Effect of Extracellular pH on Selectin Adhesion: Theory and Experiment

Abstract

Selectins mediate circulatory leukocyte trafficking to sites of inflammation and trauma, and the extracellular microenvironments at these sites often become acidic. In this study, we investigated the influence of slightly acidic pH on the binding dynamics of selectins (P-, L-, and E-selectin) to P-selectin glycoprotein ligand-1 (PSGL-1) via computational modeling (molecular dynamics) and experimental rolling assays under shear in vitro. The P-selectin/PSGL-1 binding is strengthened at acidic pH, as evidenced by the formation of a new hydrogen bond (seen computationally) and the observed decrease in the rolling velocities of model cells. In the case of L-selectin/PSGL-1 binding dynamics, the binding strength and frequency increase at acidic pH, as indicated by the greater cell-rolling flux of neutrophils and slower rolling velocities of L-selectin-coated microspheres, respectively. The cell flux is most likely due to an increased population of L-selectin in the high-affinity conformation as pH decreases, whereas the velocities are due to increased L-selectin/PSGL-1 contacts. In contrast to P- and L-selectin, the E-selectin/PSGL-1 binding does not exhibit significant changes at acidic pH levels, as shown both experimentally and computationally.

Targeting Underglycosylated MUC1 for the Selective Capture of Highly Metastatic Breast Cancer Cells Under Flow

“…Our group has exploited this selectin preference while studying the efficiency of halloysite nanotubes on CTC capture,18,19 where P-selectin was utilized when cells expressed PSGL-1 and E-selectin was used otherwise. We have also found that pathologically decreasing extracellular pH can enhance PSGL-1 binding to P- and L-selectin, while having no effect on E-selectin:PSGL-1 binding 5. Taken together, the use of different selectins can offer another axis of control to more efficiently and selectively capture CTCs.…”

Evaluation of the Relationship of Serum Lactate Concentration and Blood pH on Surgical Wound Healing in Cats Submitted to Total Mastectomy as an Animal Model

“…A mastectomy is a surgical procedure characterised by the exeresis of a variable amount of mammary gland tissue, and represents the first choice and the main approach for treating mammary neoplasia. [29] This type of cancer is the third most common in cats, 26 occurring in middle-aged to old animals between 8 and 12 years, and about 90% of neoplasms are malignant. [30][31][32] The mean age of the patients sample (11.1 years old) was within the interval cited by the literature, as well as for the histopathological neoplasm characterisation, considering that all patients of the sample presented a tubular adenocarcinoma which in cats, represents the most frequent type of mammary gland tumors.…”

“…All changes in blood pH, in physiological and pathological conditions, occur through variations in three major variables: the CO2, the electrolyte concentrations, and total weak acid concentrations. [26,42] When CO 2 elimination is inadequate relative to the rate of tissue production, will going to increase the H + concentration inducing a decrease in the pH value. [43][44][45][46][47][48][49][50][51][52] pH values below 7.35 are associated with acidaemia, whereas values higher than 7.45 are indicative of alkalaemia (7.4 is considered neutral).…”

“…An indicator of this is the lower venous blood pH compared to the arterial blood pH. [53,54] When a decrease of tissue blood flow occurs, such as in surgical wounds, ischemia will lead to a lactate increase with an inadequate extraction of metabolites promoting a decrease the local pH level, [26,55,56] which will promote angiogenesis of injured tissues. [57] Also the tissue hypoxia serves as a physiological sign to drive angiogenic response, and to raise lactate production and lower pH.…”

“…[24,25] Lactate and other products are removed from the tissues by the return blood flow of venulas, promoting therefore a decrease in the pH values of venous blood, with the establishment of an acidosis in the early stages of tissue healing process. [26][27][28] The present study was developed in a sample of 40 female cats (N=40) with diagnosis of mammary neoplasia and submitted to total unilateral mastectomy with lymph nodes deflation, and aimed to 1) evaluate the relationship of serum lactate concentration and blood pH on surgical wound healing in cats submitted to total mastectomy.…”