Tissue Repair Markers Research Articles

Role of macrophage bioenergetics in N-acetylcysteine-mediated mitigation of lung injury and oxidative stress induced by nitrogen mustard

Nitrogen mustard (NM) is a toxic vesicant that causes acute injury to the respiratory tract. This is accompanied by an accumulation of activated macrophages in the lung and oxidative stress which have been implicated in tissue injury. In these studies, we analyzed the effects of N-acetylcysteine (NAC), an inhibitor of oxidative stress and inflammation on NM-induced lung injury, macrophage activation and bioenergetics. Treatment of rats with NAC (150 mg/kg, i.p., daily) beginning 30 min after administration of NM (0.125 mg/kg, i.t.) reduced histopathologic alterations in the lung including alveolar interstitial thickening, blood vessel hemorrhage, fibrin deposition, alveolar inflammation, and bronchiolization of alveolar walls within 3 d of exposure; damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage fluid protein and cells, was also reduced by NAC, along with oxidative stress as measured by heme oxygenase (HO)-1 and Ym-1 expression in the lung. Treatment of rats with NAC attenuated the accumulation of macrophages in the lung expressing proinflammatory genes including Ptgs2, Nos2, Il-6 and Il-12; macrophages expressing inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)α protein were also reduced in histologic sections. Conversely, NAC had no effect on macrophages expressing the anti-inflammatory proteins arginase-1 or mannose receptor, or on NM-induced increases in matrix metalloproteinase (MMP)-9 or proliferating cell nuclear antigen (PCNA), markers of tissue repair. Following NM exposure, lung macrophage basal and maximal glycolytic activity increased, while basal respiration decreased indicating greater reliance on glycolysis to generate ATP. NAC increased both glycolysis and oxidative phosphorylation. Additionally, in macrophages from both control and NM treated animals, NAC treatment resulted in increased S-nitrosylation of ATP synthase, protecting the enzyme from oxidative damage. Taken together, these data suggest that alterations in NM-induced macrophage activation and bioenergetics contribute to the efficacy of NAC in mitigating lung injury.

Caloric restriction improves inflammation in different tissues of the Wistar rats with obesity and 2K1C renovascular hypertension.

Renovascular hypertension (RHV) is the cause of high blood pressure due to left renal ischemia, and obesity and hypertension cause an inflammatory response. This work analyzed the inflammatory and tissue repair profile in renal, hepatic, and cardiac tissues in an animal model of RVH associated with a high-fat diet and caloric restriction. The expressions of RORγ-t, IL-17, T-bet, and TNF-α decreased and IFN-γ increased in the right kidney. In relation to the left kidney, caloric restriction decreased the expression of IFN-γ. In the liver, caloric restriction decreased RORγ-t, IL-17, and T-bet. Hypertension associated with obesity decreased the expression of IFN-γ, while caloric restriction increased. In the right kidney, hypertension and obesity, associated or not with caloric restriction, increased the area of collagen fibers. In the heart and liver, caloric restriction reduced the area of collagen fibers. Caloric restriction increased vascular endothelial growth factor, reduced levels of growth transformation factor-β1 (TGF-β), and increased collagen I in the left kidney. Hypertension/obesity, submitted or not having caloric restriction, increased TGF-β in liver. The results suggest that caloric restriction has beneficial effects in lowering blood pressure and regulating tissue proinflammatory cytokines. However, there was no change in the structure and composition of tissue repair markers.

Lung inflammation and interstitial fibrosis by targeted alveolar epithelial type I cell death.

The pathogenesis of chronic lung diseases is multifaceted with a major role of recurrent micro-injuries of the epithelium. While several reports clearly indicated a prominent role for surfactant-producing alveolar epithelial type 2 (AT2) cells, the contribution of gas exchange-permissive alveolar epithelial type 1 (AT1) cells has not been addressed yet. Here, we investigated whether repeated injury of AT1 cells leads to inflammation and interstitial fibrosis. We chose an inducible model of AT1 cell depletion following local diphtheria toxin (DT) administration using an iDTR flox/flox (idTRfl/fl) X Aquaporin 5CRE (Aqp5CRE) transgenic mouse strain. We investigated repeated doses and intervals of DT to induce cell death of AT1 cells causing inflammation and interstitial fibrosis. We found that repeated DT administrations at 1ng in iDTRfl/fl X Aqp5CRE mice cause AT1 cell death leading to inflammation, increased tissue repair markers and interstitial pulmonary fibrosis. Together, we demonstrate that depletion of AT1 cells using repeated injury represents a novel approach to investigate chronic lung inflammatory diseases and to identify new therapeutic targets.

Maternal high-fat diet consumption programs male offspring to mitigate complications in liver regeneration.

In the last decades, obesity and nonalcoholic fatty liver disease (NAFLD) have become increasingly prevalent in wide world. Fatty liver can be detrimental to liver regeneration (LR) and offspring of obese dams (HFD-O) are susceptible to NAFLD development. Here we evaluated LR capacity in HFD-O after partial hepatectomy (PHx). HFD-O re-exposed or not to HFD in later life were evaluated for metabolic parameters, inflammation, proliferation, tissue repair markers and survival rate after PHx. Increasing adiposity and fatty liver were observed in HFD-O. Despite lower IL-6 levels, Ki67 labeling, cells in S phase and Ciclin D1/PCNA protein content, a lower impact on survival rate was found after PHx, even when re-exposed to HFD. However, no difference was observed between offspring of control dams (SC-O) and HFD-O after surgery. Although LR impairment is dependent of steatosis development, offspring of obese dams are programmed to be protected from the damage promoted by HFD.

The Evaluation of Acute Lung Injury Induced by Nitrogen Mustard in Mouse Precision Cut Lung Slices

Nitrogen Mustard (NM; mechlorethamine hydrochloride) is a cytotoxic alkylating agent known to cause progressive pulmonary injury. Its toxic properties elicit extensive tissue remodeling within the respiratory tract, contributing to the development of chronic lung disease. Precision-Cut Lung Slices (PCLS) represent an ex vivo alternative to in vivo studies, minimizing animal numbers while increasing experimental replicates, which is advantageous for mechanistic toxicology studies and evaluating potential therapeutics. PCLS are three-dimensional excerpts of the lung that include all resident cell types; they remain viable in culture for up to 14 days, allowing for evaluation of functional activity, structural alterations and cytotoxicity. In the present studies, PCLS were used to assess NM-induced lung injury and alterations in pulmonary mechanics. C57BL/6 mice were euthanized, the lungs filled with agarose, isolated after congealment, and sliced (300 mM in thickness); slices were cultured in Dulbecco's Modified Eagle's Medium (DMEM) and Ham's F-12 Nutrient Mixture (DMEM/F-12). Twenty-four hours later, PCLS were treated with NM (1, 10, and 100 mM) for one hour, washed, refed with medium and cultured for 3 days. NM caused a dose-related increase in cytotoxicity and a decrease in mitochondrial activity as measured by lactate dehydrogenase (LDH) and WST-1 assays, respectively. Analysis of histologic sections revealed that NM caused damage to the airway epithelium; this was associated with decreased mRNA expression of collagen1A1 and collagen3A1, markers of tissue repair. To determine if these changes were linked to altered pulmonary function, we measured airway responsiveness using video microscopy. In these studies, changes in airway area after stimulation with increasing concentrations of methacholine were assessed in cross-sectional airways. Consistent with structural alterations, NM caused a ~30% decrease in maximal airway contraction after methacholine, relative to control, indicating a loss in airway smooth muscle function. These data demonstrate that PCLS can be used effectively to mechanistically assess the progression of injury induced by NM. Further understanding of the progression of damage and repair processes following exposure to mustards is essential in order to develop therapeutics for treating pulmonary toxicity.

Inflammatory Cell Differentiation and Chemotaxis and Extracellular Tissue Repair Markers Are Correlated with Pulmonary Dysfunction in HIV Infected Individuals Presenting with Community-Acquired Pneumonia.

Prior studies have shown that HIV patients develop permanent pulmonary dysfunction following an episode of community-acquired pneumonia (CAP). However, the mechanism causing pulmonary dysfunction remains an enigma. HIV patients experience chronic inflammation. We hypothesized that CAP exacerbates inflammation in HIV patients resulting in an accelerated decline in lung function. A prospective cohort pilot study enrolled HIV patients hospitalized in Medellin, Colombia, with a diagnosis of CAP. Sixteen patients were eligible for the study; they were split into 2 groups: HIV and HIV+CAP. Plasma, sputum, and pulmonary function test (PFT) measurements were retrieved within 48 h of hospital admission and at 1 month follow-up. The concentrations of 13 molecules and PFT values were compared between the 2 cohorts. The HIV+CAP group had lower lung function compared to the HIV group; forced vital capacity (FVC)% predicted and forced expiratory volume in 1 s (FEV1)% predicted decreased, while FEV1/FVC remained constant. APRIL, BAFF, CCL3, and TIMP-1 correlated negatively with FVC% predicted and FEV1% predicted; the relationships however were moderate in strength. Furthermore, the concentrations of BAFF, CCL3, and TIMP-1 were statistically significant between the 2 groups (P ≤ 0.05). Our results indicate that HIV patients with CAP have a different inflammatory pattern and lower lung function compared to HIV patients without CAP. BAFF, CCL3, and TIMP-1 were abnormally elevated in HIV patients with CAP. Future studies with larger cohorts are required to verify these results. In addition, further investigation is required to determine if BAFF, CCL3, and TIMP-1 play a role in the process causing pulmonary dysfunction.

Low-Energy Extracorporeal Shock Wave Therapy Ameliorates Kidney Function in Diabetic Nephropathy.

Background Diabetic nephropathy is the most common cause of end-stage renal disease. Traditional therapy for diabetic nephropathy has focused on supportive treatment, and there is no significant effective therapy. We investigated the effect of low-energy extracorporeal shock wave therapy on a diabetic nephropathy rat model. Methods Streptozotocin-induced diabetic nephropathy rats were treated with six sessions of low-energy extracorporeal shock wave therapy (weekly for six consecutive weeks) or left untreated. We assessed urinary creatinine and albumin, glomerular volume, renal fibrosis, podocyte number, renal inflammation, oxidative stress, and tissue repair markers (SDF-1 and VEGF) six weeks after the completion of treatment. Results The six-week low-energy extracorporeal shock wave therapy regimen decreased urinary albumin excretion as well as reduced glomerular hypertrophy and renal fibrosis in the rat model of diabetic nephropathy. Moreover, low-energy extracorporeal shock wave therapy increased podocyte number in diabetic nephropathy rats. This was likely primarily attributed to the fact that low-energy extracorporeal shock wave therapy reduced renal inflammation and oxidative stress as well as increased tissue repair potency and cell proliferation. Conclusions Low-energy extracorporeal shock wave therapy preserved kidney function in diabetic nephropathy. Low-energy extracorporeal shock wave therapy may serve as a novel noninvasive and effective treatment of diabetic nephropathy.

Clinical, pathomorphological and immunohistochemical evaluation of tissue repair in diabetic foot ulcers

Background: It is known that wound healing is Impaired in diabetes mellitus. Possible reasons are widely being searched. However, despite all the available data, reliable markers of reparative processes in diabetes mellitus are needed to be found.
 Aim: To study morphological and some immunohistochemical markers of tissue repair in patients with diabetic foot ulcers after local treatment.
 Materials and methods: 70 patients with diabetic foot ulcers before and after surgical debridement were included. Histological (light microscopy) and immunohistochemical (CD68, MMP-9, TIMP-1) characteristics of tissue repair processes in soft tissues of the lower extremities in patients with diabetes mellitus were analyzed. Histological and immunohistochemical examination of soft tissues were performed in 63 patients before and after surgical debridement and 10 days after local treatment.
 Results: After the surgical debridement a significant reduction in the area of wounds was registered by 23.4% (p 0.05), wound depth by 29.4% (p 0.05). Based on the results of the morphological study, the presence of mature granulation tissue in the wounds was confirmed. Immunohistochemical study of wound biopsies demonstrated a significant decrease in proteolytic activity in the wound as a decrease in MMP-9 expression (p 0.05). Statistically significant changes in the number of macrophages against the initial data were not found, as well as increased expression of TIMP-1 was observed (p 0.05 and 0.05, respectively).
 Conclusion: According to the data, there was a significant decrease in the area and depth of wounds during local treatment. The intensity of tissue repair was confirmed by the results of histological and immunohistochemical studies. However, the absence of a statistically significant change in the amount of macrophages on the background of treatment suggests that this repair link is disrupted in diabetes mellitus, which is the reason for the "chronic" wounds and requires further studies.

A non-invasive biomarker of type III collagen degradation reflects ischaemia reperfusion injury in rats.

Maintenance of kidney function in kidney allografts remains a challenge, as the allograft often progressively develops fibrosis after kidney transplantation. Fibrosis is caused by the accumulation of extracellular matrix proteins like type I and III collagen (COL I and III) that replace the functional tissue. We assessed the concentrations of a neo-epitope fragment of COL III generated by matrix metalloproteinase-9 cleavage (C3M) in two rat models resembling the ischaemic injury taking place following kidney transplantation. We measured C3M in urine (U-C3M) and plasma (P-C3M) samples of rats subjected to unilateral nephrectomy followed by sham operation (NTx) or ischaemia reperfusion injury (NTxIRI) as well as in rats subjected to bilateral ischaemia reperfusion injury (BiIRI). Levels of U-C3M were normalized to urinary creatinine and were correlated to plasma creatinine, blood urea nitrogen, messenger ribonucleic acid (mRNA) of markers of kidney injury, and mRNA and protein levels of markers of tissue repair and fibrosis. Levels of U-C3M were significantly elevated 7 days after ischaemia reperfusion in the NTxIRI. BiIRI animals showed higher levels of U-C3M after 7 and 14 days of reperfusion but not at 21 days. P-C3M did not change in any of the models. There was a significant correlation between U-C3M and mRNA levels of fibronectin, COL I alpha 1 chain (COL Ia1) and neutrophil gelatinase-associated lipocalin (NGAL), and protein levels of alpha smooth muscle actin (αSMA), fibronectin and COL III in NTxIRI but not in NTx animals. Levels of U-C3M increased significantly in the BiIRI animals subsequent to reperfusion, and mirrored the histological alterations. Furthermore, U-C3M was associated with the extent of fibrosis, and remained elevated even after plasma creatinine levels decreased. These results demonstrate that degradation of COL III increases after ischaemia reperfusion injury, and that U-C3M may be a non-invasive marker of tissue repair and fibrosis in the ischaemic kidney.

Markers of Tissue Repair and Cellular Aging Are Increased in the Liver Tissue of Patients With HIV Infection Regardless of Presence of HCV Coinfection.

Liver disease is a leading cause of HIV-related mortality. Hepatitis C virus (HCV)–related fibrogenesis is accelerated in the setting of HIV coinfection, yet the mechanisms underlying this aggressive pathogenesis are unclear. We identified formalin-fixed paraffin-embedded liver tissue for HIV-infected patients, HCV-infected patients, HIV/HCV-coinfected patients, and controls at Duke University Medical Center. De-identified sections were stained for markers against the wound repair Hedgehog (Hh) pathway, resident T-lymphocytes, and immune activation and cellular aging. HIV infection was independently associated with Hh activation and markers of immune dysregulation in the liver tissue.

Supplementation with tocotrienols from Bixa orellana improves the in vivo efficacy of daptomycin against methicillin-resistant Staphylococcus aureus in a mouse model of infected wound

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) is a common cause of skin and soft-tissue infection worldwide. An adequate immune response acts as a first line of defence against infections and therefore plays an essential role in the maintenance of health. Tocotrienols (T3s), the lesser known isomers of vitamin E, possess many biological properties and have been recognized as immunomodulators. PurposeThe aim of this study was to investigate whether the in vivo supplementation with a mixture of 87.1% δ- and 12.9% γ-T3s extract from seeds of Bixa orellana, (T3s) could be effective in increasing the effect of daptomycin (DAP) in a mouse model of wound infection due to MRSA. Study design/methodsBacteria were inoculated onto full-thickness wound on the dorsal side of BALB/c mice at 5 × 106 CFU per mouse. Mice were randomized into five groups: an uninfected group, an infected-untreated group, a T3s-pretreated group with no antibiotics given after challenge, a T3s-pretreated group plus DAP given after challenge, a group only given DAP after challenge. Main outcome measures were: bacterial load on the wounds, analysis of Natural Killer (NK) cytotoxicity, immunological phenotype and markers of tissue repair. ResultsOur results showed that bacterial load in wounds from mice receiving T3s or DAP alone was 1- or 3-log10 lower, respectively, compared with the infected-untreated group. T3s plus daptomycin showed the highest efficacy, achieving a 4-log10 decrease in bacterial load. This higher antimicrobial effect was associated with increased levels of NK cytotoxicity and markers of wound repair. ConclusionThese data suggest that treatment with T3s may be useful for the management of infected wounds as immune adjuvants in combination with DAP.

ANALYSIS OF THE EXPRESSION OF INFLAMMATORY AND TISSUE REPAIR MARKERS IN INFLAMMATORY PERIRADICULAR CYSTS PRE AND POST DE

To evaluate the expression of inflammatory and tissue repair markers in periradicular inflammatory cysts before and after surgical decompression.

Vancomycin pre-treatment impairs tissue healing in experimental colitis: Importance of innate lymphoid cells

Background and aimsThe interplay between luminal microbes and innate immunity during colonic epithelial repair has been well noted. At the same time, antibiotic has widely been used during flare-ups of ulcerative colitis. The possible effects of luminal microbiota disruption caused by antibiotics usage on epithelial repairing have been scarcely discussed. Innate lymphoid cells (ILCs) embedded in the lamina propria can be modulated by gut microbes, resulting in altered colonic IL-22/pSTAT3 levels, which is considered a prominent molecular axis in tissue repairing after epithelium damage. This study aimed to investigate whether antibiotics could interfere with ILCs-dependent tissue repair. MethodsDextran sodium sulfate (DSS)-induced colitis was established in mice pre-treated with reagent of different antibiotic spectrum. Both morphological and molecular markers of tissue repair after DSS cessation were detected. ILCs population and function status were also recorded. Further attention was paid to the response of dendritic cells after antibiotics treatment, which were claimed to regulate colonic ILC3s in an IL-23 dependent way. ResultsUsing of vancomycin resulted in delayed tissue repairing after experimental colitis. Both colonic IL-22/pSTAT3 axis and ILC3 population were found decreased in this situation. Vancomycin treatment diminished the upstream IL-23 and producer dendritic cell population. The reduced dendritic cell number may due to inadequate chemokines and colony-stimulating factors supply. ConclusionPresence of vancomycin-sensitive microbiota is required for the maturation of ILC3-activating dendritic cells hence maintain the sufficient IL-22/pSTAT3 level in the colon during tissue healing. Manipulation of colonic microbiota may help achieve colonic mucosal healing post inflammation and injury.

P0469 : Markers of tissue repair and cellular aging are increased in liver tissue of patients with dual chronic HIV/HCV infections

P0469 : Markers of tissue repair and cellular aging are increased in liver tissue of patients with dual chronic HIV/HCV infections

Acute injury in the peripheral nervous system triggers an alternative macrophage response.

BackgroundThe activation of the immune system in neurodegeneration has detrimental as well as beneficial effects. Which aspects of this immune response aggravate the neurodegenerative breakdown and which stimulate regeneration remains an open question. To unravel the neuroprotective aspects of the immune system we focused on a model of acute peripheral nerve injury, in which the immune system was shown to be protective.MethodsTo determine the type of immune response triggered after axotomy of the sciatic nerve, a model for Wallerian degeneration in the peripheral nervous system, we evaluated markers representing the two extremes of a type I and type II immune response (classical vs. alternative) using real-time quantitative polymerase chain reaction (RT-qPCR), western blot, and immunohistochemistry.ResultsOur results showed that acute peripheral nerve injury triggers an anti-inflammatory and immunosuppressive response, rather than a pro-inflammatory response. This was reflected by the complete absence of classical macrophage markers (iNOS, IFNγ, and IL12p40), and the strong up-regulation of tissue repair markers (arginase-1, Ym1, and Trem2). The signal favoring the alternative macrophage environment was induced immediately after nerve damage and appeared to be established within the nerve, well before the infiltration of macrophages. In addition, negative regulators of the innate immune response, as well as the anti-inflammatory cytokine IL-10 were induced. The strict regulation of the immune system dampens the potential tissue damaging effects of an over-activated response.ConclusionsWe here demonstrate that acute peripheral nerve injury triggers an inherent protective environment by inducing the M2 phenotype of macrophages and the expression of arginase-1. We believe that the M2 phenotype, associated with a sterile inflammatory response and tissue repair, might explain their neuroprotective capacity. As such, shifting the neurodegeneration-induced immune responses towards an M2/Th2 response could be an important therapeutic strategy.

Time course of markers of tissue repair after ablation of atrial fibrillation and their relation to left atrial structural changes and clinical ablation outcome

BackgroundRadiofrequency ablation of atrial fibrillation (AF) creates left atrial (LA) tissue damage with a subsequent healing process. We sought to prospectively assess the time course of biomarkers of tissue repair after ablation and to evaluate their association with clinical variables. Methods30 consecutive patients (57.9±1.7yrs, 63% males) with paroxysmal AF underwent a CARTO-guided LA circumferential ablation, Lasso-guided segmental pulmonary vein isolation and ablation of complex fractionated atrial electrograms. Matrix metalloproteinase-9 (MMP-9) and transforming growth factor-β1 (TGF-β1), both key regulators of tissue repair, and the aminoterminal propeptide of type III procollagen (PIIINP), reflecting collagen synthesis, were determined in blood samples before and 6h, 1, 2, 7, 30, 90 and 180days post-ablation. ResultsAll markers showed a significant ablation-induced up-regulation (MMP-9: 1.8±0.1-fold, TGF-β1: 2.4±0.4-fold, PIIINP: 1.3±0.1-fold). MMP-9 was significantly up-regulated until day 90, TGF-β1 only on day 2. PIIINP increased from day 2 to 7. The area under the curve (AUC) of MMP-9 and TGF-β1 correlated with the ablation-induced reduction of LA volume (both p<0.05). The AUC of MMP-9 was additionally associated with the amount of radiofrequency energy delivered during ablation (p<0.05). At 12months of follow-up 57% of patients were free of AF off antiarrhythmic drugs. The AUC of PIIINP independently predicted recurrent AF (p<0.05). ConclusionsMarkers of healing showed a significant up-regulation after AF ablation detectable for up to 90days. A more pronounced up-regulation of MMP-9 or TGF-β1 is associated with a greater reduction of LA size. High PIIINP levels after ablation predict a poor ablation outcome.

Inflammation and tissue repair markers distinguish the nodular sclerosis and mixed cellularity subtypes of classical Hodgkin's lymphoma

Background:Classical Hodgkin's lymphoma (cHL), although a malignant disease, has many features in common with an inflammatory condition. The aim of this study was to establish the molecular characteristics of the two most common cHL subtypes, nodular sclerosis (NS) and mixed cellularity (MC), based on molecular profiling and immunohistochemistry, with special reference to the inflammatory microenvironment.Methods:We analysed 44 gene expression profiles of cHL whole tumour tissues, 25 cases of NS and 19 cases of MC, using Affymetrix chip technology and immunohistochemistry.Results:In the NS subtype, 152 genes showed a significantly higher expression, including genes involved in extracellular matrix (ECM) remodelling and ECM deposition similar to wound healing. Among these were SPARC, CTSK and COLI. Immunohistochemistry revealed that the NS-related genes were mainly expressed by macrophages and fibroblasts. Fifty-three genes had a higher expression in the MC subtype, including several inflammation-related genes, such as C1Qα, C1Qβ and CXCL9. In MC tissues, the C1Q subunits were mainly expressed by infiltrating macrophages.Conclusions and interpretations:We suggest that the identified subtype-specific genes could reflect different phases of wound healing. Our study underlines the potential function of infiltrating macrophages in shaping the cHL tumour microenvironment.

Markers of collagen synthesis and degradation are increased in serum in severe sepsis: a longitudinal study of 44 patients

IntroductionSepsis-related multiple organ dysfunction is a common cause of death in the intensive care unit. The effect of sepsis on markers of tissue repair is only partly understood. The aim of this study was to measure markers of collagen synthesis and degradation during sepsis and investigate the association with disease severity and outcome.MethodsForty-four patients with severe sepsis participated in the study and 15 volunteers acted as controls. Blood samples were collected for 10 days after the first sepsis-induced organ dysfunction and after three and six months. Procollagen type I and III aminoterminal propeptides (PINP and PIIINP) and cross-linked telopeptides of type I collagen (ICTP) were measured.ResultsThe PIIINP concentration was elevated in the septic patients (8.8 ug/L, 25th to 75th percentile = 6.8 to 26.0) when compared with controls (3.0 ug/L, 25th to 75th percentile = 2.7 to 3.3; P < 0.001) on day one. Maximum serum PIIINP concentrations during sepsis were higher in non-survivors compared with survivors (26.1 ug/L, 25th to 75th percentile = 18.7 to 84.3; vs. 15.1 ug/L, 25th to 75th percentile = 9.6 to 25.5; P = 0.033) and in multiple organ failure (MOF) compared with multiple organ dysfunction syndrome (MODS) (24.2 ug/L, 25th to 75th percentile = 13.4 to 48.2; vs. 8.9 ug/L, 25th to 75th percentile = 7.4 to 19.4; P = 0.002). Although the PINP values of the septic patients remained within the laboratory reference values, patients with MOF had higher values than patients with MODS (79.8, 25th to 75th percentile = 44.1 to 150.0; vs.40.4, 25th to 75th percentile = 23.6 to 99.3; P = 0.007). Day one ICTP levels were elevated in septic patients compared with the controls (19.4 ug/L, 25th to 75th percentile = 12.0 to 29.8; vs. 4.1 ug/L, 25th to 75th percentile = 3.4 to 5.0; P < 0.001).ConclusionsMarkers of collagen metabolism are increased in patients with severe sepsis and can be investigated further as markers of disease severity and outcome.

Progressive fascial wound failure impairs subsequent abdominal wall repairs: A new animal model of incisional hernia formation

Fascial wound failure alters the phenotype of the abdominal wall. This study introduces a novel animal model of progressive failure of the ventral abdominal wall fascia, which generates large incisional hernias. A mechanistic model of incisional hernia was compared with a model of acute myofascial defect hernia repair. Using biological tissue repair markers, tensiometric measurements and recurrent hernia rate, we measured the mechanism by which incisional hernias regenerate abdominal wall structure and function after mesh and suture herniorrhaphy. Recurrent incisional hernia formation was significantly increased after repairs of the hernia model, compared with the myofascial defect model (6/16 vs 0/16, P < .05). In the hernia model, there were significant decreases in the recovery of wound strength, energy, and extensibility before mechanical disruption, compared with the myofascial defect model. Unexpectedly, excision of fascial hernia wound edges did not significantly improve tissue repair outcomes in the hernia model group. Clinically accurate animal modeling can recreate the wound pathology expressed in mature incisional hernias. Progressive fascial wound failure decreases the fidelity of subsequent incisional hernia repair, compared with identically sized acute abdominal wall defect repairs. The mechanism appears to include decreased fascial wound strength and decreased tissue compliance after herniorrhaphy.

Time-course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS). EAE and MS are characterized by CNS inflammation, demyelination and neurodegeneration. The inflammatory response occurring within the CNS leads to glial activation, dysfunction and death, as well as axonal damage and neurological deficit. Although the pathogenic mechanisms involved in EAE/MS are not well understood, accumulating data suggest that oxidative stress plays a major role in lesion development, and contributes to axonal dysfunction and degeneration. Metallothionein-I and -II are anti-inflammatory, neuroprotective, antioxidant proteins expressed during EAE and MS, in which they might play a protective role. The present study aimed to describe the expression profile of a group of inflammatory, neurodegenerative and tissue repair markers as well as metallothioneins during proteolipid protein-induced EAE, and to establish the time-relationships these molecules had during EAE. Interestingly, we found two marker expression profiles. In the first, marker expression increased as clinical signs worsened and reverted to baseline expression during recovery; in the second, marker expression increased at a later point during relapse, peaked at highest clinical score, and remained elevated throughout recovery. Of note, metallothionein expression was found to be related to the second profile, which would suggest that metallothionein proteins are implicated in the clinical recovery of EAE and perhaps these antioxidant proteins may provide therapeutic benefits in MS.