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PubMed1993

Inflammation-induced cartilage degradation in female rodents. Protective role of sex hormones.

OBJECTIVE: To investigate the effects of physiologic levels of sex steroids on inflammation and cytokine production and their consequential cartilage degradation. METHODS: We used an in vivo model of inflammation-induced cartilage degradation in female mice to study the effects of ovariectomy and hormone treatment, and in vitro culture systems to examine the influence of sex steroids on cartilage metabolism, interleukin-1 (IL-1) production by granulomatous tissue, and its effects on female mouse articular cartilage. RESULTS: Ovariectomy resulted in accelerated cartilage breakdown associated with increased production of IL-1 by granulomatous tissue. The effects of ovariectomy on cartilage were reversed by treatment with estradiol and androgen, but not by progesterone treatment. Estradiol and progesterone reduced both spontaneous and IL-1-induced cartilage degradation in vitro. Testosterone antagonized the effects of IL-1 on both proteoglycan loss and proteoglycan synthesis. CONCLUSION: These data suggest that sex steroids have an important influence on inflammation-induced cartilage breakdown in female animals, with protective effects of both estradiol and androgens. Multiple mechanisms may be involved, and they are likely to include direct immunomodulatory effects as well as interactions with the effects of cytokine and of the glucocorticoid response to inflammation.

Animals↗
PubMed2004

Lack of requirement of osteopontin for inflammation, bone erosion, and cartilage damage in the K/BxN model of autoantibody-mediated arthritis.

OBJECTIVE: Osteopontin (OPN) is a secreted glycoprotein involved in a range of physiologic processes, including inflammation, immunity mediated by Th1 cells, and bone remodeling. It is expressed in the joints of rheumatoid arthritis patients and has been the subject of conflicting reports concerning its role in arthritis induced by antibodies against type II collagen. This study assessed the role of OPN in the K/BxN serum-transfer model of autoantibody-induced arthritis. METHODS: Expression of OPN gene transcripts was assessed by microarray analysis of ankle RNA taken at 6 time points after transfer of K/BxN serum. OPN-sufficient or OPN-deficient littermates backcrossed for 10 generations onto the C57BL/6 genetic background were given K/BxN serum. Arthritis severity was measured by ankle thickening and a clinical index. Hind limb sections were stained with hematoxylin and eosin or toluidine blue and scored for inflammation, cartilage damage, and bone erosion. RESULTS: OPN messenger RNA transcripts progressively increased in ankle joints during the course of K/BxN serum-transferred arthritis. OPN-deficient mice receiving K/BxN serum developed arthritis with kinetics and clinical severity comparable with those of OPN-sufficient littermates. Histologic assessment of arthritic joints from OPN-deficient mice revealed synovial hyperplasia, pannus formation, mononuclear cell infiltration, bone erosion, cartilage damage at sites adjacent to and distal from pannus invasion, and tartrate-resistant acid phosphatase-positive multinucleated cells at sites of bone erosion. Histopathologic scoring demonstrated comparable levels of inflammation, cartilage damage, and bone erosion in OPN-sufficient and OPN-deficient mice. CONCLUSION: OPN does not have a required role in inflammation, bone erosion, and cartilage damage in the K/BxN serum-transfer model.

Animals↗
PubMed2006

Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury.

Susceptibility to neuroinflammatory disease is influenced in part by genetics. Recent data indicate that survival of traumatized neurons is strain dependent and influenced by polygenic loci that control resistance/susceptibility to experimental autoimmune encephalomyelitis (EAE), a model of CNS autoimmune disease. Here, we describe patterns of neurodegeneration and intraparenchymal inflammation after traumatic spinal cord injury (SCI) in mice known to exhibit varying degrees of EAE susceptibility [EAE-resistant (r) or EAE-susceptible (s) mice]. Spinal cords from C57BL/6 (EAE-s), C57BL/10 (EAE-r), BALB/c (EAE-r), and B10.PL (EAE-s) mice were prepared for stereological and immunohistochemical analysis at 6 hours or 3, 7, 14, 28, or 42 days following midthoracic (T9) spinal contusion injury. In general, genetic predisposition to EAE predicted the magnitude of intraparenchymal inflammation but not lesion size/length or locomotor recovery. Specifically, microglia/macrophage activation, recruitment of neutrophils and lymphocytes, and de novo synthesis of MHC class II were greatest in C57BL/6 mice and least in BALB/c mice at all times examined. However, lesion volume and axial spread of neurodegeneration were similar in C57BL/6 and BALB/c mice and were significantly greater than in C57BL/10 or B10.PL mice. Strains with marked intraspinal inflammation also developed the most intense lesion fibrosis. Thus, strain-dependent neuroinflammation was observed after SCI, but without a consistent relationship to EAE susceptibility or lesion progression. Only in C57BL/6 mice was the magnitude of intraspinal inflammation predictive of secondary neurodegeneration, functional recovery, or fibrosis.

Analysis of Variance↗
PubMed1994

Adjuvant-induced inflammation of rat paw is associated with altered calcitonin gene-related peptide immunoreactivity within cell bodies and peripheral endings of primary afferent neurons.

Local inflammation is associated with profound changes in the biochemistry and physiology of primary afferent nerve fibers and the central neurons responding to their signals. In some tissues, the neural changes accompanying inflammation include sprouting and cytochemical changes that are delayed several days after the initial injury. In the present study, we have analyzed the effect of complete Freund's adjuvant (CFA)-induced inflammation in the rat paw on calcitonin gene-related peptide (CGRP) immunoreactivity (IR) in dorsal root ganglia and within tissue of the inflamed paw. We quantified the CGRP-IR within the L1, L4, and L6 ganglia, and in ankle, midpaw, joint and toe tissues. Analysis of the processed tissue revealed a significant increase in the percentage of CGRP-positive cells within L4 dorsal root ganglia ipsilateral to an inflamed hindpaw six days after administration of CFA. There was a parallel increase in the number and staining density of detectable CGRP-immunoreactive fibers in periarticular and perivascular tissues of the inflamed digits and inflamed ankle. The other tissues of the paw, including epidermis and the regions surrounding the abcesses, did not have detectable changes in CGRP-immunoreactive fibers, despite tissue swelling and dystrophic changes in the foot that included loss of mast cell staining. These data demonstrate that local inflammation of the rat paw has delayed influences on the peripheral nervous system, in addition to a number of previously characterized acute effects. The alterations of CGRP-IR were focused around specific tissue types, such as joints and subdermal blood vessels, and absent from others, such as epidermis or in the areas surrounding abscesses. This suggests production of local factors within reactive tissues that selectively interact with nerve fibers to induce changes in CGRP-IR within the fibers.

Animals↗
PubMedDate not supplied

Inflammation and the etiology of type 2 diabetes.

Type 2 diabetes is increasingly common worldwide and is beginning to strike younger age groups. Almost 90% of all patients with diabetes show insulin resistance, which also precedes the first symptoms of diabetes. The mechanisms underlying the development of insulin resistance are not well understood. In recent years, several studies have been published that implicate subclinical chronic inflammation as an important pathogenetic factor in the development of insulin resistance and type 2 diabetes. This opens new perspectives for diagnosis and treatment of early insulin resistance and incipient glucose intolerance. Surrogate markers for this low-grade chronic inflammation include CRP, IL-6 and TNF-alpha. Some antidiabetic agents, for example, glitazones that reduce insulin resistance, and insulin itself, reduce inflammation. Conversely, antiinflammatory drugs (ASA/NSAID) may improve glucose tolerance. Vasoactive drugs that are often prescribed to people with diabetes, for example, statins and ACE inhibitors/angiotensin receptor antagonists, also counteract inflammation and reduce the risk of type 2 diabetes. More specific and sensitive biomarkers should be identified, which may predict early disturbances in insulin sensitivity and cardiovascular risk. Also, inflammatory signalling pathways need to be explored in greater detail, and may form the basis of drugable targets against the epidemic of insulin resistance and atherosclerosis.

Cardiovascular Diseases↗
PubMed1997

Tumor necrosis factor (TNF) receptor type 1 (p55) is a main mediator for TNF-alpha-induced skin inflammation.

Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic proinflammatory cytokine that elicits a large number of biological effects, including inflammatory and immunoregulatory responses. Biological activities of TNF-alpha are mediated by two distinct TNF receptors, p55 type 1 receptor (TNFR1) and p75 type 2 receptor (TNFR2). To determine the role of TNF-alpha in the induction of inflammatory responses in the skin, gene-targeted mutant mice lacking either TNFR1 or TNFR2 were painted with irritant chemicals. Both phenol and croton oil painting onto the ears induced less inflammation in TNFR1(-) mice than normal and TNFR2(-) mice. Intradermal injection of TNF-alpha (0.2-200 ng for 3 days) into the ear induced less inflammation in TNFR1(-) mice than in normal mice. TNFR2(-) mice developed a normal inflammatory reaction to high doses of TNF-alpha (20-200 ng for 3 days), while they showed minimal reactivity to low doses of TNF-alpha (0.2-2 ng for 3 days). TNF-alpha is known to trigger the release of a series of other cytokines and to induce the expression of cell adhesion molecules, thus contributing to the development of inflammation. The levels of protein and mRNA for interleukin (IL)-6 were elevated in keratinocytes from normal as well as TNFR2(-) mice after treatment with TNF-alpha, while keratinocytes from TNFR1(-) mice did not show any up-regulation of IL-6. TNF-alpha induced intercellular adhesion molecule (ICAM)-1 expression in the keratinocytes from normal and TNFR2(-) mice, but not in those from TNFR1(-) mice. These results indicate that TNFR1 is critical for induction of skin inflammation by TNF-alpha.

Administration, Topical↗
PubMed2006

A common pathway in differentiation and inflammation: p38 mediates expression of the acute phase SIP24 iron binding lipocalin in chondrocytes.

SIP24 is an acute phase iron binding lipocalin physiologically expressed in vivo in developing cartilage by prehypertrophic/hypertrophic chondrocytes. Taking advantage of the chondrocytic cell line MC615 and using SIP24 as a marker we investigated the pathways active in cartilage differentiation and inflammation. MC615 cells were cultured as: (i) proliferating prechondrogenic cells expressing type I collagen (ii) differentiated hyperconfluent cells expressing Sox9 and type II collagen. In proliferating cells the pathway PKC/ERK1, ERK2 was activated and SIP24 was not expressed while in differentiated cells the pathway p38/NF-kappaB was activated and SIP24 was expressed. Proliferating cells treated with inflammatory agents expressed a large amount of SIP24 and showed activation of p38/NF-kappaB pathway and inhibition of PKC/ERK1, ERK2 pathway indicating that in inflammation and differentiation the same factors are activated (p38, NF-kappaB) or inactivated (PKC, ERKs). Treatment of proliferating cells with the p38 specific inhibitor SB203580 inhibited the inflammation induced activation of p38 and the synthesis of SIP24. PMA treatment induced activation of PKC, inactivation of p38 and suppression of SIP24 synthesis, suggesting that PKC activation inhibits p38 activation. In differentiated hyperconfluent cells the same factors (p38/NF-kappaB/SIP24) are constitutively activated: treatment with inflammatory agents does not increase synthesis of SIP24 while treatment with SB203580 and with PMA does not repress activation of p38 nor synthesis of SIP24. We propose that the SIP24 stress related protein is expressed via p38 activation/NF-kappaB recruitment both in chondrocyte differentiation and inflammation and that a signaling pathway active in the acute phase response is physiologically activated in differentiation.

Acute-Phase Proteins↗
PubMed2001

Arterial wall MRI characteristics are associated with elevated serum markers of inflammation in humans.

Inflammation contributes to atherosclerosis, but assessment in humans is largely restricted to measurement of markers in blood. We determined whether MRI properties of large arteries were associated with markers of inflammation in serum. Double inversion recovery, fast spin-echo images of the common carotid arteries and infrarenal aorta were obtained at 1.5 T both before and after gadolinium-DTPA (0.1 mmol/kg) in 52 subjects > or =40 years of age, 17 of whom had no risk factors for atherosclerosis and thus served as controls. Twenty-two study participants had increases in wall thickness (14), T2-weighted signal intensity (11), and/or contrast enhancement values (7) that were >2 standard deviations (SDs) from control group mean values. Ten subjects in this group had evidence of focal plaques in the carotids (5) and/or aorta (6). Compared with the remaining 30 subjects, these 22 had significantly higher levels of interleukin-6 (3.53 +/- 2.46 vs. 1.97 +/- 1.37 pg/mL, P = 0.004), C-reactive protein (0.56 +/- 0.98 vs. 0.30 +/- 0.52 mg/dL, P = 0.019), vascular cell adhesion molecule-1 (572 +/- 153 vs. 471 +/- 130 ng/mL, P = 0.012), and intercellular adhesion molecule-1 (244 +/- 80 vs. 202 +/- 45 ng/mL, P = 0.015), and nonsignificant differences in levels of E-selectin (46.1 +/- 18.9 vs. 42.3 +/- 11.3 ng/mL, P = 0.369). Thus, MRI characteristics of the aorta and carotid arteries were associated with elevated serum markers of inflammation, frequently in the absence of definite atheroma. MRI of large arteries may provide a new approach to investigate the contribution of inflammation to atherogenesis.

Adult↗
PubMed2002

Effects of intrauterine inflammation on developing rat brain.

Damage to the white matter in the brain during development can lead to cerebral palsy (CP), a heterogeneous group of clinical syndromes that results in life-long disorders of movement and posture. Periventricular leukomalacia (PVL) is a pathological process within the white matter characterized by oligodendrocyte loss and is associated with the development of CP. Clinically, CP and PVL are associated with intrauterine infection and inflammation, but mechanisms involved are not well understood. We developed a model of intrauterine inflammation in Lewis and Fischer 344 rats to study the effects of intrauterine inflammation on developing glia. Pregnant rats were intracervically injected with lipopolysaccharide (LPS) at 15 days of gestation (E15) and a dose of LPS that caused low fetal mortality was determined. At E20, treated fetuses had increased TUNEL(+) nuclei and tumor necrosis factor (TNF)-alpha-immunoreactive areas within the brains. In a second series of animals allowed to survive until postnatal day 21 (PND 21), immunostaining was performed against several glial markers. Staining for the oligodendrocyte-specific proteins 2', 3'-cyclic nucleotide phosphodiesterase (CNP) and myelin proteolipid protein (PLP) was decreased in treated pups compared to shams within the corpus callosum, a white matter structure used as a representative area of developing white matter. Treated pups had activated astrocytes lining cerebral blood vessels, as observed by glial fibrillary acidic protein (GFAP) staining, while sham pups did not. Activated microglia were not detected using OX42 as a cell marker. Our model of intrauterine inflammation causes increased TUNEL and TNF-alpha staining early after injury, suggesting increased apoptotic cell death, possibly by cytokine-related mechanisms.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2007

Novel cyclooxygenase-catalyzed bioactive prostaglandin F2alpha from physiology to new principles in inflammation.

Prostaglandin F2alpha (PGF2alpha), a foremost stable vasoactive cyclooxygenase (COX)-catalyzed prostaglandin, regulates a number of key physiological functions such as luteolysis, ovarian function, luteal maintenance of pregnancy, and parturition as a constitutive part of ongoing reproductive processes of the body. It has recently been implicated in the regulation of intricate pathophysiological processes, such as acute and chronic inflammation, cardiovascular and rheumatic diseases. Since the discovery of a second isoform of COXs, it has been shown that PGF2alpha can be formed in vivo from arachidonic acid through both isoforms of COXs, namely cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Being synthesized in various parts of the body, it metabolizes instantly to a number of rather inactive metabolites mainly in the lungs, liver, kidney, and efficiently excretes into the urine. 15-Keto-dihydro-PGF2alpha, a major stable metabolite of PGF2alpha that reflects in vivo PGF2alpha biosynthesis, is found in larger quantities than its parent compound in the circulation and urine in basal physiological conditions, with short-lived pulses during luteolysis, induced termination of pregnancy and parturition, and is increased in tissues and various body fluids during acute, sub-chronic, and severe chronic inflammation. Further, the close relationship of PGF2alpha with a number of risk factors for atherosclerosis indicates its major role in inflammation pathology. This review addresses multiple aspects of PGF2alpha in addition to its emerging role in physiology to inflammation.

Animals↗
PubMed1981

Excess plasma proteins as a cause of chronic inflammation and lymphoedema: biochemical estimations.

The subcutaneous tissue of rats was injected with plasma, PVP or saline. Precautions were taken to avoid immunological reactions and the release of mediators. The repeated injection of plasma proteins caused changes typical of chronic inflammation in the skin and to a much greater extent in the fascia. Coumarin significantly reduced the extent of this inflammatory reaction in the skin but not in the fascia. It increased the numbers of cells in the skin and may have stimulated them to lyse the excess protein. After 32 days, PVP injection caused some of the changes seen in chronic inflammation, but to a much lesser extent than those found with plasma. The only effect of coumarin was to reduce the water content of the skin (and hence the skin weight). It is concluded that the accumulation of excess proteins in the tissues can indeed cause chronic inflammation. In particular, chronic lymphoedema can be regarded as a form of chronic inflammation. It is also concluded that in the presence of excess protein, the benzopyrone, coumarin, is capable of stimulating cells, other than macrophages, in the skin.

Animals↗
PubMed1995

Update in allergy testing in childhood asthma: how do you know whether you are successfully controlling the patient's inflammation?

The levels of serum eosinophil cationic protein (ECP) in asthmatic patients have been shown to be increased in acute and undertreated asthma as a result of inflammation. ECP is released during in vitro clotting of peripheral blood. The exposure of the atopic individual to an offending allergen stimulates the activation of the blood eosinophils and their release of ECP into serum. Serum ECP levels reflect avoidance of the allergen, and successful treatment of asthma inflammation with corticosteroids cause a reduction of the inflammation in the lung. When individual patients with asthma are followed, the level of serum ECP can be used (1) as an early indicator of the degree of inflammation, (2) for monitoring the efficacy of corticosteroid therapy, and (3) for possible noncompliance with treatment.

Anti-Inflammatory Agents↗
PubMed2006

Airway inflammation in asymptomatic children with episodic wheeze.

Airway pathologies have been comprehensively researched in adult asthma, but in children, the extent of airway inflammation associated with episodic wheeze, often diagnosed as asthma, has not been fully characterized. It is not clear whether persistent airway inflammation is present in the absence of wheezing symptoms, and there is controversy regarding the role of age and atopy. This study assessed cellular and cytokine markers of airway inflammation in asymptomatic children with a history of episodic wheeze. Children with a history of episodic wheeze and cough (study group) and nonasthmatic patients requiring elective surgery (control group) were recruited. All subjects in the study group had a history of significant episodic wheezing (>2 episodes per year), and used only as-needed beta-agonist treatment. Bronchoalveolar lavage (BAL) was obtained using bronchoscopic lavage (study group) and nonbronchoscopic lavage (control group). Differential cell counts of BAL and flow cytometry were performed to identify T-lymphocyte phenotypes, and intracellular cytokine profiles were measured after phorbol-12-myristate 13-acetate (PMA) stimulation of BAL fluid T-cells. Twenty-one children with a history of 2-12 episodes of wheeze per year and 21 nonasthmatic subjects without respiratory symptoms were recruited. Study and control subjects were matched for age (median age, 5 years) and demographic characteristics. Study subjects had higher IgE levels, but their measurements were still within normal range. No significant differences in BAL differential cell counts were noted, and in both groups, the majority of T-cells were CD3+ CD8+, with a median CD4:CD8 ratio of 0.6. There was no significant difference in T-cell expression of the activation markers HLA-DR and CD25 (IL-2 receptor), or in PMA-induced production of the intracellular cytokines IFN-gamma, IL-2, IL-4, IL-5, and IL-10. The results of this study suggest that significant T-cell-driven airway inflammation is absent in mild or nonatopic, asymptomatic children of this age group who have episodic wheeze. Our findings support asthma management guidelines that do not recommend long-term treatment of this group of patients with anti-inflammatory medications.

Asthma↗
PubMed2002

Effect of methanol extract from flower petals of Tagetes patula L. on acute and chronic inflammation model.

The methanol extract of the florets of Tagetes patula (MEFTP) inhibited acute and chronic inflammation in mice and rats. MEFTP significantly suppressed hind-paw oedema induced by gamma-carrageenin in mice. Furthermore, MEFTP not only inhibited the hind-paw oedema induced by various acute phlogogens, such as histamine, serotonin, bradykinin and prostaglandin E1, but also suppressed the increase of vascular permeability by acetic acid, indicating that it primarily acts at the exudative stage of inflammation. In the chronic inflammation, MEFTP did not inhibit the proliferation of granulation tissue when tested by the cotton pellet method, however, it was effective on the development of adjuvant arthritis in rats. Oral MEFTP inhibited acute and chronic inflammation in mice and rats.

Acetic Acid↗
PubMed1996

Regulation of signal transducer, GP13O and the LIF receptor in acute inflammation in vivo.

Recently we examined the expression of the IL-6 receptor (gp80) in three different models of acute inflammation [Geisterfer et al., 1993, Cytokine 5:1]. To continue these studies, we examined the mRNA expression of signal transducing molecule, gp130, and the LIF-R as associated members of a receptor family. Rats were treated with either Freund's complete adjuvant (FA) via intraperitoneal injection, LPS via intravenous injection, or turpentine via subcutaneous injection. The levels of gp130 and LIF-R mRNA expression had a maximum 2-3-fold increase over a 24 h period. However, the time of the maximum increase differed depending on the treatment the rats received. FA treated rats had a maximum induction of gp130 mRNA levels of 2.2-fold (for the 7.5 kb transcript) and 1.3-fold (for the 9.0 kb transcript) at 12 h. LPS treated rats had a maximum increase at 3 h where message levels increased 2.5-fold (7.5 kb) and 1.2-fold (9.0 kb). Turpentine-injected rats showed little difference in gp130 mRNA levels at any time after injection compared to controls. Maximum LIF-R mRNA levels also differed depending on the type of treatment the rats received. FA-injected rats showed a 2.1-fold mRNA increase at 3 h, whereas LPS treated rats show a maximum 2.4-fold increase at 18 h. Turpentine-injected rats showed little increase in mRNA levels compared to controls. Injection of purified recombinant rat IL-6 (rIL-6) had little effect on LIF-R mRNA levels, but had a dramatic inducing effect on gp130 mRNA levels. Rats were also injected (i.p.) with Dexamethasone (Dex) and this had no effect on either gp130 or LIF-R mRNA level expression. These in vivo results indicated that IL-6 has a major role in the regulation of its own receptors, IL-6R (gp80), and gp130, and the onset of acute phase response. We found that the maximum IL-6R (gp80), gp130 and LIF-R mRNA levels peaked at different times depending on the type of acute inflammation induced in the rat. It seems that various combinations of cytokines and hormones are released depending on the type of acute inflammation, and these in turn regulate the expression of diverse receptors on the hepatocyte, resulting in different acute phase kinetics in the various models of inflammation.

Acute Disease↗
PubMed2001

Leukaemia inhibitory factor (LIF): a cytokine of emerging importance in chronic airway inflammation.

Inflammation is a complex set of mechanisms by which tissues respond to an injury. These responses involve the coordinated interaction between the nervous and immune systems. An integral part of this interaction is the release of a variety of cytokines that regulate cellular and molecular responses. Leukaemia Inhibitory Factor (LIF), a member of the IL-6 family of cytokines, has been shown to be an integral component of the interface between nerves and the immune system. However, little is known about this cytokine in the context of normal lung function or indeed, inflammation. Evidence is emerging that this cytokine may play an important role in regulating the neural-immune system interaction during acute inflammatory insult and the subsequent healing and restitution process. However, LIF may act as either a pro- or antiinflammatory cytokine, depending on the cell type and a number of other variables. In this review, the role of LIF in airway inflammation and resolution of inflammation is discussed. In particular, recent work suggesting that LIF is a mediator of bi-directional cross-talk between neural tissue and the immune system is highlighted.

Animals↗
PubMed1996

Epidermal cytokinetics, DNA adducts, and dermal inflammation in the mouse skin in response to repeated benzo[a]pyrene exposures.

Few studies have investigated the chronic cytokinetic effects of carcinogen exposure in the mouse skin. We report two experiments involving the repeated application of benzo[a]pyrene (BaP) to the dorsal skin of female Ha/ICR mice. In the first experiment, the cytokinetic, inflammatory, and DNA adduct responses were studied daily over a 9-day period encompassing the fourth and fifth weekly applications of BaP at doses of 16, 32, and 64 micrograms. The second experiment involved the same cytokinetic measurements at 1, 3, 5, and 8 months, and the weekly BaP doses were 4, 8, and 16 micrograms. The first study showed that after each application of 32 or 64 micrograms BaP, there was a wave of slow DNA synthesis in the epidermis which peaked at 24 hr, in coincidence with a wave of BaP-DNA adducts, followed by the appearance of dead and damaged keratinocytes. For the first few days after BaP application there was a depression in the mitotic rate which recovered several days before the next BaP application. There was a predominantly monocytic dermal inflammation throughout the observation period. In the second experiment, at the lower BaP doses, there was proliferative depression at 1 month, without dermal inflammation. With continued exposure, the proliferative depression changed to a dose-dependent increase in the rate of proliferation and dermal inflammation. The level of BaP-DNA adducts was followed in the 4 micrograms/week dose group, which showed a threefold increase after 4 months with the appearance of inflammation and heightened cell proliferation. These results suggest that the delayed inflammatory reaction, possibly based on a cell-mediated immune reaction to BaP, might have been responsible for the late cytokinetic responses and the associated increase in the level of BaP-DNA adducts.

Animals↗
PubMed1997

Inhalation of high concentrations of low toxicity dusts in rats results in impaired pulmonary clearance mechanisms and persistent inflammation.

This study was carried out to assess the time course of pulmonary clearance impairment and persistence of inflammation following high-dose inhalation exposures to titanium dioxide (TiO2) or carbonyl iron (CI) particles. Male rats were exposed to air, TiO2 or CI particles 6 hr/day, 5 days/week, for 4 weeks at concentrations of 5, 50, and 250 mg/m3 and evaluated at selected intervals through 6 months postexposure. Indices of pulmonary inflammation as well as alveolar macrophage clearance functions (i.e., morphology, in vivo and in vitro phagocytosis, and chemotaxis), cell proliferation, and histopathology endpoints were measured at several postexposure time periods through 6 months. In addition, amounts of TiO2 or CI in lungs and tracheobronchial lymph nodes were measured to allow an evaluation of particle clearance and translocation patterns. Four-week exposures to TiO2 or CI particles at concentrations of 250 mg/m3 resulted in lung burdens of 12 mg titanium and 17 mg iron, respectively, with particle retention half-times ranging from 68 days for 5 mg/m3 TiO2 to approximately 330 days for 250 mg/m3. The impact of this TiO2 dust load and similar lung burdens of CI particles produced a sustained pulmonary inflammatory response measured through a period of 3-6 months postexposure concomitant with increases in BrdU cell labeling of terminal airway and pulmonary parenchymal cells. The impairment of particle clearance mechanisms was accounted for by deficits in in vitro phagocytic and chemotactic potential of alveolar macrophages recovered from the lungs of high-dose, TiO2- or CI-exposed rats. Free granular pigment (TiO2 or CI) was present on the hypertrophic mucosal surfaces of bronchioles and bronchi, and particle-laden macrophages, found individually, were numerous throughout alveoli and within lymphoid tissues immediately after exposure. Aggregates of particle-laden macrophages were present within alveoli and alveolar ducts from 1 week postexposure through the entire 6-month recovery period. Macrophage accumulations increased in size and number from 1 week through 1 month postexposure and then appeared to remain constant through the remaining 5-month postexposure period. Minimal cellular hypertrophy and hyperplasia were evident at alveolar duct bifurcations adjacent to macrophage aggregates, and this effect was most prominent at 3 to 6 months postexposure. The results of this study clearly demonstrate that exposure to high dust concentrations of two different innocuous particle types produced sustained pulmonary inflammation, enhanced proliferation of pulmonary cells, impairment of particle clearance, deficits in macrophage function, and the appearance of macrophage aggregates at sites of particle deposition. In addition, the mass deposition rate determination appears to be a less sensitive indicator of "overload" when compared to biomarkers of pulmonary toxicity, such as macrophage function and cellular inflammation and proliferation indices.

Administration, Inhalation↗