Characterization of orofacial features in sclerodermatous chronic graft-versus-host disease.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (alloHCT). The sclerodermatous form of cGVHD can be particularly debilitating; however, orofacial sclerodermatous involvement remains poorly described. OBJECTIVE: To characterize orofacial features of sclerodermatous cGVHD in a single center cohort of patients who underwent alloHCT. STUDY DESIGN: Retrospective data were collected from electronic medical records and analyzed descriptively. RESULTS: There were 39 patients who received alloHCT between 1993 and 2017 and developed orofacial sclerodermatous cGVHD. Concomitant cutaneous sclerodermatous cGVHD was common (n = 20, 51%). Orofacial sclerodermatous cGVHD features included fibrous bands of the buccal mucosa (n = 23, 59%), limited mouth opening (n = 19, 54%), perioral fibrosis (n = 8, 21%), and focal gingival recession (n = 4, 10%). Oral mucosal fibrosis was observed at the site of active or resolved chronic lichenoid inflammation in 30 patients, with all but two also presenting with a history of ulcerations. Management included jaw stretching exercises (n = 10; 6 stable/improved), surgery (n = 3; 2 improved), and intralesional corticosteroid injections (n = 2; 2 improved). CONCLUSIONS: Orofacial involvement with sclerodermatous cGVHD can present with multiple manifestations including fibrous banding, limited mouth opening, perioral fibrosis, and focal gingival recession. Surgical and non-surgical management strategies may improve clinical function and reduce morbidity.

In vitro Study of the Role of Human Neutrophil Enzymes on Root Caries Progression.

The role of the host immune system in caries progression is mainly speculative, and it is believed that it entails the enzymatic degradation of the dentin organic matrix. The aim of this study was to evaluate the proteolytic effect of human neutrophil enzymes on root caries progression. For this, specimens of bovine root dentin were divided into 4 groups (n = 30): caries (C), caries + neutrophils (C + N), no caries (Control), and no caries + neutrophils (Control + N). Streptococcus mutans biofilm (105 CFU/mL) was grown on the root surface to artificially induce root carious lesions (C and C + N groups). Specimens were then exposed to neutrophils (5 × 106 cells/mL) for 48 h (C + N and Control + N groups). Caries development and neutrophil exposures were repeated a 2nd and 3rd time. Caries depth (CD) and dentin demineralization (DD) were assessed by infiltration of rhodamine B using fluorescence microscopy. Collagen fibril ultrastructure was characterized under a polarized microscope with Picrosirius red staining. There were no significant differences (p > 0.05) in CD and DD between the C and C + N groups for 1, 2, and 3 caries-neutrophil exposures. Immature collagen was significantly less present in the carious groups (C, p = 0.003; C + N, p = 0.01) than in the noncarious groups in the most superficial 200 µm. We thus concluded that human neutrophil enzymes did not influence short-term root caries progression, and immature collagen fibrils were more susceptible to degradation during S. mutans-induced root caries progression.

Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial.

Importance: Proliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape revealed a cytotoxic T-cell-rich microenvironment, providing strong rationale to investigate immune checkpoint therapy. Objective: To determine the safety and clinical activity of anti-programmed cell death 1 protein (PD-1) therapy to treat high-risk PVL. Design, Setting, and Participants: This nonrandomized, open-label, phase 2 clinical trial was conducted from January 2019 to December 2021 at a single academic medical center; median (range) follow-up was 21.1 (5.4-43.6) months. Participants were a population-based sample of patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia). Intervention: Patients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab (480 mg intravenously) every 28 days, followed by rebiopsy and intraoral photographs at each visit. Main Outcomes and Measures: The primary end point was the change in composite score (size and degree of dysplasia) from before to after treatment (major response [MR]: >80% decrease in score; partial response: 40%-80% decrease). Secondary analyses included immune-related adverse events, cancer-free survival (CFS), PD-1 ligand 1 (PD-L1) expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response. Results: A total of 33 patients were enrolled (median [range] age, 63 [32-80] years; 18 [55%] were female), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%) (95% CI, 20.4%-54.8%) had a response by composite score (3 MRs [9%]), 4 had progressive disease (>10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the trial, with a 2-year CFS of 73% (95% CI, 53%-86%). Two patients (6%) discontinued because of toxic effects; 7 (21%) experienced grade 3 to 4 immune-related adverse events. PD-L1 combined positive scores were not associated with response or CFS. Of 20 whole-exome sequenced patients, all 6 patients who had progression to OSCC after nivolumab treatment exhibited 9p21.3 somatic copy-number loss on pretreatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss. Conclusions and Relevance: This immune checkpoint therapy precancer nonrandomized clinical trial met its prespecified response end point, suggesting potential clinical activity for nivolumab in high-risk PVL. Findings identified immunogenomic associations to inform future trials in this precancerous disease with unmet medical need that has been difficult to study. Trial Registration: ClinicalTrials.gov Identifier: NCT03692325.

A prototype tobacco-associated oral squamous cell carcinoma classifier using RNA from brush cytology.

BACKGROUND: Oral cancer in the form of squamous cell carcinoma (OSCC) is typically detected in advanced stages when treatment is complex and may not be curative. The need for surgical biopsy may contribute to delays in diagnosis and impede early detection. Multiple studies of RNA from surgically obtained tumor samples have revealed many genes differentially expressed with this disease. We sought to determine whether the identified mRNAs could be used as markers by a non-invasive detection system for OSCC using RNA from brush cytology. METHODS: Levels of mRNAs from 21 genes known to be differentially expressed in head and neck squamous cell carcinoma surgical samples, compared with controls, were shown to be quantifiable in oral brush cytology samples. These mRNAs were quantified in a training set of 14 tumor and 20 non-malignant brush cytology samples from tobacco/betel nut users. With the measurement of two additional mRNAs and analysis using support vector machines algorithm for class prediction of these cancers was produced. RESULTS: This OSCC classifier based on the levels of 5 mRNAs in RNA from brush cytology initially showed 0.93 sensitivity and 0.91 specificity in differentiating OSCC from benign oral mucosal lesions based on leave-one-out cross-validation. When used on a test set of 19 samples from 6 OSCCs and 13 non-malignant oral lesions, we found misclassification of only one OSCC and one benign lesion. CONCLUSIONS: This shows the promise of using RNA from brush cytology for early OSCC detection and the potential for clinical usage of this non-invasive classifier.

Synthetic decapeptide reduces bacterial load and accelerates healing in the wounds of restraint-stressed mice.

Wound healing is a complex process involving four transitional yet concurrent stages: coagulation, inflammation, cell proliferation/epithelialization and remodeling. These overlapping stages occur uneventfully in normal physiology. However, during psychological stress, the inflammatory response can become dysregulated and result in increased susceptibility to bacterial infection and delayed wound closure. In our restraint stress model, cutaneous wounds of stressed SKH-1 mice demonstrate significantly higher levels of bacterial load, and healing progresses at a rate 30% slower, than in non-stressed mice. The purpose of this study was to test the hypothesis that a synthetic antimicrobial decapeptide (KSLW) enhances bacterial clearance during stress-impaired healing in mice. Here, using a Pluronic block copolymer nanocarrier, we endeavored to identify an efficient drug delivery system for KSLW, which would enhance the stability, substantivity and function of the cationic peptide in delayed-healing wounds. In this study, intradermal treatment of excisional wounds of stressed mice with 2mg/ml KSLW loaded in Pluronic F68, resulted in a sustained antimicrobial effect through post-operative day 5, with a 2-log (p<0.01) reduction in bacterial load compared with other stressed mice. The demonstrated bacterial reduction in KSLW-treated stressed mice did not approach the levels observed among control mice. Furthermore, treatment of stressed mice with KSLW improved healing, resulting in significantly faster (p<0.05) wound closure from days 2 to 5 post-wounding, relative to untreated stressed mice and stressed mice treated with Pluronic alone. These findings suggest that Pluronic F68 is an efficient carrier for KSLW, which improves its stability and activity in impaired dermal wounds.

Effect of COVID-19 on training and mental health of oral medicine residents in North America.

OBJECTIVE: The objective of this study was to assess resident and faculty perception of the effect of the coronavirus disease 2019 pandemic on the training experience, education, and psychological well-being of oral medicine (OM) residents. STUDY DESIGN: An anonymous 16-item online questionnaire was e-mailed to faculty and residents of all Commission on Dental Accreditation-accredited OM residency programs in North America. Survey questions asked about the pandemic's effect on resident educational, clinical, and research activities and the well-being of the residents. Survey data were collected using Qualtrics XM. RESULTS: Forty participants (52.5% residents and 47.5% faculty members) responded to the survey. Regarding the effect on clinical activities, 67.5% reported 50% or less reduction in patient volume seen by residents at its worst during the pandemic. With respect to educational activities, most reported a complete switch of didactic training (85.3%), academic examinations (60%), and off-site resident rotations (45%) to a virtual platform. Research activities were affected the most; 55% reported complete cessation for some time. Thirty-three percent perceived a negative effect, 18% perceived no effect, 11% perceived a positive effect, and 38% were unsure regarding the effect of coronavirus disease 2019 on resident morale. Despite the interruptions in the clinical, research, and educational activities, 62.5% expected on-time resident graduation. CONCLUSION: Despite constraints due to the pandemic, OM residency programs successfully continued clinical activities, didactic training, and research productivity through virtual means and a hybrid delivery care model while supporting their residents' morale.

A Review of Oral Chronic Graft-Versus-Host Disease: Considerations for dental hygiene practice.

Purpose: Allogeneic hematopoietic cell transplantation (alloHCT), also known as stem cell or bone marrow transplantation, is a cellular therapy performed to treat a variety of malignant and non-malignant hematologic diseases. Chronic graft-versus-host disease (cGVHD) is a common immune-mediated complication of alloHCT that can affect various organs of the body, with approximately 70% of affected patients presenting with oral features. Oral manifestations of cGVHD include lichenoid lesions (diagnostic feature), erythema, pseudomembranous ulcerations, superficial mucoceles, salivary gland hypofunction, xerostomia, orofacial sclerosis, trismus, and increased sensitivity to spicy, acidic, hard, and crunchy foods. Patients with oral cGVHD are also at increased risk for developing secondary conditions, such as oral candidiasis, dental caries, and oral squamous cell carcinoma. Given these complex oral health challenges, the dental hygienist can play a key role in optimizing patients' oral health care from pre-stem cell transplantation through survivorship. Optimal care includes a comprehensive health history assessment, thorough extraoral and intraoral examinations, detailed hard and soft tissue evaluations, oral hygiene, and dietary assessment, along with the delivery of patient-centered, oral health instruction and preventive therapies. Appropriate monitoring and management of oral cGVHD require a collaborative care approach between dental, oncology, and oral medicine providers. As part of a multidisciplinary care team, dental hygienists play an important role in the management of patients with oral cGVHD. The purpose of this review is to provide an overview of alloHCT and its oral health considerations, with a focus on oral cGVHD etiology, signs and symptoms, and management considerations for the dental team.

Ala42S100A8 ameliorates psychological-stress impaired cutaneous wound healing.

Although wound healing is generally a successful, carefully orchestrated and evolutionary sound process, it can be disregulated by extrinsic factors such as psychological-stress. In the SKH-1 restraint stress model of cutaneous wound healing, the rate of wound closure is approximately 30% slower in stressed mice. Delay in healing is associated with exaggerated acute inflammation and deficient bacterial clearance at the wound site. It has been suggested that wound hypoxia may contribute to the mechanisms of impaired cutaneous wound healing in the mouse SKH-1 model. Optimal healing of a cutaneous wound is a stepwise repair program. In its early phase, an inflammatory oxidative burst generated by neutrophils is observed. About 40% of neutrophils cytosolic protein weight is comprised of two calcium binding proteins S100A8 and S100A9. Our previous work has shown that S100A8 act as an oxidation-sensitive repellent of human neutrophils in-vitro. Ala(42)S100A8, a site-directed mutant protein is resistant to oxidative inhibition and inhibits neutrophil recruitment in-vivo. Accordingly, we tested the hypothesis that S100A8 may ameliorate wound healing in this model. We examined the effect of wild-type and ala(42)S100A8 for their ability to ameliorate wound closure rates. The data indicated that a single local application of ala(42)S100A8 ameliorated the decreased rate of wound closure resulting from stress. This occurred without significantly affecting wound bacterial clearance. Wild-type S100A8 only had a partial beneficial effect on the rate of wound closure. Those findings support further translational studies of S100 based intervention to ameliorate impaired wound healing.

Oxidation of methionine 63 and 83 regulates the effect of S100A9 on the migration of neutrophils in vitro.

The calcium-binding proteins S100A8 and S100A9 and their heterocomplex calprotectin are abundant cytosolic constituents in human neutrophils, constitutively expressed by mucosal epithelium and in association with inflammation by epidermal keratinocytes. S100A8 and S100A9 are pleiotropic proteins, which partake in the regulation of leukocyte migration. This study was designed to investigate the effect of S100A9 on neutrophil migration and to explore the mechanisms that regulate this effect. Based on previous results with S100A8, we hypothesized that S100A9 repels neutrophils and that oxidation of S100A9 regulates this function. Using standard Transwell chemotaxis assays and site-directed mutagenesis, we show that S100A9 exerts a chemo-repulsive (fugetactic) effect on peripheral neutrophils, an effect abolished by oxidation of S100A9. After substitution of methionine 63 and 83 for alanine, S100A9 maintained its fugetaxis activity, even in inhibitory, oxidative conditions. Together, the data suggest that S100A9 serves as a molecular switch for oxidative control of inflammation regulated by the oxidation of species-conserved methionine residues. In healthy mucosal tissue, expression of S100A9 by the epithelium may serve to inhibit leukocyte recruitment. However, conditions of oxidative stress, including infection and overgrowth of opportunistic pathogens, may abrogate this activity by neutralizing S100A9 as a result of its oxidative alteration.

Oral Assessment and Management of the Patient with Head and Neck Cancer.

Patients undergoing treatment of head and neck cancer risk developing significant acute and chronic changes that affect the hard and soft tissue of the oral cavity and the head and neck region. This article discusses considerations and recommendations for patients before, during, and after treatment of head and neck cancer. The objective of these recommendations is to maintain oral health, compensate for treatment- and disease-associated morbidities, and improve quality of life. To achieve this objective, treatment of head and neck cancer must include an oral evaluation and management plan well-integrated within the overall oncologic treatment plan from the initiation of therapy.

Vitamin D deficiency and periodontal clinical attachment loss in HIV-seropositive women: A secondary analysis conducted in the Women's Interagency HIV Study (WIHS).

OBJECTIVE: The aim of this study was to test a hypothesized positive association between low vitamin D (VitD) serum levels and the severity of periodontal disease in women with HIV infection. STUDY DESIGN: This was a cross-sectional secondary analysis of data from an oral substudy conducted within the Chicago site of the Women's Interagency HIV Study. Serum VitD levels and clinical attachment loss (CAL) measurements were available for 74 women with HIV infection. VitD levels were treated as both continuous and categorical variables in bivariate and multivariate analyses. Mean clinical attachment loss (mCAL) was determined for each subject by obtaining the averages of measurements taken at 4 sites in each measured tooth. RESULTS: Average age of study participants (n = 74) was 39.6 years (standard deviation 7.2), and the majority were African Americans (70.3%) with VitD deficiency (58.1%). VitD deficiency was positively associated with higher mCAL (P = .012). After adjustment for race, age, smoking, and HIV viral load, an association was found between VitD deficiency and mCAL (Beta 0.438; P = .036). CONCLUSIONS: We identified a previously unreported association between VitD deficiency and mCAL in women with HIV infection. Larger and more inclusive, multisite, longitudinal studies are warranted to investigate whether these findings can be generalized to all individuals with HIV infection in the current treatment era and to determine causality.

Changes in the pattern of oral lesions associated with HIV infection: implications for dentists.

Broad access to better HIV treatment has resulted in a significant reduction in the prevalence of HIV-associated oral lesions in western industrialized countries. However, a possible increased prevalence of oral warts and a potential dissociation between CD4+ T-cell counts and oral manifestations of HIV require continued vigilance by oral health care providers. Head and neck and oral examination coupled with a careful consideration of the complications associated with hyposalivation remain essential components of a comprehensive oral health care program.

Common oral complications of head and neck cancer radiation therapy: mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease, and osteoradionecrosis.

Patients undergoing radiation therapy for the head and neck are susceptible to a significant and often abrupt deterioration in their oral health. The oral morbidities of radiation therapy include but are not limited to an increased susceptibility to dental caries and periodontal disease. They also include profound and often permanent functional and sensory changes involving the oral soft tissue. These changes range from oral mucositis experienced during and soon after treatment, mucosal opportunistic infections, neurosensory disorders, and tissue fibrosis. Many of the oral soft tissue changes following radiation therapy are difficult challenges to the patients and their caregivers and require life-long strategies to alleviate their deleterious effect on basic life functions and on the quality of life. We discuss the presentation, prognosis, and management strategies of the dental structure and oral soft tissue morbidities resulting from the administration of therapeutic radiation in head and neck patient. A case for a collaborative and integrated multidisciplinary approach to the management of these patients is made, with specific recommendation to include knowledgeable and experienced oral health care professionals in the treatment team.

Patient reported outcomes of the -clinical use of a proprietary topical dry mouth product.

PURPOSE: To present patient reported changes in oral symptoms in response to an open-label product trial conducted in patients self-identifying as having Sjögren's syndrome. METHODS: A survey was conducted in conjunction with the Sjögren's Syndrome Foundation and 151 foundation members completed a survey rating their common oral symptoms, based upon the Vanderbilt Head and Neck Symptom Survey before and after use of the trial products, including rinse, -lozenges, gel, and spray. RESULTS: Subjects reported multiple oral symptoms with the highest rated symptoms involving dry mouth with 80% of symptoms showing statistically significant reduction from pre- to posttest. The largest symptom reductions were in dry mouth symptoms and dietary problems. CONCLUSIONS: Symptoms of dry mouth were improved with use of MedActive® products. Increased ease of taking oral medications also was reported. Improvement in mouth/throat pain was noted. Subjects reported considerable effect of the test product upon dry mouth and oral symptoms.

Beta 2-adrenergic receptor regulation of human neutrophil function is sexually dimorphic.

While the mechanisms underlying the marked sexual dimorphism in inflammatory diseases are not well understood, the sexually dimorphic sympathoadrenal axis profoundly affects the inflammatory response. We tested whether adrenergic receptor-mediated activation of human neutrophil function is sexually dimorphic, since neutrophils provide the first line of defense in the inflammatory response. There was a marked sexual dimorphism in beta(2)-adrenergic receptor binding, using the specific beta(2)-adrenergic receptor ligand, [(3)H]-dihydroalprenolol, with almost three times more binding sites on neutrophils from females (20,878 +/- 2470) compared to males (7331 +/- 3179). There was also a marked sexual dimorphism in the effects of isoprenaline, a beta-adrenergic receptor agonist, which increased nondirected locomotion (chemokinesis) in neutrophils obtained from females, while having no effect on neutrophils from males. Isoprenaline stimulated the release of a chemotactic factor from neutrophils obtained from females, but not from males. This chemotactic factor acts on the G protein-coupled CXC chemokine receptor 2 (CXCR2) chemokine receptor, since an anti-CXCR2 antibody and the selective nonpeptide CXCR2 antagonist SB225002, inhibited chemotaxis produced by this factor. While interleukin- (IL-) 8 is a principal CXCR2 ligand, isoprenaline did not produce an increase in IL-8 release from neutrophils. IL-8-induced chemotaxis was inhibited in a sexually dimorphic manner by isoprenaline, which also stimulated release of a mediator from neutrophils that induced chemotaxis, that was inhibited by anti-CXCR2 antibodies. These findings indicate an important role for adrenergic receptors in the modulation of neutrophil trafficking, which could contribute to sex-differences in the inflammatory response.

Self-care intervention to reduce oral candidiasis recurrences in HIV-seropositive persons: a pilot study.

OBJECTIVES: This single-blind randomized controlled pilot study evaluated the efficacy of a behavioral intervention program, PRO-SELF: Candidiasis, to reduce time to recurrence of oral candidiasis over 6 months in susceptible HIV-seropositive persons. The intervention involved instruction by dentists on improving oral hygiene, minimizing sugar intake, and self-diagnosing candidiasis. METHODS: Participants were adults with oral candidiasis responsive to antifungals who presented to the UCSF Stomatology Clinic between 1997 and 2000. At 2-3 weeks of follow-up visits, a dentist "examiner", masked to group assignment, quizzed participants as to the presence of candidiasis, and assessed candidiasis status. A second, unmasked dentist "instructor" then delivered the program to intervention participants. Participants recorded dietary and oral hygiene practices in 24-h recall diaries: intervention participants at each visit and controls at initial and final visits. RESULTS: At randomization, CD4+ cell counts (cells/mm(3)) were 298 +/- 188 among 18 intervention participants and 396 +/- 228 among 17 controls. The candidiasis recurrence rates at 6 months were 78% among intervention compared with 88% among control participants (hazard ratio 0.72; 95% CI 0.35-1.50). Performing oral hygiene after meals/snacks showed the largest relative improvement: intervention-control difference in proportion of meals/snacks affected was 24% (95% CI -1 to 48%). Self-diagnoses of candidiasis were inaccurate, possibly because of mild episodes. CONCLUSIONS: The results weakly indicate that regular instruction from healthcare professionals helps patients delay candidiasis recurrence by improving oral hygiene. Among HIV-seropositive persons, those with poor oral hygiene, and high-sugar diets are most likely to benefit.

Gene expression based evidence of innate immune response activation in the epithelium with oral lichen planus.

OBJECTIVE: Oral lichen planus (OLP) is a disease of the oral mucosa of unknown cause producing lesions with an intense band-like inflammatory infiltrate of T cells to the subepithelium and keratinocyte cell death. We performed gene expression analysis of the oral epithelium of lesions in subjects with OLP and its sister disease, oral lichenoid reaction (OLR), in order to better understand the role of the keratinocytes in these diseases. DESIGN: Fourteen patients with OLP or OLR were included in the study, along with a control group of 23 subjects with a variety of oral diseases and a normal group of 17 subjects with no clinically visible mucosal abnormalities. Various proteins have been associated with OLP, based on detection of secreted proteins or changes in RNA levels in tissue samples consisting of epithelium, stroma, and immune cells. The mRNA level of twelve of these genes expressed in the epithelium was tested in the three groups. RESULTS: Four genes showed increased expression in the epithelium of OLP patients: CD14, CXCL1, IL8, and TLR1, and at least two of these proteins, TLR1 and CXCL1, were expressed at substantial levels in oral keratinocytes. CONCLUSIONS: Because of the large accumulation of T cells in lesions of OLP it has long been thought to be an adaptive immunity malfunction. We provide evidence that there is increased expression of innate immune genes in the epithelium with this illness, suggesting a role for this process in the disease and a possible target for treatment.

The anti-oxidative, anti-inflammatory, and protective effect of S100A8 in endotoxemic mice.

Polymorphonuclear neutrophils (PMNs) produce and release copious amounts of reactive oxygen species (ROS) which target potential bacterial invaders but also contribute to the inflammation-associated organ injuries seen in sepsis. Calprotectin is an immune regulatory protein complex made of S100A8 and S100A9 that inhibits the oxidative metabolism of PMNs in vitro, an effect that can be potentiated by the controlled activation of the protease activated receptor-2 (PAR2). The aim of this study was to test the use of a dual strategy of calprotectin and PAR2 administration to mitigate the deleterious inflammation seen in sepsis. We hypothesized that exogenous calprotectin would protect against the injuries produced by lipopolysaccharides (LPS)-induced endotoxemia and that the controlled activation of PAR2 would potentiate this beneficial effect. Exogenous S100A8 and/or a PAR2 activating peptide (PAR2 AP) were administered in a mouse model of LPS induced endotoxemia. The survival rates as well as markers of inflammation and oxidative damage were measured in the lungs, kidneys, and livers of endotoxemic mice. Mice treated with S100A8 following LPS had less PMN infiltration and less severe histological changes in their lungs, kidneys, and livers. A significantly lower score of oxidative damage in the livers and lungs of S100A8/LPS treated mice was also noted when compared to mice treated with LPS alone. This protective and anti-inflammatory effect of S100A8 was potentiated by the controlled activation of PAR2. Finally, in further support to our hypothesis, the survival rate was almost doubled from 33% to 65% and 63% in mice treated by, respectively, S100A8 and PAR2 AP, whereas 85% of the mice treated with both PAR2 AP and S100A8 survived, a statistically significant higher rate. These results support an anti-inflammatory, anti-oxidative, and protective effect of S100A8 in sepsis, and warrant further studies on the role of PAR2.