Heme Oxygenase, Inflammation, and Fibrosis: The Good, the Bad, and the Ugly?

Upon injury, prolonged inflammation and oxidative stress may cause pathological wound healing and fibrosis, leading to formation of excessive scar tissue. Fibrogenesis can occur in most organs and tissues and may ultimately lead to organ dysfunction and failure. The underlying mechanisms of pathological wound healing still remain unclear, and are considered to be multifactorial, but so far, no efficient anti-fibrotic therapies exist. Extra- and intracellular levels of free heme may be increased in a variety of pathological conditions due to release from hemoproteins. Free heme possesses pro-inflammatory and oxidative properties, and may act as a danger signal. Effects of free heme may be counteracted by heme-binding proteins or by heme degradation. Heme is degraded by heme oxygenase (HO) that exists as two isoforms: inducible HO-1 and constitutively expressed HO-2. HO generates the effector molecules biliverdin/bilirubin, carbon monoxide, and free iron/ferritin. HO deficiency in mouse and man leads to exaggerated inflammation following mild insults, and accumulating epidemiological and preclinical studies support the widely recognized notion of the cytoprotective, anti-oxidative, and anti-inflammatory effects of the activity of the HO system and its effector molecules. In this review, we address the potential effects of targeted HO-1 induction or administration of HO-effector molecules as therapeutic targets in fibrotic conditions to counteract inflammatory and oxidative insults. This is exemplified by various clinically relevant conditions, such as hypertrophic scarring, chronic inflammatory liver disease, chronic pancreatitis, and chronic graft rejection in transplantation

Effects of Remote Ischemic Preconditioning on Heme Oxygenase-1 Expression and Cutaneous Wound Repair

Contains fulltext : 169649.pdf (publisher's version ) (Open Access)Skin wounds may lead to scar formation and impaired functionality. Remote ischemic preconditioning (RIPC) can induce the anti-inflammatory enzyme heme oxygenase-1 (HO-1) and protect against tissue injury. We aim to improve cutaneous wound repair by RIPC treatment via induction of HO-1. RIPC was applied to HO-1-luc transgenic mice and HO-1 promoter activity and mRNA expression in skin and several other organs were determined in real-time. In parallel, RIPC was applied directly or 24h prior to excisional wounding in mice to investigate the early and late protective effects of RIPC on cutaneous wound repair, respectively. HO-1 promoter activity was significantly induced on the dorsal side and locally in the kidneys following RIPC treatment. Next, we investigated the origin of this RIPC-induced HO-1 promoter activity and demonstrated increased mRNA in the ligated muscle, heart and kidneys, but not in the skin. RIPC did not change HO-1 mRNA and protein levels in the wound 7 days after cutaneous injury. Both early and late RIPC did not accelerate wound closure nor affect collagen deposition. RIPC induces HO-1 expression in several organs, but not the skin, and did not improve excisional wound repair, suggesting that the skin is insensitive to RIPC-mediated protection

Orthodontic forces induce the cytoprotective enzyme heme oxygenase-1 in rats

Orthodontic forces disturb the microenvironment of the periodontal ligament (PDL), and induce craniofacial bone remodeling which is necessary for tooth movement. Unfortunately, orthodontic tooth movement is often hampered by ischemic injury and cell death within the PDL (hyalinization) and root resorption. Large inter-individual differences in hyalinization and root resorption have been observed, and may be explained by differential protection against hyalization. Heme oxygenase-1 (HO-1) forms an important protective mechanism by breaking down heme into the strong anti-oxidants biliverdin/bilirubin and the signaling molecule carbon monoxide. These versatile HO-products protect against ischemic and inflammatory injury. We postulate that orthodontic forces induce HO-1 expression in the PDL during experimental tooth movement. Twenty-five 6-week-old male Wistar rats were used in this study. The upper three molars at one side were moved mesially using a Ni-Ti 10 cN coil spring. The contralateral side served as control. After 6, 12, 72, 96 and 120 hrs rats were killed. On parasagittal sections immunohistochemical staining was performed for analysis of HO-1 expression and quantification of multinuclear osteoclasts. Orthodontic force induced a significant time-dependent HO-1 expression in the mononuclear cell population within the PDL at both the apposition- and resorption side. Shortly after appliance placement HO-1 expression was highly induced in PDL cells but dropped to control levels within 72 hours. Some osteoclasts were HO-1 positive but this induction was shown to be independent of time- and mechanical stress. It is tempting to speculate that differential induction of cytoprotective enzymes as HO-1 in the PDL determines the level of hyalinization and, subsequently, fast and slow tooth movers during orthodontic treatment

Educational Psychology: Advances in learning, cognition and motivation

Mesenchymal stem cell (MSC) administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of injury. Heme oxygenase (HO) generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO) and iron/ferritin by breaking down heme. Since HO-activity mediates anti-apoptotic, anti-inflammatory, and anti-oxidative effects, we hypothesized that modulation of the HO-system affects MSC survival. Adipose-derived MSCs (ASCs) from wild type (WT) and HO-2 knockout (KO) mice were isolated and characterized with respect to ASC marker expression. In order to analyze potential modulatory effects of the HO-system on ASC survival, WT and HO-2 KO ASCs were pre-treated with HO-activity modulators, or downstream effector molecules biliverdin, bilirubin, and CO before co-exposure of ASCs to a toxic dose of H2O2. Surprisingly, sensitivity to H2O2-mediated cell death was similar in WT and HO-2 KO ASCs. However, pre-induction of HO-1 expression using curcumin increased ASC survival after H2O2 exposure in both WT and HO-2 KO ASCs. Simultaneous inhibition of HO-activity resulted in loss of curcumin-mediated protection. Co-treatment with glutathione precursor N-Acetylcysteine promoted ASC survival. However, co-incubation with HO-effector molecules bilirubin and biliverdin did not rescue from H2O2-mediated cell death, whereas co-exposure to CO-releasing molecules-2 (CORM-2) significantly increased cell survival, independently from HO-2 expression. Summarizing, our results show that curcumin protects via an HO-1 dependent mechanism against H2O2-mediated apoptosis, and likely through the generation of CO. HO-1 pre-induction or administration of CORMs may thus form an attractive strategy to improve MSC therapy

Thermosensitive biomimetic polyisocyanopeptide hydrogels may facilitate wound repair

Changing wound dressings inflicts pain and may disrupt wound repair. Novel synthetic thermosensitive hydrogels based on polyisocyanopeptide (PIC) offer a solution. These gels are liquid below 16 °C and form gels beyond room temperature. The architecture and mechanical properties of PIC gels closely resemble collagen and fibrin, and include the characteristic stiffening response at high strains. Considering the reversible thermo-responsive behavior, we postulate that PIC gels are easy to apply and remove, and facilitate healing without eliciting foreign body responses or excessive inflammation. Biocompatibility may be higher in RGD-peptide-functionalized PIC gels due to enhanced cell binding capabilities. Full-thickness dorsal skin wounds in mice were compared to wounds treated with PIC gel and PIC-RGD gel for 3 and 7 days. No foreign body reactions and similar wound closure rates were found in all groups. The level of macrophages, myofibroblasts, epithelial migration, collagen expression, and blood vessels did not significantly differ from controls. Surprisingly, granulocyte populations in the wound decreased significantly in the PIC gel-treated groups, likely because foreign bacteria could not penetrate the gel. RGD-peptides did not further improve any effect observed for PIC. The absence of adverse effects, ease of application, and the possibilities for bio-functionalization make the biomimetic PIC hydrogels suitable for development into wound dressings

Alpha-Synuclein Reactive Antibodies as Diagnostic Biomarkers in Blood Sera of Parkinson's Disease Patients

Background Auto-antibodies with specificity to self-antigens have been implicated in a wide variety of neurological diseases, including Parkinson's (PD) and Alzheimer's diseases, being sensitive indicators of neurodegeneration and focus for disease prevention. Of particular interest are the studies focused on the auto-immune responses to amyloidogenic proteins associated with diseases and their applications in therapeutic treatments such as vaccination with amyloid antigens and antibodies in PD, Alzheimer's disease and potentially other neurodegeneration ailments. Methodology/Principal Findings Generated auto-antibodies towards the major amyloidogenic protein involved in PD Lewy bodies – α-synuclein and its amyloid oligomers and fibrils were measured in the blood sera of early and late PD patients and controls by using ELISA, Western blot and Biacore surface plasmon resonance. We found significantly higher antibody levels towards monomeric α-synuclein in the blood sera of PD patients compared to controls, though the responses decreased with PD progression (P<0.0001). This indicates potential protective role of autoimmunity in maintaining the body homeostasis and clearing protein species whose disbalance may lead to amyloid assembly. There were no noticeable immune responses towards amyloid oligomers, but substantially increased levels of IgGs towards α-synuclein amyloid fibrils both in PD patients and controls, which subsided with the disease progression (P<0.0001). Pooled IgGs from PD patients and controls interacted also with the amyloid fibrils of Aβ (1–40) and hen lysozyme, however the latter were recognized with lower affinity. This suggests that IgGs bind to the generic amyloid conformational epitope, displaying higher specificity towards human amyloid species associated with neurodegeneration. Conclusions/Significance Our findings may suggest the protective role of autoimmunity in PD and therefore immune reactions towards PD major amyloid protein – α-synuclein can be of value in the development of treatment and diagnostic strategies, especially during the early disease stages.amyloid researc