Predominant Inflammatory Response Research Articles

Transcriptomic analyses of lung tissues reveal key genes associated with progression of systemic sclerosis-interstitial lung disease (SSc-ILD)

Systemic sclerosis-interstitial lung disease (SSc-ILD) is the leading cause of death in SSc, affecting around 50% of the patients. Lung tissue of patients with early-stage SSc-ILD is characterized by a predominant inflammatory response with inconspicuous fibrosis, which may progress to honeycombing fibrosis. Hence, a better understanding of the molecular mechanisms underpinning SSc-ILD pathogenesis is needed to improve treatment options and progression prediction. This transcriptomic study aims to reveal the differential gene expression between control (ctrl) lung tissue and inflammatory, prefibrotic and fibrotic lung tissue to capture progression of early to late phase SSc-ILD. Twelve explanted lungs from patients with SSc-ILD were used to analyze gene expression from formalin-fixed paraffin-embedded lung tissues with varying stages of ILD (n=18) and control lung tissue (n=6). The SSc-ILD tissues were stratified into three ROIs: inflammatory, prefibrotic, and fibrotic using histological assessments to define a longitudinal simulation of early to late phases of SSc-ILD. The nanoString (nS) nCounter Human Fibrosis Panel was used to profile the transcriptome in the regions of interest. Validation of potential targetswas performed with immunohistochemistry in the same tissues that were used for transcriptome analysis. To validate our simulation model, we performed subgroup analysis that showed an incremental increase in pathway scores related to the severity of fibrosis. Ctrl vs SSc-ILD comparison demonstrated 24 differentially expressed genes, two of which had the most pronounced p-values. Cyclin-dependent kinase inhibitor (cdkn2c) was overexpressed (P=0.00052) in SSc-ILD compared to ctrl, while expression of Pellino E3 ubiquitin-protein ligase 1 (peli1) showed lower expression (P=0.0012). Additionally, in all four groups, cdkn2c and peli1 gene expression showed an incremental increase and decrease, respectively. Immunohistochemistry of cdkn2c showed consistent results with the nS analysis. More cdkn2c and less peli1 expression were associated with more advanced stages of SSc-ILD on histologic assessment. We report the potential of the cell cycle inhibitor and senescence marker, cdkn2c (p18) to be associated with fibrosis progression.

Role of histopathology in severity assessments of post-COVID-19 rhino-orbital cerebral mucormycosis - A case-control study

BackgroundThere was an upsurge in rhino-orbital-cerebral mucormycosis (ROCM) during the second wave of the COVID-19 pandemic in India. Histopathological examination of the biopsies witnessed greater tissue invasion in these cases. The present study aimed to evaluate the histopathological scoring system in the severity assessment and to compare the scores between ROCM that required orbital exenteration (cases) and those that were treated conservatively (controls). Material and methodsA retrospective study was conducted to analyze the histopathological features using a scoring system in patients diagnosed with mucormycosis on sino nasal biopsies. The scoring was based on the following parameters: the extent of necrosis (score 1 <50% and score 2 >50%), degree of angioinvasion (score 1 <3 vessels in 10 fields and score 2 > 3 vessels in 10 fields), degree of inflammation (mild, moderate or severe), and fungal load(score 1 to 4), based on which three grades (I to III) were given. The scores were compared between the case group and the control group. The data obtained were analyzed statistically. ResultsThe study included 40 controls and 10 cases. The median age of patients in the control group was 52 with 82.5%males (n = 43) and 17.5 % females (n = 7) while in the case group, the median age was 51 years, and all were males. The predominant inflammatory response was of mixed suppurative type (70 %, n = 28). The degree of necrosis was scored 2 in 57.5 % (n = 23) of controls and 70 %(n = 7) in the case group. All the samples in the case group showed scores of 2 for angioinvasion and scores of 3 and 4 for fungal load. There was a statistically significant difference in the degree of necrosis, angioinvasion, the severity of neutrophilic infiltrates, and fungal load between the cases and controls (p-value <0.05). ConclusionThe present study analyses the predictive role of histopathology in invasive mucormycosis. Higher fungal load, degree of angioinvasion, and the absence of granulomas are associated with advanced disease in sinonasal mucormycosis. The study findings recommend incorporating the histopathological scoring criteria in evaluating patients with sinonasal mucormycosis.

Local inflammatory mediators alterations induced by Daboia siamensis venom.

The ability of Russell's viper (Daboia siamensis) venom (total RVV) and phospholipase A2 (purified PLA2) to induce the local pathological effects were investigated by the local inflammatory events and the release of inflammatory mediators. Both 0.5 μg of total RVV/mouse and 0.15 μg of purified PLA2/mouse were administered via intra-peritoneal injection. After 30 min, 1 h, 2 h, and 4 h incubation time, the peritoneal cavity was flooded with normal saline and the total leukocytes were collected. The eicosanoids (lipid mediators) and the leukocyte expression of cyclooxygenase (COX-1 and COX-2) were investigated by ELISA assay and western blotting, respectively. The amounts of total leukocytes were increased from 30 min to 2 h, then decreased at 4 h, by both total RVV and purified PLA2. Both treatments also induced the expression of COX-2 which was increased at 2 h and then decreased at 4 h, whereas only purified PLA2 induced the expression level of a COX-1 protein which was increased at 30 min, then constantly expressed until 4 h. In addition, total RVV and purified PLA2 caused the release of the eicosanoids; PGE2, TXB2, and LTB4, which reached the peak after 2 h. The findings of this study indicate that purified PLA2 has the potential effects to induce the local inflammation relating the amounts of leukocytes cells, lipid mediators and COX-2 more than the total RVV.

TNF-Signaling Modulates Neutrophil-Mediated Immunity at the Feto-Maternal Interface During LPS-Induced Intrauterine Inflammation.

Accumulation of activated neutrophils at the feto-maternal interface is a defining hallmark of intrauterine inflammation (IUI) that might trigger an excessive immune response during pregnancy. Mechanisms responsible of this massive neutrophil recruitment are poorly investigated. We have previously showed that intraamniotic injection of LPS in rhesus macaques induced a neutrophil predominant inflammatory response similar to that seen in human IUI. Here, we demonstrate that anti-TNF antibody (Adalimumab) inhibited ~80% of genes induced by LPS involved in inflammatory signaling and innate immunity in chorio-decidua neutrophils. Consistent with the gene expression data, TNF-blockade decreased LPS-induced neutrophil accumulation and activation at the feto-maternal interface. We also observed a reduction in IL-6 and other pro-inflammatory cytokines but not prostaglandins concentrations in the amniotic fluid. Moreover, TNF-blockade decreased mRNA expression of inflammatory cytokines in the chorio-decidua but not in the uterus, suggesting that inhibition of TNF-signaling decreased the inflammation in a tissue-specific manner within the uterine compartment. Taken together, our results demonstrate a predominant role for TNF-signaling in modulating the neutrophilic infiltration at the feto-maternal interface during IUI and suggest that blockade of TNF-signaling could be considered as a therapeutic approach for IUI, the major leading cause of preterm birth.

Post-treatment Neutrophil-to-Lymphocyte Ratio as a Predictor of Overall Survival in Melanoma Brain Metastases treated with Stereotactic Radiosurgery

Systemic inflammation is known to play an important role in the progression of cancer. Specifically, an increase in the neutrophil-to-lymphocyte ratio (NLR) has been associated with shorter survival in patients with various malignancies; however, this effect has yet to be elucidated for patients with melanoma brain metastases (MBM). Pathology reviews have shown that stereotactic radiosurgery (SRS) results in a leukocyte predominant inflammatory response. The aim of this study is to investigate if NLR is associated with outcomes of patients with MBM treated with SRS. After IRB approval, patients with MBM treated with SRS from 2005-2013 were retrospectively identified. NLR was calculated from full blood counts obtained from the most proximal follow-up examination following SRS. Overall survival and intracranial outcomes were calculated using the Kaplan-Meier method and cumulative incidence with competing risk for death, respectively. Multivariable Cox models were applied to adjust for confounders. Seventy-seven consecutive patients with 138 MBM received SRS for which post-treatment NLR could be calculated. Of these, 50 patients (64.9%) with 90 MBM (65.2%) had a NLR <5. The cutoff point of 5 was chosen for NLR based on results from prior studies. Baseline patient characteristics, including active systemic disease and controlled primary, were well balanced, with only lower rates of prior immune therapy (48% vs. 22%, P = 0.002) in the NLR ≥5 cohort being different. SRS treatment parameters, including number of fractions, total dose, margin size, and treatment volume (GTV and PTV), were similarly well balanced. The median time to death or last imaging follow-up was 9.12 months overall (6.8 vs. 10.2 months for NLR ≥5 vs. NLR <5). A statistically significant (P = 0.004) survival advantage was seen in patients with a NLR <5 at 6 (81.4% vs. 61.3%), 12 (54.2% vs. 26.3%), and 24 months (35.7% vs. 11.7%). Post-SRS NLR (P = 0.005) and prior immune therapy (P = 0.014) were significant on univariate analysis. Multivariable analysis confirmed that post-SRS NLR ≥5 predicted for worse survival (Hazard Ratio: 2.02; 95% confidence interval, 1.16-3.54, P = 0.013), while prior immune therapy was no longer significant. No statistically significant differences were noted in 1-year local failure (8.1% vs. 11.2%), distal failure (66.3% vs. 72.9%), or radiation necrosis (9.3% vs. 16.0%) between NLR <5 and ≥5. The post-treatment NLR value, a potential marker for post-SRS inflammatory response, is inversely associated with survival for MBM treated with SRS. If prospectively validated, NLR could be deployed as a predictive biomarker and as a stratification and/or eligibility variable in clinical research.

Mesenchymal stem cell attenuates neutrophil-predominant inflammation and acute lung injury in an in vivo rat model of ventilator-induced lung injury.

Background:Subsequent neutrophil (polymorphonuclear neutrophil [PMN])-predominant inflammatory response is a predominant feature of ventilator-induced lung injury (VILI), and mesenchymal stem cell (MSC) can improve mice survival model of endotoxin-induced acute lung injury, reduce lung impairs, and enhance the repair of VILI. However, whether MSC could attenuate PMN-predominant inflammatory in the VILI is still unknown. This study aimed to test whether MSC intervention could attenuate the PMN-predominate inflammatory in the mechanical VILI.Methods:Sprague-Dawley rats were ventilated for 2 hours with large tidal volume (20 mL/kg). MSCs were given before or after ventilation. The inflammatory chemokines and gas exchange were observed and compared dynamically until 4 hours after ventilation, and pulmonary pathological change and activation of PMN were observed and compared 4 hours after ventilation.Results:Mechanical ventilation (MV) caused significant lung injury reflected by increasing in PMN pulmonary sequestration, inflammatory chemokines (tumor necrosis factor-alpha, interleukin-6 and macrophage inflammatory protein 2) in the bronchoalveolar lavage fluid, and injury score of the lung tissue. These changes were accompanied with excessive PMN activation which reflected by increases in PMN elastase activity, production of radical oxygen series. MSC intervention especially pretreatment attenuated subsequent lung injury, systemic inflammation response and PMN pulmonary sequestration and excessive PMN activation initiated by injurious ventilation.Conclusions:MV causes profound lung injury and PMN-predominate inflammatory responses. The protection effect of MSC in the VILI rat model is related to the suppression of the PMN activation.

Clinical outcome in patients with acute coronary syndrome and outward remodeling is associated with a predominant inflammatory response.

BackgroundPro-inflammatory molecules and low-density lipoproteins play essential roles in the atherosclerosis. The aim of our study was to establish an association among the cytokines secreted by peripheral blood mononuclear cells and the serum concentration in patients with unstable angina and coronary outward remodeling before and after percutaneous coronary intervention. The clinical and coronary responses were evaluated 6 months after the procedure.FindingsTwenty-two patients with unstable angina were evaluated prior to after percutaneous coronary intervention and 6 months after procedure by coronary intravascular ultrasound. Eleven of the patients had recurrent angina, while 9 presented restenosis and an increase in the percentage of total plaque area. These 11 patients displayed higher levels of C-reactive protein than those without coronary events (1.27 vs. 0.43 mg/dl, respectively; p = 0.029) and a tendency to increase levels of interleukin (IL)-8 and transforming growth factor-β1, but lower levels of IL-10 (52.09 vs. 141.5 pg/ml, respectively; p = 0.035). Activated peripheral blood mononuclear cells from patients with restenosis presented higher levels of proliferation, CD86 expression and higher IL-1, and increased IL-10 compared to those in patients without restenosis.ConclusionsPatients with unstable angina and coronary outward remodeling who displayed a pro-inflammatory response experienced recurrent coronary events and an increased percentage of total plaque area. In contrast, better outcomes were observed in patients with anti-inflammatory responses. This response could be secondary to low-density lipoproteins.

Effect of pregnancy on anti-HEV antibody titres, plasma cytokines and the corresponding gene expression levels in the PBMCs of patients presenting with self-recovering clinical and subclinical hepatitis E.

High mortality in pregnant women (PR) is a characteristic of hepatitis E in developing countries. To understand the pathogenesis of HEV infection in self-limiting disease during pregnancy, we compared clinical (PR-patients) and subclinical-HEV-infections in pregnant women in the first (SC-PR-1) and later (2nd and 3rd, SC-PR-2+3) trimesters with the respective healthy controls and acute non-PR patients. The SC-PR-2+3 exhibited lower ALT, bilirubin levels, anti-HEV-IgM/IgG titres than the acute-PR/non-PR-patients (p<0.05–0.0001). IFNγ/IL4ratios indicated Th2/Th1 bias in non-PR and PR-patients respectively. Raised levels of 10/20 plasma cytokines in the non-PR-patients reflect predominant inflammatory response, unaltered- IFNγ/reduced-IFNα responses and a robust chemokine secretion. On contrary, the acute-PR-patients exhibited drastic reduction in majority of the cytokines relative to in the non-PR-patients. Importantly, diminished or unaltered response was noted in the acute-PR-group when compared to the corresponding controls. The only exception was sIL2RA, increasing in both patient categories. Of the 14 genes evaluated, the expression of IFNγ/IL10/IL1A/IL7/CCL2/CCL3/CXCL8/CXCL10 was higher in the non-PR patients. Of these, the expression of IFNγ/IL10/IL1A/CCL2/CCL3/CXCL8 and, additionally, IL2/IL6/TNF genes was higher in the clinical-PRs. Almost identical pattern was noted in the control-PR-2+3 category indicating no influence of HEV infection. Comparison of patient-categories identified significant elevation of IFNγ(P<0.001), CCL2(p<0.01), CXCL8(P<0.05), IL1B(p<0.05) and IL10(P<0.0001) and decrease in CXCL10(<0.05) in the PR-patients. The results suggest antibody-dependent disease severity and impaired immune response in the PR patients. Higher expression of cytokine-genes in the PBMCs did not correlate with the plasma-cytokine levels in the PR-patients.

Influence of apoptosis on the cutaneous and peripheral lymph node inflammatory response in dogs with visceral leishmaniasis

In canine visceral leishmaniasis (CVL), the abnormalities most commonly observed in clinical examination on the animals are lymphadenomegaly and skin lesions. Dogs are the main domestic reservoir for the protozoon Leishmania (L.) chagasi and the skin is the main site of contamination by the vector insect. Some protozoa use apoptosis as an immunological escape mechanism. The aim of this study was to correlate the presence of apoptosis with the parasite load and with the inflammatory response in the skin and lymph nodes of dogs naturally infected with Leishmania (L.) chagasi. Thirty-three dogs from the municipality of Araçatuba (São Paulo, Brazil) were used, an endemic area for CVL. Muzzle, ear and abdominal skin and the popliteal, subscapular, iliac and mesenteric lymph nodes of symptomatic (S), oligosymptomatic (O) and asymptomatic (A) dogs were analyzed histologically. The parasite load and percentage apoptosis were evaluated using an immunohistochemical technique. Microscopically, the lymph nodes presented chronic lymphadenitis and the skin presented plasmacytic infiltrate and granulomatous foci in the superficial dermis, especially in the ear and muzzle regions. The inflammation was most severe in group S. The parasite load and apoptotic cell density were also greatest in this group. The cause of the lymphoid atrophy in these dogs was correlated with T lymphocyte apoptosis, thus leaving the dogs more susceptible to CVL. The peripheral lymph nodes presented the greatest inflammatory response. Independent of the clinical picture, the predominant inflammatory response was granulomatous and plasmacytic, both in the skin and in the peripheral lymph nodes. The ear skin presented the greatest intensity of inflammation and parasite load, followed by the muzzle skin, in group S. The ear skin area presented a non-significant difference in cell profile, with predominance of macrophages, and a significant difference from group A to groups O and S. It was seen that in these areas, there were high densities of parasites and cells undergoing apoptosis, in group S. The association between apoptosis and parasite load was not significant in the lymph nodes, but in the muzzle regions and at the ear tips, a positive correlation was seen between the parasite load and the density of cells undergoing apoptosis. The dogs in group S had the highest parasite load and the greatest number of apoptotic cells, thus suggesting that the parasite had an immune evasion mechanism, which could be proven statistically in the skin.

Predominant inflammatory cytokine secretion pattern in response to two doses of live rubella vaccine in healthy vaccinees

We conducted a population-based study on 738 schoolchildren who received two doses of rubella vaccine in order to determine cytokine secretion patterns and their associations with demographic and clinical variables. The results showed a robust rubella-specific inflammatory cytokine response characterized by high median [inter-quartile range (IQR)] secretion levels (in pg/mL) of IL-6 [3681.0 (3160.0, 4052.0)], GM-CSF [28.0 (23.6, 32.6)], and TNF-alpha [29.7 (-7.0, 89.2)]. We also detected modest levels of rubella-specific secretion of Th1 cytokines IL-2 and IFN-gamma, while IL-12p40 was undetectable. In contrast, rubella-specific Th2 responses were hardly detectable. Age at vaccination, enrollment, and time elapsed between last vaccination and enrollment was significantly associated with the outcome of IL-2, IL-6, and IFN-gamma secretion. These results suggest an immune-deviation or "skewing" from Th1/Th2 cytokine patterns towards a predominant inflammatory response upon in vitro rubella virus stimulation.

Tumor necrosis factor-α produced in cardiomyocytes mediates a predominant myocardial inflammatory response to stretch in early volume overload

Acute stretch caused by volume overload (VO) of aorto-caval fistula (ACF) induces a variety of myocardial responses including mast cell accumulation, matrix metalloproteinase (MMP) activation, and collagen degradation, all of which are critical in dictating long-term left ventricle (LV) outcome to VO. Meanwhile, these responses can be part of myocardial inflammation dictated by tumor necrosis factor-α (TNF-α), which is elevated after acute ACF. However, it is unknown whether TNF-α mediates a major myocardial inflammatory response to stretch in early VO. In 24-h ACF and sham rats, microarray gene expression profiling and subsequent Ingenuity Pathway Analysis identified a predominant inflammatory response and a gene network of biologically interactive genes strongly linked to TNF-α. Western blot demonstrated increased local production of TNF-α in the LV (1.71- and 1.66-fold in pro- and active-TNF-α over control, respectively, P<0.05) and cardiomyocytes (2- and 4-fold in pro- and active-TNF-α over control, respectively, P<0.05). TNF-α neutralization with infliximab (5.5 mg/kg) attenuated the myocardial inflammatory response to acute VO, as indicated by inhibition of inflammatory gene upregulation, myocardial infiltration (total CD45+ cells, mast cells, and neutrophils), MMP-2 activation, collagen degradation, and cardiac cell apoptosis, without improving LV remodeling and function. These results indicate that TNF-α produced by cardiomyocytes mediates a predominant inflammatory response to stretch in the early VO in the ACF rat, suggesting an important role of TNF-α in initiating pathophysiological response of myocardium to VO.

Genome-wide differences in hepatitis C- vs alcoholism-associated hepatocellular carcinoma

To look at a comprehensive picture of etiology-dependent gene abnormalities in hepatocellular carcinoma in Western Europe. With a liver-oriented microarray, transcript levels were compared in nodules and cirrhosis from a training set of patients with hepatocellular carcinoma (alcoholism, 12; hepatitis C, 10) and 5 controls. Loose or tight selection of informative transcripts with an abnormal abundance was statistically valid and the tightly selected transcripts were next quantified by qRTPCR in the nodules from our training set (12 + 10) and a test set (6 + 7). A selection of 475 transcripts pointed to significant gene over-representation on chromosome 8 (alcoholism) or -2 (hepatitis C) and ontology indicated a predominant inflammatory response (alcoholism) or changes in cell cycle regulation, transcription factors and interferon responsiveness (hepatitis C). A stringent selection of 23 transcripts whose differences between etiologies were significant in nodules but not in cirrhotic tissue indicated that the above dysregulations take place in tumor but not in the surrounding cirrhosis. These 23 transcripts separated our test set according to etiologies. The inflammation-associated transcripts pointed to limited alterations of free iron metabolism in alcoholic vs hepatitis C tumors. Etiology-specific abnormalities (chromo-some preference; differences in transcriptomes and related functions) have been identified in hepatocellular carcinoma driven by alcoholism or hepatitis C. This may open novel avenues for differential therapies in this disease.

Keratectasia as a Presentation of Surgically Induced Necrotizing Sclerokeratitis (SINS)

A case of keratectasia is reported as a severe presentation of surgically induced necrotizing sclerokeratitis (SINS). A 72-year-old white woman had a painful, raised lesion on the superior cornea of her right eye 3 years after uncomplicated extracapsular cataract extraction with intraocular lens implantation. Examination showed a large ectatic area of the superior cornea with inflamed sclera adjacent to the surgical wound, which was diagnosed as SINS. No underlying systemic autoimmune condition or vasculitis was identified on investigation. Progressive painful keratectasia necessitated enucleation, which confirmed on histopathologic examination features of chronic nodular episcleritis and nongranulomatous scleritis with evidence of keratitis and fibrovascular scarring. The predominant inflammatory response in the cornea represents surgically induced necrotizing keratoscleritis (SINK) as a new variant presentation of SINS. Oral corticosteroids and immunosuppressive agents should not be delayed to prevent progressive tissue destruction and poor outcome.

The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness.

Parasitic filarial nematodes infect more than 200 million individuals worldwide, causing debilitating inflammatory diseases such as river blindness and lymphatic filariasis. Using a murine model for river blindness in which soluble extracts of filarial nematodes were injected into the corneal stroma, we demonstrated that the predominant inflammatory response in the cornea was due to species of endosymbiotic Wolbachia bacteria. In addition, the inflammatory response induced by these bacteria was dependent on expression of functional Toll-like receptor 4 (TLR4) on host cells.

Acute Rejection after Cardiac Transplantation: Detection by Interstitial Myocardial pH

Intramyocardial pH was assessed as a potential marker for clinical evaluation and treatment of acute rejection following cardiac transplantation. Fifteen cats underwent forty operative procedures. Following intraabdominal heterotopic heart transplantation, serial laparotomies were performed in the early (days 0 to 2), intermediate (days 5 to 7), and late (days 7 to 16) postoperative periods. Rejection was assessed by serial clinical examinations, ECG analyses, B-mode echocardiography, histological and ultrastructural analyses, and measurements of interstitial myocardial pH. Intramyocardial pH was measured by a new miniature (0.6 × 3.0 mm) fiberoptic pH transducer. At confirmed rejection, concomitant laparotomy and thoracotomy were performed and pH sensors were implanted in both native (anatomical) and graft hearts. Nine animals at rejection were given methylprednisolone and changes in graft and native heart pH were measured. The pH during absence of rejection, mild acute rejection, and severe acute rejection averaged 7.430 ± 0.019, 7.233 ± 0.040 ( p < .02), and 6.860 ± 0.066 ( p < .02), respectively (mean ± standard error of the mean). A progressive decline in pH was noted in each heart. In animals receiving steroids, graft heart pH increased over 90 minutes from 6.852 ± 0.065 to 7.043 ± 0.077 ( p < .05). Although pH decline may be secondary to either inflammatory or ischemic etiology, histological and ultrastructural analyses demonstrate a predominant inflammatory response with progressive mononuclear cell infiltration, interstitial edema, vascular wall edema, infiltration by polymorphonuclear neutrophil leukocytes, vacuolation of sarcoplasmic reticulum, and disarray of myocytes associated with falling pH. Degree of pH change correlated closely with degree of histological rejection, presence of ECG voltage decline, and change in wall thickness by ultrasound.