(Am J Pathol[TA]) articles in PubMed
- Fibromodulin Is Essential for Fetal-Type Scarless Cutaneous Wound Healing. [Journal Article]
- Am J Pathol 2016 Sep 22AJ
- In contrast to adult and late-gestation fetal skin wounds, which heal with scar, early-gestation fetal skin wounds display a remarkable capacity to heal scarlessly. Although the underlying mechanism ...
In contrast to adult and late-gestation fetal skin wounds, which heal with scar, early-gestation fetal skin wounds display a remarkable capacity to heal scarlessly. Although the underlying mechanism of this transition from fetal-type scarless healing to adult-type healing with scar has been actively investigated for decades, in utero restoration of scarless healing in late-gestation fetal wounds has not been reported. In this study, using loss- and gain-of-function rodent fetal wound models, we identified that fibromodulin (Fm) is essential for fetal-type scarless wound healing. In particular, we found that loss of Fm can eliminate the ability of early-gestation fetal rodents to heal without scar. Meanwhile, administration of Fm protein alone was capable of restoring scarless healing in late-gestation rat fetal wounds, which naturally heal with scar, as characterized by dermal appendage restoration and organized collagen architectures that were virtually indistinguishable from those in age-matched unwounded skin. High Fm levels correlated with decreased transforming growth factor (TGF)-β1 expression and scarless repair, while low Fm levels correlated with increased TGF-β1 expression and scar formation. This study represents the first successful in utero attempt to induce scarless repair in late-gestation fetal wounds by using a single protein, Fm, and highlights the crucial role that the FM-TGF-β1 nexus plays in fetal-type scarless skin repair.
- Future Perspectives on Pathogenesis of Lupus Nephritis: Facts, Problems, and Potential Causal Therapy Modalities. [Review]
- Am J Pathol 2016 Sep 21AJ
- Divergent incommensurable models have been developed to explain the pathogenesis of lupus nephritis. Most contemporary models favor a central role for anti-chromatin antibodies. How they exert their ...
Divergent incommensurable models have been developed to explain the pathogenesis of lupus nephritis. Most contemporary models favor a central role for anti-chromatin antibodies. How they exert their pathogenic effect has, however, endorsed conflicts that at least for now preclude insight into definitive pathogenic pathways. The following paradigms are contemporarily in conflict with each other: i) the impact of anti-double-stranded DNA (dsDNA) antibodies that cross-react with inherent renal antigens, ii) the impact of anti-dsDNA antibodies targeting exposed chromatin in glomeruli, and iii) the impact of relative antibody avidity for dsDNA, chromatin fragments, or cross-reacting antigens. Aside from these three themes, the pathogenic role of T cells in lupus nephritis is not clear. These different models should be tested through a collaboration between scientists belonging to the different paradigms. If it turns out that there are different pathogenic pathways in lupus nephritis, the emerging pathogenic mechanism(s) may be encountered with new individual causal therapy modalities. Today, therapy is still unspecific and far from interfering with the cause(s) of the disorder. This review attempts to describe what we know about processes that may cause lupus nephritis and how such basic processes may be affected if we can specifically interrupt them. Secondary inflammatory mechanisms, cytokine signatures, activation of complement, and other contributors to inflammation will not be discussed herein; rather, the events that trigger these factors will be discussed.
- Death Receptor 3 Promotes Chemokine-Directed Leukocyte Recruitment in Acute Resolving Inflammation and Is Essential for Pathological Development of Mesothelial Fibrosis in Chronic Disease. [Journal Article]
- Am J Pathol 2016 Sep 21AJ
- Death receptor 3 (DR3; TNFRSF25) and its tumor necrosis factor-like ligand TL1A (TNFSF15) control several processes in inflammatory diseases through the expansion of effector T cells and the inductio...
Death receptor 3 (DR3; TNFRSF25) and its tumor necrosis factor-like ligand TL1A (TNFSF15) control several processes in inflammatory diseases through the expansion of effector T cells and the induction of proinflammatory cytokines from myeloid and innate lymphoid cells. Using wild-type (DR3(+/+)) and DR3-knockout (DR3(-/-)) mice, we show that the DR3/TL1A pathway triggers the release of multiple chemokines after acute peritoneal inflammation initiated by a single application of Staphylococcus epidermidis supernatant, correlating with the infiltration of multiple leukocyte subsets. In contrast, leukocyte infiltration was not DR3 dependent after viral challenge with murine cytomegalovirus. DR3 expression was recorded on connective tissue stroma, which provided DR3-dependent release of chemokine ligand (CCL) 2 (monocyte chemoattractant protein-1), CCL7 (monocyte chemoattractant protein-3), CXCL1 (KC), and CXCL13 (BCA-1). CCL3 (macrophage inflammatory protein-1α), CCL4 (macrophage inflammatory protein-1β), and CXCL10 (IP10) production was also DR3 dependent, but quantitative RT-PCR showed that their derivation was not stromal. In vitro cultures identified resident macrophages as a DR3-dependent source of CCL3. Whether DR3 signaling could contribute to a related peritoneal pathology was then tested using multiple applications of S. epidermidis supernatant, the repetitive inflammatory episodes of which lead to peritoneal membrane thickening and collagen deposition. Unlike their DR3(+/+) counterparts, DR3(-/-) mice did not develop fibrosis of the mesothelial layer. Thus, this work describes both a novel function and essential requirement for the DR3/TL1A pathway in acute, resolving, and chronic inflammation in the peritoneal cavity.
- REV-ERBα Activates C/EBP Homologous Protein to Control Small Heterodimer Partner-Mediated Oscillation of Alcoholic Fatty Liver. [Journal Article]
- Am J Pathol 2016 Sep 21AJ
- The small heterodimer partner (SHP) nuclear receptor is an important regulator of nonalcoholic fatty liver disease. However, the molecular mechanisms that underline alcoholic fatty liver controlled b...
The small heterodimer partner (SHP) nuclear receptor is an important regulator of nonalcoholic fatty liver disease. However, the molecular mechanisms that underline alcoholic fatty liver controlled by SHP remain elusive. In the present study, we used a modified Gao-binge model of advanced liver disease to examine cyclic alterations of lipid metabolism in wild-type (WT) and Shp(-/-) mice over a 24-hour period after binge. The serum and hepatic lipid profiles, as well as the expression levels of lipid synthesis genes and markers of endoplasmic reticulum stress, exhibited distinct variations in WT and Shp(-/-) mice in response to ethanol diet plus ethanol binge (ED+E) and control diet plus maltose binge. ED+E induced steatosis in WT mice, which correlated with a marked up-regulation of activating transcription factor 4 protein levels but down-regulation of C/EBP homologous protein (CHOP) and sterol regulatory element-binding transcription factor 1c protein levels. On the contrary, the control diet plus maltose binge caused lipid accumulation in Shp(-/-) mice, which was accompanied by a sharp elevation of CHOP, sterol regulatory element-binding transcription factor 1c, and REV-ERBα proteins but diminished levels of activating transcription factor 4 protein. REV-ERBα activated CHOP promoter activity and gene transcription, which were inhibited by SHP. Knockdown of REV-ERBα in Shp(-/-) mice prevented steatosis induced by ED+E. Overall, our study revealed a new regulatory role of SHP and REV-ERBα in the control of rhythmic CHOP expression in alcoholic fatty liver.
- Fibrogenic Signaling Is Suppressed in Hepatic Stellate Cells through Targeting of Connective Tissue Growth Factor (CCN2) by Cellular or Exosomal MicroRNA-199a-5p. [Journal Article]
- Am J Pathol 2016 Sep 20AJ
- Pathways of liver fibrosis are controlled by connective tissue growth factor (CCN2). In this study, CCN2 was identified as a target of miR-199a-5p, which was principally expressed in quiescent mouse ...
Pathways of liver fibrosis are controlled by connective tissue growth factor (CCN2). In this study, CCN2 was identified as a target of miR-199a-5p, which was principally expressed in quiescent mouse hepatic stellate cells (HSCs) and directly suppressed production of CCN2. Up-regulated CCN2 expression in fibrotic mouse livers or in activated primary mouse HSCs was associated with miR-199a-5p down-regulation. MiR-199a-5p in quiescent mouse HSCs inhibited the activity of a wild-type CCN2 3' untranslated region (3'-UTR) but not of a mutant CCN2 3'-UTR lacking the miR-199a-5p-binding site. In activated mouse HSCs, CCN2, α-smooth muscle actin, and collagen 1(α1) were suppressed by a miR-199a-5p mimic, whereas in quiescent mouse HSCs, the inhibited CCN2 3'-UTR activity was blocked by a miR-199a-5p antagomir. CCN2 3'-UTR activity in human HSCs was reduced by a miR-199a-5p mimic. MiR-199a-5p was present at higher levels in exosomes from quiescent versus activated HSCs. MiR-199a-5p-containing exosomes were shuttled from quiescent mouse HSCs to activated mouse HSCs in which CCN2 3'-UTR activity was then suppressed. Exosomes from quiescent HSCs caused miR-199a-5p-dependent inhibition of CCN2, α-smooth muscle actin, or collagen 1(α1) in activated HSCs in vitro and bound to activated HSCs in vivo. Thus, CCN2 suppression by miR-199a-5p accounts, in part, for low-level fibrogenic gene expression in quiescent HSCs and causes dampened gene expression in activated HSCs after horizontal transfer of miR-199a-5p in exosomes from quiescent HSCs.
- This Month in AJP. [Journal Article]
- Am J Pathol 2016 Sep 20AJ
- The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.
The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.
- Heme Oxygenase 1 Up-Regulates Glomerular Decay Accelerating Factor Expression and Minimizes Complement Deposition and Injury. [Journal Article]
- Am J Pathol 2016 Sep 20AJ
- Complement-activation controllers, including decay accelerating factor (DAF), are gaining emphasis as they minimize injury in various dysregulated complement-activation disorders, including glomerulo...
Complement-activation controllers, including decay accelerating factor (DAF), are gaining emphasis as they minimize injury in various dysregulated complement-activation disorders, including glomerulopathies. Heme oxygenase (HO)-1 overexpression or induction has been shown to attenuate injury in complement-dependent models of glomerulonephritis. This study investigated whether up-regulation of DAF by heme oxygenase 1 (HO-1) is an underlying mechanism by using Hmox-1-deficient rats (Hmox1(+/-); Hmox1(-/-)) or rats with Hmox-1 overexpression targeted to glomerular epithelial cells (GEC(Hmox-1)), which are particularly vulnerable to complement-mediated injury owing to their terminally differentiated nature. Constitutively expressed DAF was decreased in glomeruli of Hmox1(-/-) rats and augmented in glomeruli of GEC(Hmox-1) rats. In GEC(Hmox-1) rats with anti-glomerular basement membrane antibody mediated, complement-dependent injury, complement component 3 fragment b (C3b) deposition was reduced, whereas proteinuria was diminished. In glomeruli of wild-type rats, the natural Hmox substrate, hemin, induced glomerular DAF. This effect was attenuated in glomeruli of Hmox1(-/-) rats and augmented in glomeruli of GEC(Hmox-1) rats. Hemin analogues differing in either metal or porphyrin ring functionalities, acting as competitive Hmox-substrate inhibitors, also increased glomerular DAF and reduced C3b deposition after spontaneous complement activation. In the presence of a DAF-blocking antibody, the reduction in C3b deposition was reversed. These observations establish HO-1 as a physiologic regulator of glomerular DAF and identify hemin analogues as inducers of functional glomerular DAF able to minimize C3b deposition.
- Prolonged Repetitive Head Trauma Induces a Singular Chronic Traumatic Encephalopathy-Like Pathology in White Matter Despite Transient Behavioral Abnormalities. [Journal Article]
- Am J Pathol 2016 Sep 20AJ
- Repetitive mild traumatic brain injury (rmTBI), resulting from insults caused by an external mechanical force that disrupts normal brain function, has been linked to the development of neurodegenerat...
Repetitive mild traumatic brain injury (rmTBI), resulting from insults caused by an external mechanical force that disrupts normal brain function, has been linked to the development of neurodegenerative diseases, such as chronic traumatic encephalopathy and Alzheimer disease; however, neither the severity nor frequency of head injury required to trigger adverse behavioral outcomes is well understood. In this study, the administration of 30 head impacts using two different weights to lightly anesthetized, completely unrestrained mice established a paradigm that simulates the highly repetitive nature of sports- and military-related head injury. As the number of head impacts increases, the time to recover consciousness diminishes; however, both the sensorimotor function and behavioral outcomes of impacted mice evolve during the ensuing weeks. Postmortem analyses reveal robust Alzheimer disease and chronic traumatic encephalopathy-like conditions that manifest in a singular manner throughout the white matter concomitant with evidence of chronic oligodendrogenesis. Our data suggest that latency to recover the righting reflex may be an inadequate measure of injury severity and imply that exposure to repeated head impacts may mask the severity of an underlying and developing neuropathologic condition that does not manifest itself until long after head collisions cease. In addition, our data indicate that there is a cumulative and dose-dependent effect of repetitive head impacts that induces the neurobehavioral and neuropathologic outcomes seen in humans with a history of rmTBI.
- Note of Concern. [Editorial]
- Am J Pathol 2016; 186(10):2769AJ
- This Note of Concern relates to Al-Gayyar et al Am J Pathol 177:1187-1197 and Correction 185:1795-1796.
This Note of Concern relates to Al-Gayyar et al Am J Pathol 177:1187-1197 and Correction 185:1795-1796.
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- Braf Mutations Initiate the Development of Rat Gliomas Induced by Postnatal Exposure to N-Ethyl-N-Nitrosourea. [Journal Article]
- Am J Pathol 2016; 186(10):2569-76AJ
- A single dose of N-ethyl-N-nitrosourea (ENU) during late prenatal or early postnatal development induces a high incidence of malignant schwannomas and gliomas in rats. Although T->A mutations in the ...
A single dose of N-ethyl-N-nitrosourea (ENU) during late prenatal or early postnatal development induces a high incidence of malignant schwannomas and gliomas in rats. Although T->A mutations in the transmembrane domain of the Neu (c-ErbB-2) gene are the driver mutations in ENU-induced malignant schwannomas, the molecular basis of ENU-induced gliomas remains enigmatic. We performed whole-genome sequencing of gliomas that developed in three BDIV and two BDIX rats exposed to a single dose of 80 mg ENU/kg body weight on postnatal day one. T:A->A:T and T:A->C:G mutations, which are typical for ENU-induced mutagenesis, were predominant (41% to 55% of all somatic single nucleotide mutations). T->A mutations were identified in all five rat gliomas at Braf codon 545 (V545E), which corresponds to the human BRAF V600E. Additional screening revealed that 33 gliomas in BDIV rats and 12 gliomas in BDIX rats all carried a Braf V545E mutation, whereas peritumoral brain tissue of either strain had the wild-type sequence. The gliomas were immunoreactive to BRAF V600E antibody. These results indicate that Braf mutation is a frequent early event in the development of rat gliomas caused by a single dose of ENU.