Cell-matrix interactions are fundamental to many developmental, homeostatic, immune and pathologic processes. Hyaluronan (HA), a critical component of the extracellular matrix (ECM) that regulates ...normal structural integrity and development, also regulates tissue responses during injury, repair, and regeneration. Though simple in its primary structure, HA regulates biological responses in a highly complex manner with balanced contributions from its molecular size and concentration, synthesis versus enzymatic and/or oxidative-nitrative fragmentation, interactions with key HA binding proteins and cell associated receptors, and its cell context-specific signaling. This review highlights the different, but inter-related factors that dictate the biological activity of HA and introduces the overarching themes that weave throughout this special issue of Matrix Biology on hyaluronan.
•Hyaluronan (HA) has a simple primary biochemical structure, yet a complex biology.•Diversity in the biologic actions of HA is achieved by its special properties, binding partners and signaling pathways.•HA has been implicated in a wide variety of homeostatic and pathogenetic mechanisms.•Increased knowledge of HA biology has produced several therapeutic advances, with promising new approaches on the horizon.
Organophosphate flame retardants (PFRs) are becoming popular replacements for the phased-out polybrominated diphenyl ether (PBDE) mixtures, and they are now commonly detected in indoor environments. ...However, little is known about human exposure to PFRs because they cannot be easily measured in blood or serum.
To investigate relationships between the home environment and internal exposure, we assessed associations between two PFRs, tris(1,3-dichloropropyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP), in paired hand wipe and dust samples and concentrations of their metabolites in urine samples (n = 53). We also assessed short-term variation in urinary metabolite concentrations (n = 11 participants; n = 49 samples).
Adult volunteers in North Carolina, USA, completed questionnaires and provided urine, hand wipe, and household dust samples. PFRs and PBDEs were measured in hand wipes and dust, and bis(1,3-dichloropropyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP), metabolites of TDCIPP and TPHP, were measured in urine.
TDCIPP and TPHP were detected frequently in hand wipes and dust (> 86.8%), with geometric mean concentrations exceeding those of PBDEs. Unlike PBDEs, dust TDCIPP and TPHP levels were not associated with hand wipes. However, hand wipe levels were associated with urinary metabolites. Participants with the highest hand wipe TPHP mass, for instance, had DPHP levels 2.42 times those of participants with the lowest levels (95% CI: 1.23, 4.77). Women had higher levels of DPHP, but not BDCIPP. BDCIPP and DPHP concentrations were moderately to strongly reliable over 5 consecutive days (intraclass correlation coefficients of 0.81 and 0.51, respectively).
PFR exposures are widespread, and hand-to-mouth contact or dermal absorption may be important pathways of exposure.
Hyaluronan signaling properties are unique among other biologically active molecules, that they are apparently not influenced by postsynthetic molecular modification, but by hyaluronan fragment size. ...This review summarizes the current knowledge about the generation of hyaluronan fragments of different size and size-dependent differences in hyaluronan signaling as well as their downstream biological effects.
Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA.
To reduce uncertainties about the metabolism and excretion of ...BPA in humans following oral administration.
We exposed six men and eight women to 100μg/kg bw of deuterated BPA (d6-BPA) by oral administration and conducted blood and urine analysis over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) BPA. We calculated the rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates.
Mean serum total (unconjugated and conjugated) d6-BPA Cmax of 1711nM (390ng/ml) was observed at Tmax of 1.1±0.50h. Unconjugated d6-BPA appeared in serum within 5–20min of dosing with a mean Cmax of 6.5nM (1.5ng/ml) observed at Tmax of 1.3±0.52h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48h in some subjects at concentrations near the LOD (0.001–0.002ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4±2.0h and 6.2±2.6h, respectively. Recovery of total administered d6-BPA in urine was 84–109%. Most subjects (10 of 14) excreted >90% as metabolites within 24h.
Using more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated BPA comprising less than 1% of the total d6-BPA in blood at all times. Elimination of conjugates into urine largely occurs within 24h.
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•Findings are consistent with data from animal and other human studies.•Maximum total serum levels are 3.9ng/ml for each μg ingested per kg.•Maximum unconjugated serum levels are 0.015ng/ml for each μg ingested per kg.•Unconjugated BPA in blood following oral administration is <1% of the total.•Most subjects excreted >90% as conjugated metabolites within 24h.
Lung disease causes significant morbidity and mortality, and is exacerbated by environmental injury, for example through lipopolysaccharide (LPS) or ozone (O
). Toll-like receptors (TLRs) orchestrate ...immune responses to injury by recognizing pathogen- or danger-associated molecular patterns. TLR4, the prototypic receptor for LPS, also mediates inflammation after O
, triggered by endogenous hyaluronan. Regulation of TLR4 signaling is incompletely understood. TLR5, the flagellin receptor, is expressed in alveolar macrophages, and regulates immune responses to environmental injury. Using in vivo animal models of TLR4-mediated inflammations (LPS, O
, hyaluronan), we show that TLR5 impacts the in vivo response to LPS, hyaluronan and O
. We demonstrate that immune cells of human carriers of a dominant negative TLR5 allele have decreased inflammatory response to O
exposure ex vivo and LPS exposure in vitro. Using primary murine macrophages, we find that TLR5 physically associates with TLR4 and biases TLR4 signaling towards the MyD88 pathway. Our results suggest an updated paradigm for TLR4/TLR5 signaling.
The extracellular matrix is an active participant, modulator and mediator of the cell, tissue, organ and organismal response to injury. Recent research has highlighted the role of hyaluronan, an ...abundant glycosaminoglycan constituent of the extracellular matrix, in many fundamental biological processes underpinning homeostasis and disease development. From this basis, emerging studies have demonstrated the therapeutic potential of strategies which target hyaluronan synthesis, biology and signaling, with significant promise as therapeutics for a variety of inflammatory and immune diseases. This review summarizes the state of the art in this field and discusses challenges and opportunities in what could emerge as a new class of therapeutic agents, that we term “matrix biologics”.
Engineered nanomaterials, defined as having at least one dimension smaller than 100 nm, have revolutionized many technology sectors ranging from therapeutics and diagnostics to environmental ...monitoring and remediation. This has resulted in a rapid increase in their manufacture over the past few years, accompanied by an increased human exposure potential. However, understanding of the interactions of nanomaterials with biological systems is still rudimentary. We have described that an environmentally and medically relevant nano metal (cerium dioxide) can affect primary human monocyte viability and interact with programmed cell death pathways leading to apoptosis and autophagic cell death. Cerium dioxide nanoparticles (CeO
2
NPs)-induced autophagy acts as a prodeath mechanism and leads to increased cytotoxicity of human monocytes. A better understanding of the implication and biological significance of CeO
2
NPs-induced autophagy and apoptosis will help us understand the risks associated with its uses and develop safer nanomedicine.
Epithelial injury is a central event in the pathogenesis of many inflammatory and fibrotic lung diseases like acute respiratory distress syndrome, pulmonary fibrosis, and iatrogenic lung injury. ...Mechanical stress is an often underappreciated contributor to lung epithelial injury. Following injury, differentiated epithelia can assume a myofibroblast phenotype in a process termed epithelial to mesenchymal transition (EMT), which contributes to aberrant wound healing and fibrosis. We demonstrate that cyclic mechanical stretch induces EMT in alveolar type II epithelial cells, associated with increased expression of low molecular mass hyaluronan (sHA). We show that sHA is sufficient for induction of EMT in statically cultured alveolar type II epithelial cells and necessary for EMT during cell stretch. Furthermore, stretch-induced EMT requires the innate immune adaptor molecule MyD88. We examined the Wnt/β-catenin pathway, which is known to mediate EMT. The Wnt target gene Wnt-inducible signaling protein 1 (wisp-1) is significantly up-regulated in stretched cells in hyaluronan- and MyD88-dependent fashion, and blockade of WISP-1 prevents EMT in stretched cells. In conclusion, we show for the first time that innate immunity transduces mechanical stress responses through the matrix component hyaluronan, and activation of the Wnt/β-catenin pathway.
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