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PubMed2000

Differential effects of nitric oxide synthase inhibitors in an in vivo allergic rat model.

The in vivo role of nitric oxide in inflammatory cell migration, vascular permeability and the development of hyperresponsiveness to methacholine (MCh) was studied in rats 24 h following ovalbumin (OVA) challenge. The NO synthase (NOS) inhibitors N(G)-mono-methyl-L-arginine (L-NMMA; nonselective), aminoguanidine (two-fold inducible NOS-selective), N(omega)-nitro-L-arginine methyl ester (L-NAME; 2000-fold endothelial cell NOS-selective) or S-methyl-L-thiocitrulline (100-fold neuronal NOS-selective) were administered (100 mg x kg(-1) s.c.) to OVA-sensitized Piebald-Virol-Glaxo rats on 3 consecutive days during which they were challenged with allergen (1% OVA). Responses to inhaled MCh were measured in anaesthetized animals 24 h after OVA challenge. Cellular inflammation and vascular permeability were assessed using bronchoalveolar lavage (BAL) fluid collected 30 min after administration of Evans blue (50 mg x kg(-1) i.v.). OVA challenge in sensitized animals induced hyperresponsiveness to MCh, inflammatory cell influx and increased leakage of Evans blue into the BAL fluid (n=9, p<0.001). Aminoguanidine was effective in inhibiting the allergen-induced cellular influx and microvascular leakage (n=9, p<0.001) without altering responses to MCh. This effect was reserved by L-arginine. L-NAME (n=5, p<0.01) and S-methyl-L-thiocitrulline (n=6, p<0.001) further potentiated the allergen-induced hyperresponsiveness without altering cellular inflammation. L-NMMA attenuated both the OVA-induced cellular influx and Evans blue leakage (n=8, p<0.001) as well as further potentiating the hyperresponsiveness to MCh (p<0.05). From these studies, it is suggested that, in allergic Piebald-Virol-Glaxo rats, nitric oxide production by inducible nitric oxide synthase plays a role in the migration of inflammatory cells and increase in vascular permeability following allergen challenge, whereas nitric oxide produced by the constitutively expressed neuronal nitric oxide synthase limits hyperresponsiveness to methacholine.

Animals↗

PubMed2006

Phosphatidylinositol mannosides: synthesis and suppression of allergic airway disease.

Phosphatidylinositol mannoside (PIM) extracts from mycobacteria have been shown previously to suppress allergic airway inflammation in mice. To help determine the structural requirements for activity, PIM1(2) (1), PIM1(6) (2) and PIM2 (3) were synthesized and tested for their ability to suppress cellular inflammation in a mouse model of allergic asthma. The synthetic PIMs were all effective in suppressing airway eosinophilia in the asthma model, with PIM1(6) being the most effective. Suppression of all inflammatory cells monitored was observed, indicating a general blockade of cellular inflammation. Non-mannosylated phosphatidylinositol (PI) had no suppressive effect, indicating that at least one alpha-d-mannopyranosyl residue is necessary for activity. The suppressive effect of the three PIM compounds indicates that other members of this set may be of value in treatment of a range of diseases driven by infiltration of inflammatory cells.

Animals↗

PubMed1986

Generation and partial characterization of eosinophil chemotactic activity and neutrophil chemotactic activity during early and late-phase asthmatic response.

Asthma has been recognized to consist of hyperresponsive airways and cellular inflammation. Allergen bronchoprovocation (BPC) may define the early (EAR) and late-phase asthmatic response (LAR). The LAR has now been associated with increased nonspecific airway hyperresponsiveness and cellular inflammation consisting of neutrophils and eosinophils. We used BPC to demonstrate EAR and LAR in 12 subjects with seasonal allergic asthma. One normal subject and one subject with asthma who had been treated with allergy immunotherapy were challenged but did not respond. Plasma was sampled at frequent intervals during these aeroallergen challenges and assayed for eosinophil chemotactic activity (ECA) and neutrophil chemotactic activity (NCA). Of the 12 subjects with asthma who were challenged, nine had dual responses (both EAR and LAR), and three subjects demonstrated only an LAR. Those subjects who had dual airway responses had biphasic rises in both ECA (early = 267 +/- 28%; late = 286 +/- 28%) and NCA (early = 279 +/- 24%; late = 215 +/- 15%) in their plasma, whereas those subjects who demonstrated only an LAR had only a late rise in ECA (218 +/- 61%) and NCA (188 +/- 31%). The two individuals who did not respond to aeroallergen challenge demonstrated no change in their plasma chemotactic activity toward either eosinophils or neutrophils. Those individuals with the most severe LAR (greater than or equal to 1,000 mm2) had combined ECA plus NCA peak values of greater than 500%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2002

Time course of pulmonary response of rats to inhalation of crystalline silica: NF-kappa B activation, inflammation, cytokine production, and damage.

In vitro studies suggest that silica-induced lung disease may be linked to processes regulated by nuclear factor-kappa B (NF-kappa B) activation, but this has not been examined in vivo. Rats were exposed to a silica aerosol of 15 mg/m(3) (6 h/day, 5 days/wk) for 116 days, and bronchoalveolar lavage (BAL) was conducted at various times during the exposure. Silica-induced pulmonary inflammation and damage were determined by measuring BAL cell differentials and first BAL fluid lactate dehydrogenase (LDH) activity and serum albumin concentrations, respectively. NF-kappa B activation and production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) by BAL cells were also measured. The results demonstrate that NF-kappa B activation occurred after 5 days exposure, and continued to increase thereafter. BAL cell production of IL-1 and TNF-alpha had increased incrementally by 10 and 30 days of exposure, respectively. This elevation continued through 79 days of exposure before further increasing at 116 days of exposure. Pulmonary inflammation and damage in silica-exposed rats were also significantly elevated at 5 days of exposure, further increased at a slow rate through 41 days of exposure, and dramatically increased thereafter. Taken together, the results indicate that the initial molecular response of NF-kappa B activation in BAL cells occurs in response to low levels of silica deposition in the lung and increases more rapidly versus exposure duration than silica-induced pulmonary inflammation, cellular damage, and cytokine production by BAL cells. This suggests that NF-kappa B activation in BAL cells may play an important role in the initiation and progression of silica-induced pulmonary inflammation, cellular damage, and fibrosis.

Animals↗

PubMed2002

Beta 2-microglobulin amyloidosis: role of monocytes/macrophages.

PURPOSE OF REVIEW: Macrophage infiltration is a distinctive histological characteristic of beta2-microglobulin amyloidosis. Studies reported during the past years have helped to clarify the role of monocytes/macrophages in the fibrillar precipitation of beta2-microglobulin and in the pathogenesis of osteoarticular pathology. RECENT FINDINGS: Contrary to the original view, macrophage infiltration is more likely a secondary phenomenon of amyloidosis rather than an initiating event. The observation that macrophages are associated with a later stage of beta2-microglobulin amyloidosis suggests a possible role of these cells in transformation of clinical silent deposits into symptomatic osteoarticular destruction. Accumulating evidence suggests that beta2-microglobulin modified with advanced glycation end products plays a key role in recruitment and activation of macrophages through an advanced glycation end products receptor-mediated pathway, and thus may contribute to the development of local cellular inflammation in beta2-microglobulin amyloidosis. SUMMARY: Beta 2-microglobulin amyloidosis arthropathies may result from progressive accumulation of advanced glycation end products in long-lived amyloid linked to a heightened cellular response. Antagonism of the interaction between advanced glycation end products and their receptor may be a relevant strategy for cellular inflammation in beta2-microglobulin amyloidosis.

Amyloidosis↗

PubMed1985

Kinetics of inflammatory and fibrotic pulmonary changes in a murine model of silicosis.

A murine model of experimental silicosis has been developed after the intratracheal injection of alpha-quartz crystals. Pulmonary inflammation was monitored by increases in wet lung weight and cell number and protein content of the lung lavage fluid; fibrosis was assessed by measuring increases in hydroxyproline content of the lungs. Acute pulmonary cellular inflammation occurred between weeks 1 and 2, followed by a chronic inflammatory response at week 12. Lung hydroxyproline content, an indication of collagen deposition, was initiated as early as 1 week after silica injection and continued to increase steadily over time. The inflammatory and fibrotic changes induced by silica appeared to be a specific effect of the injection of this toxic particulate and not the result of the introduction of a foreign body, because mice injected with silica crystals were found to have significantly greater increases in acute cellular inflammation and chronic collagen deposition than did mice injected with latex beads. A possible role for the immune system in modulating silica-induced damage was suggested by the variability in response of six different strains of mice (C3H/He, CBA/J, Balb/c, DBA/2, C57BL/6, C57BL/10), which differed at specific genetic loci. Both strains with high (DBA/2) and low (C3H/He) response demonstrated similar patterns of inflammation and fibrosis over a period of 12 weeks. This model demonstrates great potential in future studies for elucidating the role of the immune system in the development of pulmonary inflammation and fibrosis induced by toxic inorganic particulates.

Animals↗

PubMed2001

Heme protein-induced chronic renal inflammation: suppressive effect of induced heme oxygenase-1.

BACKGROUND: Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme; its inducible isozyme, HO-1, protects against acute heme protein-induced nephrotoxicity and other forms of acute tissue injury. This study examines the induction of HO-1 in the kidney chronically inflamed by heme proteins and the functional significance of such an induction of HO-1. METHODS: Studies were undertaken in a patient with chronic tubulointerstitial disease in the setting of paroxysmal nocturnal hemoglobinuria (PNH), in a rat model of chronic tubulointerstitial nephropathy caused by repetitive exposure to heme proteins, and in genetically engineered mice deficient in HO-1 (HO-1 -/-) in which hemoglobin was repetitively administered. RESULTS: The kidney in PNH evinces robust induction of HO-1 in renal tubules in the setting of chronic inflammation. The heme protein-enriched urine from this patient, but not urine from a healthy control subject, induced expression of HO-1 in renal tubular epithelial cells (LLC-PK1 cells). A similar induction of HO-1 and related findings are recapitulated in a rat model of chronic inflammation induced by repetitive exposure to heme proteins. Additionally, in the rat, the administration of heme proteins induces monocyte chemoattractant protein (MCP-1). The functional significance of HO-1 so induced was uncovered in the HO-1 knockout mouse: Repeated administration of hemoglobin to HO-1 +/+ and HO-1 -/- mice led to intense interstitial cellular inflammation in HO-1 -/- mice accompanied by striking up-regulation of MCP-1 and activation of one of its stimulators, nuclear factor-kappaB (NF-kappaB). These findings were not observed in similarly treated HO-1 +/+ mice or in vehicle-treated HO-1 -/- and HO-1 +/+ mice. CONCLUSION: We conclude that up-regulation of HO-1 occurs in the kidney in humans and rats repetitively exposed to heme proteins. Such up-regulation represents an anti-inflammatory response since the genetic deficiency of HO-1 markedly increases activation of NF-kappaB, MCP-1 expression, and tubulointerstitial cellular inflammation.

Adult↗

PubMed2003

Comparison of allergen-induced late inflammatory reactions in the nose and in the skin in house dust mite-allergic patients with or without asthma.

BACKGROUND: It remains to be established which factors contribute to the occurrence of asthma in allergic individuals. We hypothesized that differences in the late allergic inflammatory reaction to allergen between asthmatic and non-asthmatic house dust mite-allergic individuals might contribute to the difference in the clinical presentation of allergy. AIM: To compare allergen-induced changes in parameters for cellular inflammation during the phase of the late allergic reaction in the skin and nose, in house dust mite-allergic individuals with or without asthma. MATERIAL AND METHODS: Nasal and dermal allergen challenges with house dust mite (Dermatophagoides pteronyssinus) extract were performed in 52 house dust mite-allergic individuals, of whom 26 had mild to moderate persistent asthma and 26 had perennial rhinitis without current or past asthmatic symptoms. Serial nasal lavage samples were analyzed for the presence of inflammatory cells (eosinophils and neutrophils) and soluble markers associated with cellular inflammation [interleukin-5 (IL-5), interleukin-8 (IL-8), eosinophil cationic protein (ECP) and myeloperoxidase (MPO)]. Macroscopic late phase skin reactions were studied after intracutaneous skin tests with house dust mite extract. RESULTS: Fixed dose nasal allergen provocation elicited a similar degree of immediate allergic reaction as judged by plasma protein exudation and histamine concentrations in asthma and non-asthmatic rhinitis. Subsequently, no differences between groups were found during the phase of the late allergic reaction (4-24 h) in inflammatory cell influx, plasma protein leakage, ECP or MPO. Likewise, there were no differences in levels of chemotactic cytokines IL-5 and IL-8. In agreement with the results of nasal challenge, the late skin reaction after dermal challenge with a fixed allergen dose and after an allergen dose 10,000 times above the skin threshold for an early skin reaction did not differ between the groups. CONCLUSION: House dust mite-allergic patients with or without asthma have very similar late allergic inflammatory reactions in the skin and in the nose after allergen challenge. Hence, it is unlikely that the occurrence of pulmonary symptoms in asthma is explained by a general tendency of asthmatics to have an enhanced late allergic cellular inflammatory response. Nasal and dermal allergen provocations are adequate models to study allergen-induced inflammation but probably lack the pivotal link which is essential for the development of asthma.

Adolescent↗

PubMed1992

Relationship among mediators, inflammation, and volume history with antigen versus hyperpnea challenge in guinea pigs.

Paralyzed mechanically ventilated guinea pigs constricted to a similar degree by either isocapnic hyperpnea or antigen challenge display significantly different lung resistance (RL) volume history responses to a deep breath. We compared bronchoalveolar lavage (BAL) mediator profiles, BAL total protein concentrations, and tissue histopathology of antigen-constricted (AC), hyperpnea-constricted (HC), and control guinea pigs to determine whether patterns of volume history near peak constriction could be related to specific patterns of lung mediators, indices of microvascular leakage, or severity of tissue inflammation assessed pathologically. Methacholine constricted (MC) animals served as a second control group for assessing the effects of direct smooth-muscle contraction on indices of inflammation and volume history responses. Our results show that despite similar baseline and postchallenge RL, HC and MC animals displayed significant constriction reversal after a deep lung inflation, whereas AC animals did not. BAL concentrations of prostaglandin D2(PGD2), thromboxane B2 (TxB2), and leukotriene C4/D4/E4 (slow reacting substance of anaphylaxis, SRSA) were significantly elevated in both AC and HC animals compared with control and MC animals, with AC and HC BAL differing only with respect to PGD2 values (AC 2.4-fold higher). BAL total protein in AC animals was significantly greater than in HC, MC, and control animals. Histopathology showed significant peribronchial and interstitial cellular inflammation in AC animal specimens, whereas specimens from HC animals had little or no inflammation. Differences in volume history responses observed between equally constricted AC, HC, and MC animals may be due to differences in airway and/or parenchymal microvascular leak and cellular inflammation.

Airway Obstruction↗

PubMed2000

Placebo-controlled study of inhaled budesonide on indices of airway inflammation in bronchoalveolar lavage fluid and bronchial biopsies in cross-country skiers.

BACKGROUND: Asthma-like symptoms, methacholine hyperresponsiveness, use of inhaled steroids, airway inflammation, and increased tenascin expression in the reticular basement membrane have been reported in competitive cross-country skiers. OBJECTIVE: To investigate the effect of inhaled budesonide, 400 mug twice daily, on indices of airway inflammation in 'ski asthma', defined as asthma-like symptoms within the previous year and bronchial hyperresponsiveness to methacholine. METHODS: A randomised double-blind placebo-controlled parallel-group bronchial biopsy and bronchoalveolar lavage (BAL) study of 25 (19 male) competitive cross-country skiers (mean age 18 (16-20) years for a mean (range) treatment period of 22 (10-32) weeks over the competitive season. RESULTS: No changes were seen regarding cellular inflammation in the bronchial mucosa or tenascin expression. In the BAL fluid, both groups had a significant decrease in activated T-suppressor (CD8) lymphocytes and an increase in macrophages, with no differences across the groups. Within the budesonide group, there was a decrease in IL2 receptor-activated T-helper lymphocytes and an improvement in FEV(1). Asthma-like symptoms were unchanged in 17 (68%) skiers. Methacholine provocation test was negative in 15 subjects, and remained positive in 5 subjects in each group. The improvement in bronchial responsiveness occurred in both groups and was not accompanied by a decrease in cellular inflammation. CONCLUSIONS: We were unable to show any clear beneficial effect of budesonide in 'ski asthma'. As changes in training intensity probably accounted for the spontaneous improvement in bronchial responsiveness, more attention should be directed at reducing environmental stress to the airways than at attempting pharmacological modulation of induced inflammatory changes.

Administration, Inhalation↗

PubMed2006

Protective role of selectin ligand inhibition in a large animal model of kidney ischemia-reperfusion injury.

Experiments in rodents have demonstrated an important role for selectins in kidney ischemia-reperfusion injury (IRI). However, the relevance of this in larger mammals, as well as the impact on long-term structure and function is unknown. We tested the hypothesis that small molecule selectin ligand inhibition attenuates IRI, cellular inflammation, and long-term effects on renal interstitial fibrosis. We used a porcine model of kidney IRI and used Texas Biotechnology Corporation (TBC)-1269, a selectin ligand inhibitor. Renal function, tissue inflammation, and tubulointerstitial fibrosis development were evaluated up to 16 weeks. Both warm and cold ischemia models were studied for relevance to native and transplant kidney injury. Pigs treated with TBC-1269 during 45 min of warm ischemia (WI) showed significantly increased glomerular filtration rate compared to control animals. In pigs with severe IRI (WI for 60 min), TBC-1269 treatment during IRI significantly increased renal recovery. Cellular inflammation was strongly reduced, particularly influx of CD4 cells. Quantitative measurement of fibrosis by picrosirius red staining showed strong reduction in TBC-1269-treated groups. TBC-1269 also reduced cold IRI, inflammation, and fibrosis in kidneys preserved for 24 h at 4 degrees C and autotransplanted. The selectin ligand inhibitor TBC-1269 provides a novel and effective approach to attenuate IRI in both warm and cold ischemia in large mammals, in both short and long terms. Selectin ligand inhibition is an attractive strategy for evaluation in human kidney IRI.

Animals↗

PubMed2005

Mast cell involvement in the adenosine mediated airway hyper-reactivity in a murine model of ovalbumin-induced lung inflammation.

Airway hyper-reactivity to inhaled adenosine, mediated via mast cell activation, is a cardinal feature of asthma. Animal models have been developed in several species to mimic this phenomenon, but only in the rat has a mast cell involvement been clearly defined. In this study, a model of ovalbumin-induced adenosine hyper-reactivity was developed in BALB/c mice to determine whether mast cells are involved in this phenomenon. Sensitised mice were challenged one, two or three times, on a daily basis, and airway responses to the stable adenosine analogue NECA (5'-N-ethylcarboxamido adenosine) determined 4 and 24 h after each challenge. Airway hyper-reactivity was observed in ovalbumin-challenged mice 4 h after a single challenge and to a minor extent 24 h after a single challenge and 4 h after two challenges. Cromolyn (20 mg ml(-1)), given by aerosol an hour before the NECA provocation, fully inhibited the airway hyper-reactivity observed 4 h after a single allergen challenge, suggesting a role for mast cells in this response. The airway space cellular inflammation was not affected by cromolyn. As observed in human asthma, an acute treatment with steroid (budesonide 3 mg kg(-1), given an hour before the allergen challenge) inhibited the NECA airway hyper-reactivity and significantly inhibited the airway space cellular inflammation. These data suggest that the ovalbumin-challenged BALB/c mice can be considered as a suitable model to study the adenosine-induced airway hyper-reactivity phenomenon observed in human asthma.

Adenosine-5'-(N-ethylcarboxamide)↗

PubMed2006

Decreased bacterial clearance from the lungs of mice following primary respiratory syncytial virus infection.

Virus respiratory infections often precede bacterial pneumonia in healthy individuals. In order to determine the potential role of respiratory syncytial virus (RSV) in bacterial secondary infections, a mouse sequential pulmonary infection model was developed. Mice were exposed to RSV then challenged with Streptococcus pneumoniae (StPn). Exposure of BALB/c mice to 10(6)-10(7) plaque forming units (pfu) of virus of RSV significantly decreased StPn clearance 1-7 days following RSV exposure. This finding was not restricted to StPn alone: exposure to RSV followed by Staphylococcus aureus (SA) or Pseudomonas aeruginosa(PA) resulted in similar decreases in bacterial clearance. Both bronchoalveolar lavage (BAL) cell counts and pulmonary histopathology demonstrated that RSV-StPn exposed mice had increased lung cellular inflammation compared to mice receiving StPn or RSV alone. The effect of RSV infection on bacterial clearance was dependent on the mouse genetic background: C57BL/6J mice (relatively resistant to RSV infection) demonstrated a modest change in StPn clearance following RSV exposure, whereas FVBN/J mice (similar to the BALB/cJ mice in RSV susceptibility) demonstrated a similar degree of RSV-associated decrease in StPn clearance 7 days following RSV exposure. Neutrophils from the RSV-StPn sequentially exposed BALB/cJ mice were functionally altered-produced greater levels of peroxide production but less myeloperoxidase (MPO) compared to mice receiving StPn alone. These data demonstrate that RSV infection decreases bacterial clearance, potentially predisposing to secondary bacterial pneumonia despite increased lung cellular inflammation, and suggest that functional changes occur in the recruited neutrophils that may contribute to the decreased bacterial clearance.

Animals↗

PubMed2004

AKT1 drives endothelial cell membrane asymmetry and microglial activation through Bcl-xL and caspase 1, 3, and 9.

Protein kinase B (Akt1) holds a central role for cellular growth, development, and survival, but the cellular pathways of Akt1 that prevent inflammatory demise in the vascular system remain undefined. Employing a constitutively active form of Akt1 (myristoylated Akt1) in endothelial cells (ECs), we demonstrate that Akt1 not only modulates intrinsic pathways of EC injury that involve genomic DNA destruction, but also uniquely regulates extrinsic mechanisms of cellular inflammation mediated by phosphatidylserine exposure (PS) and microglial activation. Activation of Akt1 is necessary and sufficient to prevent apoptotic EC destruction, since inhibition of the phosphatidylinositide-3-kinase pathway as well as transfection of ECs with a dominant-negative Akt1 mutant abrogates vascular protection. Furthermore, we illustrate that control of microglial activation by Akt1 is directly dependent on the modulation of EC membrane PS exposure. Akt1 provides a novel capacity to foster EC survival through the prevention of cysteine protease degradation of Bcl-x(L) that is intimately linked to the specific inhibition of caspase 1-, 3-, and 9-like activities and the modulation of mitochondrial membrane potential and cytochrome c release. Our work elucidates the critical role of Akt1 during cellular inflammation and identifies new downstream targets of Akt1 that may offer therapeutic potential against vascular disease.

Animals↗

PubMed1995

PET of peripheral benzodiazepine binding sites in the microgliosis of Alzheimer's disease.

UNLABELLED: Animal and human autoradiographic studies have shown increased in vitro binding of the peripheral benzodiazepine binding site antagonist PK 11195 in areas of microgliosis, including the temporal association cortex of patients with Alzheimer's disease. To further elucidate the role of cellular inflammation and microgliosis in Alzheimer's disease during life, we used PET and [11C]PK 11195, a peripheral benzodiazepine receptor ligand known to bind avidly to microglia. METHODS: Eight patients with a diagnosis of probable Alzheimer's disease underwent PET of the brain using [11C]PK 11195 and, for comparison, with [18F]FDG to determine cerebral glucose metabolism. Uptake of [11C]PK 11195 in various brain regions was expressed relative to that in the cerebellum and compared to values determined in one normal elderly subject and in clinically and anatomically unaffected hemispheres of seven patients with small unilateral gliomas. RESULTS: No increases in peripheral benzodiazepine binding were identified in patients with probable Alzheimer's disease, and binding was lowest in regions that were most hypometabolic. CONCLUSION: The peripheral benzodiazepine binding sites associated with microgliosis and cellular inflammation in Alzheimer's disease at postmortem are undetectable by PET using [11C]PK 11195 in patients with mild-to-moderate dementia.

Aged↗

PubMed1993

Effects of prostaglandins and indomethacin on the cellular inflammatory response following surgical trauma in fetal rabbits.

This study has examined the effects of prostaglandins E2 and F2a (PGE2 and PGF2a) and indomethacin on cellular inflammation in fetal rabbits. Fetuses heal differently from adults: incisions heal with no scar or inflammation; excisional wounds exposed to amniotic fluid (AF) do not heal or become inflamed, and have high tissue levels of PGE2 and PGF2a; excisional wounds protected from AF do heal and become inflamed, and have low tissue PG levels. The authors inserted slow-release pellets [control, PGE2 (10 micrograms), PGF2a (10 micrograms), indomethacin (10 micrograms)] into subcutaneous pockets in fetal rabbits on day 25 of gestation (one per fetus). Pellets were also placed in subcutaneous pockets in the does. Fetuses and doe tissues were recovered 72 h after surgery. Control pellets in fetuses had a slight inflammatory response, with some cells present. Fetal PGE2 pellets had a layer 5-10 cells thick surrounding the pellet, and fetal PGF2a pellets had a 10-15-cell layer. Fetal indomethacin pellets had no response, with no inflammatory cells present. All pellets placed in does elicited a slight cellular inflammatory response, equal to that seen with control pellet in fetuses. These results show that PGE2 and PGF2a are potent in-vivo promoters of cellular inflammation in fetal rabbits, but not in adult rabbits. Indomethacin suppresses the foreign-body response in fetal rabbits, but not in adult rabbits.

Animals↗

PubMed1984

Role of oxygen radicals in ocular inflammation and cellular damage.

Oxyradicals probably play a major role in a number of specific pathological conditions of intraocular tissues, such as cataract formation and retinal degeneration. This paper reviews some of the mechanistic concepts relating to tissue damage by highly reactive oxidants derived from endogenous precursors, hydrogen peroxide and superoxide. Experimental generation of superoxide in the anterior chamber of the rabbit eye showed leucocyte infiltration to be the principal acute response occurring in 4 hr. This finding suggests that superoxide may play a significant role in the ocular inflammatory response, possibly by reacting with a precursor substance in the aqueous humor to produce a chemotactic factor as has been previously found for blood plasma.

Animals↗

PubMed2006

Inflammation and cellular immune responses in abdominal aortic aneurysms.

Expansion and rupture of abdominal aortic aneurysms (AAA) result in high morbidity and mortality rates. Like stenotic atherosclerotic lesions, AAA accumulate inflammatory cells, but usually exhibit much more extensive medial damage. Leukocyte recruitment and expression of pro-inflammatory Th1 cytokines typically characterize early atherogenesis of any kind, and modulation of inflammatory mediators mutes atheroma formation in mice. However, the mechanistic differences between stenotic and aneurysmal manifestations of atherosclerosis remain unexplained. We recently showed that aortic allografts deficient in interferon-gamma (IFN-gamma) signaling developed AAA correlating with skewed Th2 cytokine environments, suggesting important regulatory roles for Th1/Th2 cytokine balance in modulating matrix remodeling and important implications for the pathophysiology of aortic aneurysm and atherosclerosis. Further probing of their distinct aspects of immune and inflammatory responses in vascular diseases should continue to shed new light on the pathophysiologic mechanisms that give rise to aneurysmal versus occlusive manifestations and atherosclerosis.

Animals↗