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At least 91 records · Page 5Linked to original sources
PubMed1999

In vitro culture of microdissected rat nasal airway tissues.

The surface epithelium lining the nasal airways is a potential target for inhaled contaminants such as ozone, endotoxin, formaldehyde, tobacco smoke, and organic dusts. The epithelial response to injury may depend on the toxicant, the type of epithelium, the severity of the injury, and the presence of inflammatory cells and their secreted products. To study mechanisms of toxicant-induced epithelial injury and repair, in the absence of cellular inflammation or other systemic effects, we have developed a culture system to maintain morphologically distinct nasal airway epithelium in vitro. Microdissected maxilloturbinates and proximal nasal septa of male F344/N rats were cultured at an air-liquid interface for up to 14 d in supplemented serum-free medium. Maxilloturbinates are lined by nonciliated cuboidal nasal transitional epithelium (NTE) with few or no mucous cells. The proximal nasal septum is lined by a mucociliary respiratory epithelium (RE) that normally contains numerous mucous cells. Preservation of the normal RE and NTE phenotype in culture was assessed by light and electron microscopy, and analysis of an airway mucin gene (rMuc-5AC) messenger RNA (mRNA). Both RE and NTE retained normal cell morphology for 14 d in culture (DIC). After 14 DIC there were 20% fewer RE cells in the septa (equal loss of ciliated and mucous cells) and 25% more NTE cells in the maxilloturbinates (increased number of basal cells). Compared with the RE, the NTE expressed consistently low levels of rMuc-5AC mRNA and had little to no histochemically detectable intraepithelial mucosubstances (IM) after 0, 3, 7, or 14 DIC. The amount of stored IM and the steady-state levels of rMuc-5AC mRNA in the RE decreased with time in culture. In summary, this culture system can maintain fully differentiated secretory and nonsecretory rat airway epithelia in vitro for up to 14 d. This study was an essential first step in developing a system to study the pathogenesis of toxicant-induced airway epithelial injury and mechanisms of cellular repair and adaptation in the absence of cellular inflammation and other systemic influences.

Animals↗
PubMed1993

The mast cell--a potential link between inflammation and cellular cholesterol deposition in atherogenesis.

Mast cells are present in the arterial intima, the site of atherogenesis. In fatty streaks (the initial stage of atherogenesis) some of these cells are detected in the close vicinity of cholesterol-loaded macrophage foam cells. To ascertain whether mast cells could be involved in the formation of foam cells, a model system was developed in which isolated rat serosal mast cells were incubated with mouse peritoneal macrophages in a medium enriched with either low density lipoproteins (LDL) or high density lipoproteins (HDL3). Stimulation of the mast cells was found to induce 50-fold enhancement of LDL uptake by the macrophages. When stimulated, mast cells exocytose their secretory granules, which lose their membranes in the process. The granules then come in contact with the medium, which dissolves their histamine, a fraction of their heparin proteoglycans and all their chondroitin sulphate proteoglycans, leaving insoluble 'granule remnants'. These remnants consist of neutral proteases embedded in a heparin proteoglycan matrix. Some of the LDL particles in the incubation medium bind to this matrix, become degraded by the matrix-bound proteases, and fuse into larger particles on the surfaces of the remnants. These LDL particles are ingested by the macrophages as they phagocytose the remnants. Simultaneously, the soluble heparin proteoglycans interact with other LDL particles, forming insoluble complexes which are also phagocytosed by the macrophages. Cholesterol from the phagocytosed LDL particles ultimately becomes esterified in the macrophages, with formation of foam cells. In addition, mast cells block the removal of cholesterol from the foam cells: the remnant enzymes proteolyse HDL particles, so lessening their ability to induce efflux of cholesterol from the foam cells. These observations suggest that mast cells play an active role in the intracellular deposition of cholesteryl esters that is characteristic of early atherosclerotic lesions.

Animals↗
PubMed1991

Chronic non-ischaemic congestive heart disease and endomyocardial biopsies. Worth the extra?

The diagnostic yield of endomyocardial biopsies in patients with chronic congestive heart failure of non-ischaemic aetiology remains questionable and, therefore, the use of endomyocardial biopsies under such circumstances is at stake. The present report documents the correlation between the histologic interpretation of endomyocardial biopsies and the corresponding cardiac explants in 13 patients who underwent cardiac transplantation. The biopsy diagnoses in these patients varied from 'compatible with dilated cardiomyopathy' (n = 6) to 'non-conclusive' (n = 4), 'ischaemia' (n = 2) and 'borderline myocarditis' (n = 1). Correlation with the corresponding cardiac explants revealed hypertrophy of myocytes as the leading histologic feature in the majority of cases. Because of the non-specific histopathology of dilated cardiomyopathy, the discrepancy between biopsy diagnoses and the leading explant diagnosis is mostly a matter of semantics. Ischaemia was present at high incidence, but is considered a result of imparied myocardial perfusion rather than the prime mechanism of heart failure. In four cardiac explants myocarditis was encountered, while the corresponding biopsies showed no cellular inflammation. In two, the cellular infiltrates suggested an early state of repair. One heart contained an active and extensive lymphocytic myocarditis. The fourth case showed an eosinophilic myocarditis, most likely acquired after the biopsy was taken. These discrepancies almost certainly relate to the sampling error and the time interval between biopsy and onset of symptoms. The immediate diagnostic yield of the biopsy, in this particular subset of patients, was minimal, particularly with respect to the diagnosis 'myocarditis'. Nevertheless, biopsy diagnoses such as 'compatible with' and 'non-conclusive' do contribute to the final categorization and management of these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2004

Relation of nocturnal blood pressure dipping to cellular adhesion, inflammation and hemostasis.

BACKGROUND: Subjects who fail to dip their nocturnal blood pressure (BP) are at substantially increased risk for cardiovascular diseases. The pathogenetic mechanisms of this relationship have not been elucidated. We investigated whether non-dipping would relate to procoagulant and proinflammatory activity. DESIGN: Study participants were 76 unmedicated normotensive and hypertensive subjects (44 male, 32 female; 41 white, 35 black; mean age, 36 +/- 8 years) who underwent 24-h outpatient ambulatory BP monitoring. Based on whether their average nocturnal systolic BP relative to their average daytime systolic BP declined by less than 10%, 34 subjects were categorized as non-dippers. D-dimer, plasminogen activator inhibitor-1, von Willebrand factor, soluble intercellular adhesion molecule-1, and interleukin-6 were measured in plasma. RESULTS: Multivariate analyses showed that D-dimer (median/interquartile range, 242/162-419 ng/ml versus 175/132-254 ng/ml; P=0.041), plasminogen activator inhibitor-1 (36/19-61 ng/ml versus 17/6-44 ng/ml; P=0.010), von Willebrand factor (122/91-179% versus 92/66-110%; P=0.001), and soluble intercellular adhesion molecule-1(227/187-291 ng/ml versus 206/185-247 ng/ml; P=0.044) were all higher in non-dippers than in dippers. Adjustment for gender, ethnicity, age, body mass index, smoking status, hypertension status, and social class revealed independent effects of non-dipping. Non-dippers continued to have higher D-dimer (P=0.030) and von Willebrand factor (P=0.034) than dippers. A similar trend not reaching statistical significance emerged for soluble intercellular adhesion molecule-1 (P=0.055). In contrast, dipping status had no effect on interleukin-6. CONCLUSION: Nocturnal BP non-dipping is associated with elevated levels of molecules related to endothelial dysfunction and atherosclerosis. The finding provides one possible mechanism linking non-dipping with cardiovascular disease.

Adult↗
PubMed1998

Enhancement of obliterative airway disease in rat tracheal allografts infected with recombinant rat cytomegalovirus.

BACKGROUND: Cytomegalovirus infection has been identified as a significant risk factor for the development of obliterative bronchiolitis in human lung transplant recipients. This study was designed to assess the influence of rat cytomegalovirus (RCMV) on the pathogenesis and development of obliterative bronchiolitis in an experimental model of obliterative airway disease, which occurs after allogenic heterotopic tracheal transplantation in rodents. METHODS: Sixty Lewis rats were infected intraperitoneally with 10(7) plaque-forming units of recombinant lac-Z-tagged RCMV expressing the gene for beta-galactosidase. Rats were either infected at the time of surgery (acute infection, n = 30) or 56 days before surgery (chronic infection, n = 30). Tracheae from Brown Norway (allograft) or Lewis (isograft) rats were implanted and wrapped in the greater omentum of infected Lewis rats. RCMV infection was verified in different recipient tissues by in vitro plaque-assays and by direct in situ staining for beta-galactosidase activity. The tracheal grafts were harvested on days 7, 14, and 21 after transplantation and stained with hematoxylin-eosin and Masson's trichrome. The peritracheal cellular inflammation was scored visually. The cellular density of the infiltrating cells and the extent of airway obliteration were analyzed by use of computer-digitized morphometry and compared with uninfected allografts as control. RESULTS: Both acute and chronic cytomegalovirus infection produced significantly higher mononuclear cell density values on days 7 and 14 compared with noninfected controls, indicating a more intense immune response in the infected allografts. Tracheal allograft obliteration was also more extensive after acute and, in particular, after chronic cytomegalovirus infection (64% narrowing after 21 days compared with 36% in grafts from noninfected control animals). CONCLUSIONS: Our experimental results provide direct evidence that the tracheal grafts were infected with RCMV and that the development of obliterative airway disease was enhanced in the acutely and chronically infected allografts compared with grafts from noninfected control animals.

Animals↗
PubMed1987

Local allergen challenge and bronchoalveolar lavage of allergic asthmatic lungs. Description of the model and local airway inflammation.

The local mechanisms that result in the cellular inflammation and bronchial airway hyperreactivity that characterize allergic bronchial asthma are poorly defined. In order to study these processes, we developed a method for local allergen challenge using a fiberoptic bronchoscope and direct observation and bronchoalveolar lavage (BAL) to assess the airway responses to allergen. In these studies, 11 allergic asthmatics (all of whom had previously demonstrated a late-phase asthmatic response to aeroallergen challenge) and 6 healthy, asymptomatic subjects volunteered to undergo bronchoalveolar lavage after local airway challenge via a bronchoscope wedged into subsegmental airways. These studies revealed that asthmatic airways respond to allergen with an immediate pallor followed by reactive hyperemia, edema, and bronchial narrowing. This site and a control site were relavaged at 48 or 96 h after the immediate response. Neutrophils and eosinophils increased significantly at 48 h after challenge, as did helper T-lymphocytes. Characteristically, at 96 h, neutrophil counts returned to normal values, whereas eosinophiles and helper T-cells remained elevated. Peroxidase-staining cells were also elevated at 48 h after local allergen challenge. Electron microscopy revealed degranulation of mast cells and eosinophils, both immediately and later (48 and 96 h) after local allergen challenge. Macrophages were highly activated and had phagocytized, partially intact granules from both eosinophils and mast cells. There was a significant correlation (p less than 0.001) between the concentration of allergen required to produce a visible airway response and a positive end-point skin titration in the asthmatic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2004

Chemokines in eosinophil-associated gastrointestinal disorders.

Eosinophil-associated gastrointestinal disorders (EGDs) are characterized by a pronounced cellular inflammation. Recent clinical and experimental investigations have implicated a family of molecules known as chemokines in the regulation of leukocyte recruitment in these diseases. The underlying cellular and molecular mechanisms involved in chemokine-mediated cellular infiltration are largely unknown. In this review, we describe the role of CD4+ T cells and eosinophils in the clinical manifestations of EGDs and discuss the current understanding of the role of chemokines in the recruitment of these cells in the expression of diseases.

Animals↗
PubMed2006

Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications.

The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.

Animals↗
PubMed2003

Semiquantitative analysis of the histopathological features of the neuropathic foot ulcer: effects of pressure relief.

OBJECTIVE: This study was designed to evaluate the histopathology of neuropathic ulcers and whether pressure relief could change such histological patterns. RESEARCH DESIGN AND METHODS: We compared neuropathic plantar ulcers tissue excised from 10 diabetic patients (group A) with those taken from 10 patients with comparable lesions and glycemic control after 20 days in a total contact cast (group B). Tissue specimens were blindly examined by two independent pathologists for hyperkeratosis, fibrosis, cutaneous annexes, capillaries, inflammation, cellular debris, and granulating tissue. For each parameter, quantification was obtained according to an arbitrary score: 0, absent; 1, present in <33%; 2, present in 34-66%; and 3, present in >67% of the lesion. RESULTS: Patients in group B showed a marked reduction in ulcer size after 20 days of casting (P < 0.01). The histopathological features of the two groups markedly differed. Group A patients showed a predominance of inflammatory elements as well as matrix alterations, vessel disruptions, inflammation, and debris. Group B ulcers showed a shift toward a reparative pattern with prevalence of neoformed capillaries and fibroblasts. Semiquantitative analysis confirmed the prevalence of hyperkeratosis, fibrosis, inflammation, and cellular debris in group A patients (P < 0.05), whereas cutaneous annexes, capillaries, and granulating tissue were more prevalent in group B lesions (P < 0.01). CONCLUSIONS: These results indicate that pressure relief with a total contact cast is associated with changes in the histology of neuropathic foot ulcers, indicating reduction of inflammatory and reactive components and acceleration of reparative processes.

Aged↗
PubMed1990

Intravitreal biocompatibility of mussel adhesive protein. A preliminary study.

Mussel adhesive protein (MAP) is a new tissue adhesive derived from the sea mussel Mytilus edulis. Rabbit eyes were injected intravitreally with 1 mg of MAP or balanced salt solution in order to determine the intraocular effects of this new biologic tissue adhesive. Two concentrations of MAP were used: one was undiluted and the other was diluted to a concentration of 1:10. A marked cellular inflammatory response, compared with the control eyes, was seen clinically in the vitreous cavity of animals in which MAP was used undiluted. This response persisted for up to two weeks and was suggestive of inflammatory response to a foreign protein. When MAP was used at a dilution of 1:10, a mild transient cellular reaction was observed in the vitreous; this cleared after seven days. There was no increase in intraocular pressure, and none of the eyes developed cataract or optic nerve damage. Fluorescein angiography demonstrated no vascular leakage and electroretinography was normal in all of the eyes at two weeks. Histopathologic evaluation of the eyes at 7 and 14 days after injection revealed localized cellular inflammation in the vitreous and adjacent retina when MAP was used undiluted, but no reaction in the control eyes or in eyes injected with MAP at 1:10 dilution. This preliminary study suggests that MAP produces a marked intraocular inflammatory reaction when used at full concentration. By diluting the adhesive, a less severe inflammatory response was observed, which cleared with no complications.

Animals↗
PubMed2000

Airway inflammation and remodeling in asthma.

An important advance in our understanding of the pathophysiology of asthma has been the discovery that airway inflammation is not confined to severe asthma but also characterizes mild and moderate asthma. Inflammation in asthma may be the result of a peculiar type of lymphocytic inflammation whereby Th2 lymphocytes secrete cytokines that orchestrate cellular inflammation and promote airway hyperresponsiveness. The term "airway remodeling" in asthma refers to structural changes that occur in conjunction with, or because of, chronic airway inflammation. Airway remodeling results in alterations in the airway epithelium, lamina propria, and submucosa, leading to thickening of the airway wall. The consequences of airway remodeling in asthma may include incompletely reversible airway narrowing, bronchial hyperresponsivenesss, airway edema, and mucus hypersecretion. Airway remodeling in asthma thus may predispose persons with asthma to asthma exacerbations and even death from airway obstruction caused by smooth muscle contraction, airway edema, and mucus plugging. Although much has been learned in the past 25 years about the pathophysiology of airway inflammation and airway remodeling in asthma, important questions remain about the relation between airway inflammation and remodeling, the natural history of airway remodeling, and the effects of current asthma treatments on remodeled airways.

Airway Obstruction↗
PubMedDate not supplied

CD34+ cells in peripheral blood of healthy human beings and allergic subjects: clue to acute and minimal persistent inflammation.

BACKGROUND: There is compelling evidence that hemopoietic precursor cells (HPC) play a crucial role in establishing cellular inflammation in allergic diseases. Increased levels of circulating CD34+ HPC committed to the myeloid lineage have been extensively reported in allergic rhinitis, asthma and eczema, whereas CD34+ cells have been identified within the cellular infiltrates of tissues, at peripheral sites of inflammation. METHOD: We conducted a pilot study to evaluate CD34+ traffic in the peripheral blood of 22 consecutive patients (13 men and nine women; mean age 28.9 years), independently of treatment. The patients presented rhinitis, asthma, eczema, urticaria and adverse food reactions of suspected allergic origin. Allergic reactions were extrinsic in 18 patients and intrinsic in four. In 12 patients who underwent sublingual specific immunotherapy, CD34+ cells were quantified at enrollment (T0), one year later (T1) and two years later (T2). The severity of symptoms was graded on a five-point scale (0 = absence of symptoms and 4 = severe symptoms). Twenty healthy human subjects (10 men and 10 women; mean age 24.5 years) were evaluated as controls. To obtain information about the total amount of circulating HPC, independently of the lineage commitment (Lin+/-) and the degree of differentiation (CD34bright/dim), we used a modification of the Milan protocol of peripheral blood CD34+ cell estimation. The cells were analyzed using a BD FACScan or FACSCalibur and the results were expressed as the percentage of positive cells. RESULTS: CD34+ cell traffic in the control group was very low since all values were < 0.10 (median value: 0.03 %). Values in the patient group were increased in both extrinsic and intrinsic forms with a median value of 0.25 % (interquartile range: 0.13- 0.33 %). The relationship between CD34+ traffic and the severity score was highly significant (Spearman's rho = 0.954; test of Ho: CD34; independent score: Pr > t = 0.000). CONCLUSIONS: The data reported herein suggest that the method employed is effective in assessing acute allergic inflammation, as well as minimal persistent inflammation underlying an asymptomatic clinical condition. Evaluation of CD34bright/dim peripheral traffic, if confirmed by the outcomes of a multicenter study currently being planned together with traditional study of circulating IgE, could be a reliable non-invasive laboratory tool for monitoring allergic inflammation.

Adolescent↗
PubMed2004

Navigating novel mechanisms of cellular plasticity with the NAD+ precursor and nutrient nicotinamide.

Interest in neuroprotectants for the central nervous system continues to garner significant attention. Nicotinamide, the amide form of niacin (vitamin B3), is the precursor for the coenzyme beta-nicotinamide adenine dinucleotide (NAD+) and is considered to be necessary for cellular function and metabolism. However, recent work has focused on the development of nicotinamide as a novel agent that is critical for modulating cellular plasticity, longevity, and inflammatory microglial function. The ability of nicotinamide to preserve both neuronal and vascular cell populations in the brain during injury is intriguing, but further knowledge of the specific cellular mechanisms that determine protection by this agent is required. The capacity of nicotinamide to govern not only intrinsic cellular integrity, but also extrinsic cellular inflammation rests with the modulation of a host of cellular targets that involve protein kinase B, glycogen synthase kinase-3 beta (GSK-3 beta), Forkhead transcription factors, mitochondrial dysfunction, poly(ADP-ribose) polymerase, cysteine proteases, and microglial activation. Intimately tied to the cytoprotection of nicotinamide is the modulation of an early and late phase of apoptotic injury that is triggered by the loss of membrane asymmetry. Identifying robust cytoprotective agents as nicotinamide in conjunction with the elucidation of the cellular mechanisms responsible for cell survival will continue to solidify the development of therapeutic strategies against neurodegenerative diseases

Aging↗
PubMed2006

Cell Life versus cell longevity: the mysteries surrounding the NAD+ precursor nicotinamide.

Nicotinamide, the amide form of niacin (vitamin B(3)), is the precursor for the coenzyme beta-nicotinamide adenine dinucleotide (NAD(+)) and plays a significant role during the enhancement of cell survival as well as cell longevity. Yet, these abilities of nicotinamide appear to be diametrically opposed. Here we describe the development of nicotinamide as a novel agent that is critical for modulating cellular metabolism, plasticity, longevity, and inflammatory microglial function as well as for influencing cellular life span. The capacity of nicotinamide to govern not only intrinsic cellular integrity, but also extrinsic cellular inflammation rests with the modulation of a host of cellular targets that involve mitochondrial membrane potential, poly(ADP-ribose) polymerase, protein kinase B (Akt), Forkhead transcription factors, Bad, caspases, and microglial activation. Further knowledge acquired in regards to the ability of nicotinamide to foster cellular survival and regulate cellular lifespan should significantly promote the development of therapies against a host of disorders, such as aging, Alzheimer's disease, diabetes, cerebral ischemia, Parkinson's disease, and cancer.

Animals↗
PubMed1999

Mechanisms of immune regulation in the peripheral nervous system.

The peripheral nervous system (PNS) is a target for heterogenous immune attacks mediated by different components of the systemic immune compartment. T cells, B cells, and macrophages can interact with endogenous, partially immune-competent glial cells and contribute to local inflammation. Cellular and humoral immune functions of Schwann cells have been well characterized in vitro. In addition, the interaction of the humoral and cellular immune system with the cellular and extracellular components in the PNS may determine the extent of tissue inflammation and repair processes such as remyelination and neuronal outgrowth. The animal model experimental autoimmune neuritis (EAN) allows direct monitoring of these immune responses in vivo. In EAN contributions to regulate autoimmunity in the PNS are made by adhesion molecules and by cytokines that orchestrate cellular interactions. The PNS has a significant potential to eliminate T cell inflammation via apoptosis, which is almost lacking in other tissues such as muscle and skin. In vitro experiments suggest different scenarios how specific cellular and humoral elements in the PNS may sensitize autoreactive T cells for apoptosis in vivo. Interestingly several conventional and novel immunotherapeutic approaches like glucocorticosteroids and high-dose antigen therapy induce T cell apoptosis in situ in EAN. A better understanding of immune regulation and its failure in the PNS may help to develop improved, more specific immunotherapies.

Animals↗