irregularity. Topical losartan decreased scar-producing stromal myofibroblasts after irregular PTK over a metal screen but early smoothing of irregularity would also likely be needed to significantly decrease corneal opacity.

Epithelial polarity-driven membrane separation but not cavitation regulates lumen formation of rat eccrine sweat glands

BackgroundEach eccrine sweat gland (ESG) is a single-tubular structure with a central lumen, and the formation of hollow lumen in the initial solid cell mass is a key developmental process. To date, there are no reports on the mechanism of native ESG lumen formation. MethodsTo investigate the lumen morphogenesis and the lumen formation mechanisms of Sprague-Dawley (SD) rat ESGs, SD rat hind-footpads at E20.5, P1–P5, P7, P9, P12, P21, P28 and P56 were obtained. The lumen morphogenesis of ESGs was examined by HE staining and immunofluorescence staining for polarity markers. The possible mechanisms of lumen formation were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay and autophagy marker LC3B immunofluorescence staining, and further explored by ouabain intervention experiment. ResultsIn SD rat ESGs, the microlumen was formed at P1, and the small intact lumen with apical-basal polarity appeared at P3. The expression of apical marker F-actin, basal marker Laminin, basolateral marker E-cadherin was consistent with the timing of lumen formation of SD rat ESGs. During rat ESG development, apoptosis and autophagy were not detected. However, inhibition of Na+-K+-ATPase (NKA) with ouabain resulted in decreased lumen size, although neither the timing of lumen formation nor the expression of polarity proteins was altered. ConclusionsEpithelial polarity-driven membrane separation but not cavitation regulates lumen formation of SD rat ESGs. NKA-regulated fluid accumulation drives lumen expansion.

Epithelial Membrane Protein-3 and Chitinase-3-like Protein-1 as New Prognostic Predictors of Glioma, a Two-Gene Study.

Glioblastoma multiforme is the most common primary intracranial tumor, with a high degree of malignancy, poor therapeutic effect, and poor prognosis. According to previous studies, CHI3L1 and EMP3 are two independent tumor predictors that are of great significance for the prognostic prediction of other tumors, and their expression levels may be related to the prognosis of glioma patients. using Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), the Chinese Glioma Genome Atlas (CGGA), cBioPortal, LinkedOmics, and other databases, 693 glioma patients were screened to analyze the relationship between EMP3 and CHI3L1 expression and prognosis in glioma patients. low-grade glioma patients with a low expression of EMP3/CHI3L1 had a better prognosis, and the combination of EMP3/CHI3L1 is a new predictor for glioma patients. We used the TCGA and CGGA databases to analyze the effect of EMP3 and CHI3L1 expression on the prognosis of glioma patients and their correlation with gene expression using bioinformation analysis. The results showed that low-grade glioma patients with a low expression of EMP3 and CHI3L1 had a better prognosis, and EMP3 and CHI3L1 co-expression genes were correlated. The combination of these two factors could be a new prognostic index for glioma patients.

Matrix Metalloproteinases and the Pathogenesis of Recurrent Corneal Erosions and Epithelial Basement Membrane Dystrophy.

Matrix metalloproteinases (MMPs) are a group of proteolytic enzymes which are members of the zinc endopeptidase family. They have the ability to degrade extracellular matrix elements, allowing for the release of binding molecules and cell migration. Although metalloproteinases regulate numerous physiological processes within the cornea, overexpression of metalloproteinase genes and an imbalance between the levels of metalloproteinases and their inhibitors can contribute to the inhibition of repair processes, the development of inflammation and excessive cellular proliferation. The involvement of MMPs in the pathogenesis of dystrophic corneal diseases needs clarification. Our analyses focus on the involvement of individual metalloproteinases in the pathogenesis of recurrent corneal erosions and highlight their impact on the development of corneal epithelial basement membrane dystrophy (EBMD). We hypothesize that abnormalities observed in patients with EBMD may result from the accumulation and activation of metalloproteinases in the basal layers of the corneal epithelium, leading to basement membrane degradation. A barrier formed from degradation materials inhibits the normal migration of epithelial cells to the superficial layers, which contributes to the development of the aforementioned lesions. This hypothesis seems to be lent support by the elevated concentrations of metalloproteinases in the corneal epithelium of these patients found in our previous studies on the relationships between MMPs and recurrent corneal erosions.

EMP3 as a key downstream target of miR-663a regulation interferes with MAPK/ERK signaling pathway to inhibit gallbladder cancer progression

Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract, and its molecular pathogenesis remains unclear. Here we explore the functional roles of epithelial membrane protein 3 (EMP3) in GBC progression, which is aberrantly expressed in various types of cancers. The results showed that the expression level of EMP3 was reduced in human GBC tissues compared with non-malignant tissues. Further, the low expression of EMP3 was associated with the poor prognosis of GBC patients by Kaplan-Meier analysis. The ectopic expression of EMP3 inhibited GBC cell proliferation, migration and invasion in vitro and in vivo. Conversely, the depletion of EMP3 promoted GBC cell growth and metastasis. In addition, we found that EMP3 was a target gene of miR-663a, and the downregulation of EMP3 in GBC was attributed to the overexpression of miR-663a. MiR-663a was also shown to be a tumor-promoting factor mediating GBC development. In this study, we demonstrate that downregulation of EMP3 activates MAPK/ERK signaling, which regulates GBC progression. These data reveal the mechanism by which EMP3 inhibits the progression of GBC, suggesting that the miR-663a/EMP3/MAPK/ERK axis may be a new therapeutic target for GBC treatment.

Scavenger receptor endocytosis controls apical membrane morphogenesis in the Drosophila airways.

The acquisition of distinct branch sizes and shapes is a central aspect in tubular organ morphogenesis and function. In the Drosophila airway tree, the interplay of apical extracellular matrix (ECM) components with the underlying membrane and cytoskeleton controls tube elongation, but the link between ECM composition with apical membrane morphogenesis and tube size regulation is elusive. Here, we characterized Emp (epithelial membrane protein), a Drosophila CD36 homolog belonging to the scavenger receptor class B protein family. emp mutant embryos fail to internalize the luminal chitin deacetylases Serp and Verm at the final stages of airway maturation and die at hatching with liquid filled airways. Emp localizes in apical epithelial membranes and shows cargo selectivity for LDLr-domain containing proteins. emp mutants also display over elongated tracheal tubes with increased levels of the apical proteins Crb, DE-cad, and phosphorylated Src (p-Src). We show that Emp associates with and organizes the βH-Spectrin cytoskeleton and is itself confined by apical F-actin bundles. Overexpression or loss of its cargo protein Serp lead to abnormal apical accumulations of Emp and perturbations in p-Src levels. We propose that during morphogenesis, Emp senses and responds to luminal cargo levels by initiating apical membrane endocytosis along the longitudinal tube axis and thereby restricts airway elongation.

Clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma.

The aim of this study was to investigate the clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma. Histopathology, immunohistochemistry, and human epidermal growth factor receptor 2 (HER2) gene testing were conducted for seven cases of gastric pleomorphic giant cell carcinoma. In histomorphological terms, all seven cases involved pleomorphic giant cell carcinoma, accounting for more than 10% of the entire tumor, with pleomorphic spindle cells and giant cells mixed with various histomorphological structures of adenocarcinoma with high, intermediate, and low differentiation. There was large heterogeneity in the HER2 protein expression and HER2 gene amplification in the gastric pleomorphic giant cell carcinoma, and both levels of HER2 were focal in three cases, accounting for 42.9% (3/7). The mismatch repair gene proteins MLH1, MSH2, PMS2, and MSH6 were positive. Routine immunohistochemical markers, i.e., pan-cytokeratin, epithelial membrane antigen, villin, caudal-type homeobox 2, E-cadherin, and p53, were positive in the gastric pleomorphic giant cell carcinoma, while vimentin, calponin, smooth muscle actin, nestin, S-100, cluster of differentiation (CD) 99, desmin, and CD34 were focally expressed in both the spindle and the giant cells, with Ki-67-positive cells accounting for 70-80%. Gastric pleomorphic giant cell carcinoma presents multiple histomorphological features and is easily confused with various tumors. Clarifying the histopathological features of this type of tumor is important for differential diagnosis and precise treatment.

Gill structure and respiratory ability of Euchiloglanis kishinouyei (Osteichthyes: Siluriformes: Sisoridae).

Glyptosternoid fishes are distributed in the torrent environment of alpine canyons, where they often leave the water to climb rocky cliffs. As one of the most primitive species of glyptosternoid fishes, Euchiloglanis kishinouyei was examined in the current study to analyse its gill microstructure and respiratory ability. We first found that the oxygen consumption rate was relatively high and negatively correlated with body mass and that the average oxygen consumption at night was higher than during the day. The asphyxiation point of E. kishinouyei (5.05 ± 0.22 g) was c. 1.93 mg/L. Subsequently, the surface morphology, gross gill tissue structure, and ultra-microstructure of gill lamellae were investigated using optical microscopy and SEM. The gills showed an overall trend of regression, with five pairs of gill arches in each gill cavity. The adjacent gill filaments had large gaps, and the gill lamellae were thick. The gill filaments were closely arranged on the gill arches, their folded respiratory surface was highly vascularized with no tiny crest, and there were obvious tiny crests, grooves, pits, and pores on the nonrespiratory surface. The gill lamellae were closely embedded on both sides of gill filaments, which were composed of flat epithelial cells, basement membrane, pillar cells, and mucous cells. The gill total respiratory area correlated positively with body mass and length, whereas the gill relative respiratory area correlated negatively with body mass. We comprehensively analysed the gill microstructure and respiratory capacity of E. kishinouyei to provide fundamental data for the adaptive evolution of the gill structures of bimodally respiring fishes and offer insights into further study on the accessory air-breathing function of skin.

What is new in intraneural perineurioma?

Since the initial description of intraneural (IN) perineurioma in 1964, advances in the understanding of the clinical presentation, diagnostic imaging, pathologic features, and genetic underpinnings have changed how this pathology is managed. IN perineuriomas are rare, benign peripheral nerve sheath tumors, most frequently coming to clinical attention when patients present with painless, progressive weakness or sensory loss in adolescence or young adulthood. The gold standard of diagnosis has traditionally been with targeted tissue biopsy demonstrating "pseudo-onion bulb" formation with positive epithelial membrane antigen (EMA) staining. However, modern magnetic resonance imaging is allowing some patients to forgo biopsy. Recent genetic studies of IN perineuriomas have demonstrated common TRAF7 point mutations and rare NF2 mutations, which may present targets for diagnosis or therapy in the future. Current advances have allowed for us to provide improved patient counseling with informed understanding for various clinical scenarios. With the workup and diagnosis now clearly defined, the next frontier is for improving the lives of patients with IN perineuriomas through the interaction between restoration of functional deficits and advances in our understanding of the genetics of this entity.

Lymphoplasmacyte-Rich Meningioma or IgG4-Related Disease

Lymphoplasmacyte-rich meningioma (LP meningioma) is a rare form of grade 1 meningioma. It shows dense lymphoplasmacytic infiltrate, mimicking an inflammatory lesion. We present a case of Lymphoplasmacyte-rich (LP) meningioma in the left parasagittal region in a 47-year-old female. On histological examination, it showed dense lymphoplasmacytic infiltrate masking the meningothelial component. There was dense fibrosis and numerous IgG4-positive plasma cells (100-120/hpf), admixed with lymphocytes and few histiocytes. The meningothelial component was highlighted by epithelial membrane antigen (EMA) immunostain. The patient had normal serum IgG4 level. This case highlights the morphological overlap between LP meningioma and IgG4-related disease. The presence of fibrosis and increased IgG4-positive plasma cells as a major inflammatory component in LP meningioma, as demonstrated in the present case and some other previous studies raise suspicion of its association with IgG4-related disease. However, this hypothesis requires further detailed studies for confirmation.

Transforming growth factor beta-3 localization in the corneal response to epithelial-stromal injury and effects on corneal fibroblast transition to myofibroblasts

The purpose of this study was to evaluate the localization of TGF beta-3 in situ in unwounded rabbit corneas and corneas that had epithelial-stromal injuries produced by photorefractive keratectomy (PRK) in rabbits and to evaluate the in vitro effects of TGF beta-3 compared to TGF beta-1 on alpha-smooth muscle actin (α-SMA) protein expression and myofibroblast development in corneal fibroblasts. Forty-eight New Zealand white rabbits underwent either -3 diopter (D) or -9D PRK and were studied from one to eight weeks (four corneas in each group at each time point) after surgery with immunohistochemistry for TGF beta-3, laminin alpha-5, and alpha-smooth muscle actin (α-SMA). Rabbit corneal fibroblasts were treated with activated TGF beta-1 and/or TGF beta-3 at different concentrations and duration of exposure and studied with immunocytochemistry for myofibroblast development and the expression of α-SMA using Jess automated Western blotting. TGF beta-3 was detected at high levels in the stroma of unwounded corneas and corneas at one to eight weeks after -3D or -9D PRK, as well as in the epithelium and epithelial basement membrane (EBM). No difference was noted between corneas that healed with and without myofibroblast-mediated fibrosis, although TGF beta-3 was commonly associated with myofibroblasts. TGF beta-3 effects on corneal fibroblasts in vitro were similar to TGF beta-1 in stimulating transition to α-SMA-positive myofibroblasts and promoting α-SMA protein expression. The corneal stromal localization pattern of TGF beta-3 protein in unwounded corneas and corneas after epithelial-stromal injury was found to be higher and different from TGF beta-1 and TGF beta-2 reported in previous studies. TGF beta-3 had similar effects to TGF beta-1 in driving myofibroblast development and α-SMA expression in corneal fibroblasts cultured in medium with 1% fetal bovine serum.

Diode Character of Local Conductivity of Human Buccal Epithelial Cell Membranes

AFM methods revealed unilateral (diode) local electrical conductivity of the membrane of human buccal epithelium cells at the nanoscale and its correlation with the topology of micromechanical properties.

Expression of EMP 1, 2, and 3 in Adrenal Cortical Neoplasm and Pheochromocytoma.

The purpose of this study is to investigate the expression of the epithelial membrane proteins (EMP) 1, 2, and 3 in adrenal gland neoplasm and to explore the broader implications of this. Tissue microarrays were constructed for 132 cases of adrenal cortical neoplasms (ACN) (adrenal cortical adenoma (115 cases), and carcinoma (17 cases)) and 189 cases of pheochromocytoma. Immunohistochemical staining was performed to identify EMP 1, 2, and 3, and was compared with clinicopathological parameters. The H-score of EMP 3 (p < 0.001) was higher in pheochromocytoma when compared to that of ACN, and the H-score of EMP 1 (p < 0.001) and EMP 3 (p < 0.001) was higher in adrenal cortical carcinomas when compared to that of adrenal cortical adenomas. A higher EMP 1 H-score was observed in pheochromocytomas with a GAPP score ≥3 (p = 0.018). In univariate analysis, high levels of EMP 1 and EMP 3 expression in ACN were associated with shorter overall survival (p = 0.001). Differences were observed in the expression of EMPs between ACN and pheochromocytoma. EMPs are associated with malignant tumor biology in adrenal cortical neoplasm and pheochromocytoma, suggesting the role of a prognostic and/or predictive factor for EMPs in adrenal tumor.

Malignant mesothelioma cells with characteristic intracytoplasmic vacuolization and lipids.

In this brief report, we described some uncommon cytomorphological features of malignant mesothelioma (MM) cells in pleural effusions. The tumor cells exhibited abundant cytoplasmic vacuolization, with presence of single or multiple eccentric nuclei in several cells. In the Giemsa-stained smear, we observed a glossy spherical material in some cells, which tested positive in Sudan III stain. In immunocytochemical analysis, tumor cells were positive for calretinin, podoplanin, epithelial membrane antigen, and methylthioadenosine phosphorylase; tumor cells were negative for BRCA1-associated protein 1, CD68, and desmin. The intracytoplasmic vacuoles were positive for adipophilin expression.

Monocarboxylate Transporter 13 (MCT13/SLC16A13) Functions as a Novel Plasma Membrane Oligopeptide Transporter.

SLC16A13, which encodes the monocarboxylate transporter 13 (MCT13), is a susceptibility gene for type 2 diabetes and is expressed in the liver and duodenum. Some peptidase-resistant oligopeptides are absorbed in the gastrointestinal tract and affect glycemic control in the body. Their efficient absorption is mediated by oligopeptide transporter(s) at the apical and basolateral membranes of the intestinal epithelia; however, the molecules responsible for basolateral oligopeptide transport have not been identified. In this study, we examined whether MCT13 functions as a novel basolateral oligopeptide transporter. We evaluated the uptake of oligopeptides and peptidomimetics in MCT13-transfected cells. The uptake of cephradine, a probe for peptide transport system(s), significantly increased in MCT13-transfected cells, and this increase was sensitive to membrane potential. The cellular accumulation of bioactive peptides, such as anserine and carnosine, was decreased by MCT13, indicating MCT13-mediated efflux transport activity. In polarized Caco-2 cells, MCT13 was localized at the basolateral membrane. MCT13 induction enhanced cephradine transport in an apical-to-basal direction across Caco-2 cells. These results indicate that MCT13 functions as a novel efflux transporter of oligopeptides and peptidomimetics, driven by electrochemical gradients across the plasma membrane, and it may be involved in the transport of these compounds across the intestinal epithelia.

A critical review of microplastics toxicity and potential adverse outcome pathway in human gastrointestinal tract following oral exposure

Microplastics (MPs) are typically produced via environmental degradation of larger plastics, where they enter the human food chain. MPs are complex materials containing chemical and physical characteristics that can potentially affect their hazard and exposure. These physical properties can be altered by environmental exposure potentially altering any risk assessment conducted on the primary material. We conducted a literature review using an Adverse Outcome Pathway (AOP)-based approach from Molecular Initiating Event (MIE) to cell effect event to identify multiple knowledge gaps that affect MPs hazard assessment. There is some convergence of key biological events but could relate to most lying along well-established biological effector pathways such as apoptosis which can respond to many MIEs. In contrast, MIEs of chemicals will be via protein interaction. As MPs may occur in the lumen of the alimentary canal for example to the mucus, therefore, not requiring translocation of MPs across the epithelial membrane. At the other end of the AOP, currently it is not possible to identify a single adverse outcome at the organ level. This work did establish a clear need to understand both external and internal exposure (resulting from translocation) and develop hazard data at both levels to inform on risk assessments.

Association between immunohistochemical markers and tumor progression following resection of spinal chordomas: a multicenter study.

Chordomas are slow-growing tumors derived from notochord remnants. Despite margin-negative excision and postoperative radiation therapy, spinal chordomas (SCs) often progress. The potential of immunohistochemical (IHC) markers, such as epithelial membrane antigen (EMA), combined with machine learning algorithms to predict long-term (≥ 12 months) postoperative tumor progression, has been understudied. The authors aimed to identify IHC markers using trained tree-based algorithms to predict long-term (≥ 12 months) postoperative tumor progression. The authors reviewed the records of patients who underwent resection of SCs between January 2017 and June 2021 across the Mayo Clinic enterprise. Demographics, type of treatment, histopathology, and other relevant clinical factors were abstracted from each patient's record. Low tumor progression was defined as more than a 94.3-mm3 decrease in the tumor size at the latest radiographic follow-up. Decision trees and random forest classifiers were trained and tested to predict the long-term volumetric progression after an 80/20 data split. Sixty-two patients diagnosed with and surgically treated for SC were identified, of whom 31 were found to have a more advanced tumor progression based on the tumor volume change cutoff of 94.3 mm3. The mean age was 54.3 ± 13.8 years, and most patients were male (62.9%) and White (98.4%). The most common treatment modality was subtotal resection with radiation therapy (35.5%), with proton beam therapy being the most common (71%). Most SCs were sacrococcygeal (41.9%), followed by cervical (32.3%). EMA-positive SCs had a postoperative progression risk of 67%. Pancytokeratin-positive SCs had a progression rate of 67%; however, patients with S100 protein-positive SCs had a 54% risk of progression. The accuracy of this model in predicting the progression of unseen test data was 66%. Pancytokeratin (mean minimal depth = 1.57), EMA (mean minimal depth = 1.58), cytokeratin A1/A3 (mean minimal depth = 1.59), and S100 protein (mean minimal depth = 1.6) predicted the long-term volumetric progression. Multiway variable importance plots show the relative importance of the top 10 variables based on three measures of varying significance and their predictive role. These IHC variables with tree-based machine learning tools successfully demonstrate a high capacity to identify a patient's tumor progression pattern with an accuracy of 66%. Pancytokeratin, EMA, cytokeratin A1/A3, and S100 protein were the IHC drivers of a low tumor progression. This shows the power of machine learning algorithms in analyzing and predicting outcomes of rare conditions in a small sample size.

Digital Papillary Adenocarcinoma in Nonacral Skin: Clinicopathologic and Genetic Characterization of 5 Cases.

Digital papillary adenocarcinoma (DPA) is a rare sweat gland neoplasm that has exceptionally been reported outside acral locations. Recently, human papillomavirus 42 was identified as the main oncogenic driver of DPA. Herein, we report 5 tumors arising in extra-acral locations predominantly in the female anogenital skin. Four patients were female and 1 patient was male. The mean age at the diagnosis time was 65 years (range: 55 to 82y). Tumors were located on the vulva (n=3), perianal area (n=1), and forearm (n=1). Histologically, all tumors were lobular and mainly solid and composed of sheets of cells with rare focal papillae and frequent glandular structures in a "back-to-back" pattern and lined by atypical basophilic cells. Immunohistochemistry showed diffuse positivity for SOX10. Epithelial membrane antigen and carcinoembryonic antigen highlighted the luminal cells and staining for p63 and p40 revealed a consistent and continuous myoepithelial component around glandular structures. Follow-up was available in 3 cases (mean duration: 12mo [range: 8 to 16mo]). One patient developed local recurrence and 1 experienced regional lymph node metastases. HPV Capture Next-generation sequencing revealed the presence of the HPV42 genome in all samples. Viral reads distributions were compatible in the 5 cases with an episomal nature of the viral genome, with a recurrent deletion in the E1 and/or E2 open reading frames. In conclusion, this study demonstrates that digital DPA may rarely present in nonacral locations mainly in the female anogenital area, usually with a more solid pattern as compared with those cases presenting on the digits and it is also associated with HPV42.

Influence of SGLT1 Sugar Uptake Inhibitors on Water Transport.

Sodium glucose cotransporters (SGLTs) are cotransporters located in the cell membrane of various epithelia that uptake glucose or galactose and sodium into the cell. Its founding member, SGLT1, represents a major pharmaceutically relevant target protein for development of new antidiabetic drugs, in addition to being the target protein of the oral rehydration therapy. Previous studies focused primarily on the transport of substrates and ions, while our study focuses on the effect of water transport. SGLT1 is implicated in the absorption of water, yet the exact mechanism of how the water absorption occurs or how inhibitors of SGLT1, such as phlorizin, are able to inhibit it is still unclear. Here we present a comprehensive study based on molecular dynamics simulations with the aim of determining the influence of the energetic and dynamic properties of SGLT1, which are influenced by selected sugar uptake inhibitors on water permeation.

Computational pulmonary edema: A microvascular model of alveolar capillary and interstitial flow.

We present a microvascular model of fluid transport in the alveolar septa related to pulmonary edema. It consists of a two-dimensional capillary sheet coursing by several alveoli. The alveolar epithelial membrane runs parallel to the capillary endothelial membrane with an interstitial layer in between, making one long septal tract. A coupled system of equations uses lubrication theory for the capillary blood, Darcy flow for the porous media of the interstitium, a passive alveolus, and the Starling equation at both membranes. Case examples include normal physiology, cardiogenic pulmonary edema, acute respiratory distress syndrome (ARDS), hypoalbuminemia, and effects of PEEP. COVID-19 has dramatically increased ARDS in the world population, raising the urgency for such a model to create an analytical framework. Under normal conditions fluid exits the alveolus, crosses the interstitium, and enters the capillary. For edema, this crossflow is reversed with fluid leaving the capillary and entering the alveolus. Because both the interstitial and capillary pressures decrease downstream, the reversal can occur within a single septal tract, with edema upstream and clearance downstream. Clinically useful solution forms are provided allowing calculation of interstitial fluid pressure, crossflows, and critical capillary pressures. Overall, the interstitial pressures are found to be significantly more positive than values used in the traditional physiological literature. That creates steep gradients near the upstream and downstream end outlets, driving significant flows toward the distant lymphatics. This new physiological flow provides an explanation to the puzzle, noted since 1896, of how pulmonary lymphatics can function so far from the alveoli: the interstitium is self-clearing.