Perivascular Cellular Infiltration Research Articles

Infantile polymyositis with normal serum creatine kinase level

A 30-month-old boy who has been suffering progressive proximal muscle weakness and severe atrophy in shoulder and hip muscles from 11 months of age had prominent perivascular inflammatory cellular infiltration in his muscle biopsy and myopathic EMG changes. But his serum creatine kinase (CK) levels were repeatedly found to be within normal ranges. Oral prednisolone therapy (2 mg/kg/d) brought a complete recovery of muscle power and normalization of EMG and muscle biopsy findings. This report provides an additional support that the cases of infantile polymyositis with normal serum CK levels may respond well to steroid therapy.

CYCLOSPORIN A LIPOSOME AEROSOL: LAC K OF ACUTE TOXICITY IN RATS WITH A HIGH INCIDENCE OF UNDERLYING PNEUMONITIS

Cyclosporin A (CsA)-dilauroylphosphatidylcholine (DLPC) liposome aerosol was evaluated for potential toxicity in a 28-day, acute toxicity study in rats. Rats of both sexes were housed in a nose-only chamber and exposed to aerosols of room air, water, DLPC liposomes (37.5 mg DLPC/ml in reservoir) or CsA-DLPC liposomes (5 mg CsA/ml and 37.5 mg DLPC in reservoir; 75.4 g CsA/L aerosol) generated by an AeroTech II nebulizer for 1 h each day for 28 consecutive days. The estimated retained dose of CsA was 1.58 mg CsA/kg body weight. The rats were monitored during the exposure period and for 2 wk after for body or organ weights, hematology, clinical chemistry, gross lesions, and histopathology of lungs, kidney, and liver. There were no differences for any of the parameters in any of the four exposure groups at any time point except for histopathology. These examinations revealed widespread chronic inflammatory lesions in all groups throughout the test period. These lesions were not associated with exposure to any of the test materials. The etiology of the pulmonary inflammation is unknown. The inflammatory lesions consisted of interstitial, perivascular, peribronchiolar, and alveolar cellular infiltrates that progressed to an organizing alveolitis with Type 2 cell hyperplasia and interstitial fibrosis. Lung lesions were observed in all experimental groups at all time points examined. The degree of severity of inflammatory lesions in the lungs increased with time through day 29 in all groups. Two weeks after final exposure to the test compounds (day 42), the average increase in severity and total number of lesions in all lobes were significantly less in the CsA-DLPC liposome-treated group (p < .04) and borderline in the DLPC group. Thus, DLPC and CsA-DLPC liposomes had no detectable adverse effects after daily inhalations over a period of 28 days, and there was a possible beneficial effect of CsA and possibly of DLPC against an opportunistic pulmonary pathogen in the rats that preexisted the aerosol exposures. </abs>

Concordant lung xenograft rejection in a hamster-to-rat model.

This study was conducted to investigate the functional and morphological aspects of orthotopic lung xenograft rejection in a concordant hamster-to-rat donor-recipient species combination. By postoperative day (POD) 3, allotransplanted grafts demonstrated good aeration, but infiltrates were seen in all the xenotransplanted lungs. Antihamster lymphocytotoxic antibody titers increased to 5.2 +/- 1.1 by POD 3 (P < 0.05 vs POD 1) and reached 7.0 +/- 0.8 by POD 5 (P < 0.05 vs PODs 1 and 3). The CD4+/CD8+ ratio in peripheral blood lymphocytes increased significantly on POD 3 (P < 0.05 vs untransplanted), but decreased by POD 5 (P < 0.05). Histologically, on POD 3 the xenotransplanted grafts were characterized by perivascular cellular infiltrates and edema. Cytologically, the cells consisted of small round lymphocytes, monocytes, and occasional neutrophils. Immunohistochemical analysis showed heavy IgM and C3 deposits in the vascular endothelium, without any IgG deposits. Allotransplanted grafts showed moderate W 3/25 + (28.3 +/- 17.3%) and MRC OX8 + (38.7 +/- 0.7%) cellular infiltrations on POD 3, but ED1 + (8.0 +/- 3.7%) cells were rare. Conversely, in the xenotransplanted grafts, ED1 + (34.2 +/- 16.4%) cells were more prevalent than MRC OX8 + (18.1 +/- 16.5%) cells on POD 3, at P < 0.01 and P < 0.05 vs allograft, respectively. These results indicate that both antidonor antibodies and macrophages/monocytes play an important role in the concordant lung xenograft rejection.

Bases for the early immune response after rechallenge or component vaccination in an animal model of acute Mycoplasma pneumoniae pneumonitis

The pathology of Mycoplasma pneumoniae pulmonary infection for a hamster model was examined after whole bacterium rechallenge or component vaccination. Animals which, after an initial infection, were rechallenged with either live or heat-killed M. pneumoniae inocula developed severe early recall lesions in the first 3 days. In contrast, animals infected once develop maximum histopathology at approximately 10–14 days. A severe perivascular inflammatory cellular infiltrate developed in the rechallenged groups, and pulmonary pathology could also be elicited by rechallenge with bacterial growth medium components. Component vaccination with protein P1 did not reduce disease in comparison to once-infected controls, and vaccination promoted an early immune recall response as well. We conclude that an early immune response needs to be sought in all future experiments of challenge/rechallenge or vaccination. Vaccine studies will require an understanding of both protective and harmful immunogens.

Histopathologic changes of the temporomandibular joint disk in patients with chronic arthritic disease: A comparison with internal derangement

Histopathologic examination was performed of the disk and the posterior attachment extirpated from 17 temporomandibular joints from 15 patients with chronic arthritic disease. Seven patients had rheumatoid arthritis (including two with juvenile type), five had ankylosing spondylitis, and three had psoriatic arthropathy, which affected more joints than the temporomandibular joint. Specimens removed from 16 temporomandibular joints from 15 patients with internal derangement were used for histopathologic comparison. In both groups of patients, inflammatory changes were observed, but no specific histopathologic signs could distinguish the groups. Patients with chronic arthritic disease seemed to have more pronounced changes of vascular proliferation, perivascular cellular infiltrate, inflammatory cells, and fibrosis throughout the soft tissues. Destruction of the disk was another finding evident in patients with chronic arthritic temporomandibular joint disease; there was no visible disk structure in 8 of these 17 joints, compared with 1 of the 16 joints in the internal derangement group.

Neurovascular permeability and fibrin deposition in the central neuraxis of Lewis rats with cell-transferred experimental allergic encephalomyelitis in relationship to clinical and histopathological features of the disease

Abrupt increases in blood-brain barrier (BBB) permeability were detected by the dual-isotope technique, coinciding with evidence of activation of coagulation cascade, occured 1 day prior to appearance of clinical neurological signs of experimental allergic encephalomyelitis (EAE) and in conjuction with initial detectable cell infiltration. Maximal increase of BBB permeability was observed on the first day of clinical signs, which was 2 days prior to maximum severity of clinical abnormalities and 1 day in advance of the greatest number of central nervous system (CNS) fibrin deposits and perivascular cellular infiltration. Returning of increased BBB permeability and CNS perivascular fibrin deposits to normal levels was demostrated prior to complete remission of neurological signs. Considerable CNS perivascular cellular filtrates, however, lasted after complete remission of neurological signs. These findings indicate that increase permeability of the BBB, in association with activation of the coagulation cascade, is the earliest expressions of immune effector activity of experimental allergic EAE.

Lupus miliaris disseminatus faciei--pathologic study of early, fully developed, and late lesions.

Lupus miliaris disseminatus faciei is a chronic inflammatory disorder, which affects adults of both sexes. This study included 25 patients with lupus miliaris disseminatus faciei. Three biopsies, representing early, fully developed, and late lesions, were taken from each patient. Histopathologic examination of the different lesions revealed that in early lesions, all of them showed superficial perivascular and periappendigeal cellular infiltrate composed mostly of lymphocytes and few histiocytes with occasional neutrophils. The fully developed lesions showed a sarcoidal granuloma only (40%), sarcoidal granuloma with abscess (24%), sarcoidal granuloma around areas of caseation necrosis (20%), and a mixture of sarcoidal and tuberculoid granulomas (16%). All the late lesions showed extensive fibrosis especially in the perifollicular areas. Scattered lymphocytes, histiocytes and neutrophils were present within the fibrotic areas. A possible explanation of the pathogenesis is discussed.

Effect of desferrioxamine on the hepatotoxicity of adriamycin in normal mice

AbstractThe effect of the iron chelator, desferrioxamine (DFO) upon the hepatotoxic effects associated with the use of adriamycin as a cytotoxic agent were evaluated in normal albino mice. Hepatocellular toxicity was assessed by measuring serum aspartate transaminase (SGOT), serum alanine transaminase (SGPT) and serum alkaline phosphatase (ALP) activity. In addition, glucose‐6‐phosphatase (G‐6‐PTase) activity, nucleic acids, calcium, magnesium, and iron levels in liver tissue were also measured. Adriamycin treatment (2 mg/kg i.p.), administered every other day for a total of 5 doses produced a 2.5‐fold increase in SGOT and SGPT, while ALP activity showed a 30% increase in comparison to normal, untreated controls. However, hepatic G‐6‐PTase activity showed a significant decrease after the adriamycin treatment regimen. The calcium and iron content of liver showed also a marked decrease, while magnesium levels were increased two‐fold after treatment with adriamycin. In the presence of the iron chelator, DFO (100 mg/kg i.p., administered every other day for 5 doses), adriamycin treatment did not result in any significant changes in SGOT, SGPT, ALP, or hepatic G‐6‐PTase activity. Histopathological examination of mouse liver showed diffuse ballooning degeneration of liver cells with perivascular cellular infiltration after adriamycin treatment. In the presence of DFO, only focal cellular degenerative and minimal fatty changes were observed. The observed hepatocellular damage is believed to be a result of the lipid peroxidation induced by adriamycin. The role of DFO in preventing lipid peroxidation has been discussed. This study provides evidence that DFO may be useful for prevention of the lipid peroxidation and hepatocellular damage induced by adriamycin. © 1993 Wiley‐Liss, Inc.

TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase

Intracerebral hemorrhage occurs in tumors, stroke and head trauma. Proteolysis of the extracellular matrix around cerebral capillaries by naturally occurring mammalian 72-kDa type IV collagenase may initiate this pathologic event. To investigate this hypothesis adult rats underwent intracerebral injection of type IV collagenase purified from human melanoma cells. Histologically, at 4 h there was perivascular cellular infiltration with hemorrhage, and by 24 h there was infarction with necrosis, edema and hemorrhage. Ultrastructurally, the basal lamina of endothelial cells was disrupted at 2 h. Brain uptake of [ 14C]dextran and [ 3H]sucrose increased after intracerebral injection of type IV collagenase compared to controls ( P < 0.0001). Tissue inhibitor of metalloproteinase-2 (TIMP-2) reduced the tracer uptake ( P < 0.02). Metalloproteinase inhibitors reduce extracellular matrix proteolysis and protect the blood-brain barrier.

Neurovascular fibrinolytic activity in normal Lewis rats and rats with cell-transferred experimental allergic encephalomyelitis

Fibrinolytic activity in the form of plasminogen activator (PA) was assessed using a histochemical fibrin slide technique in spinal cords of normal Lewis rats and rats with the cell-transferred from of experimental allergic encephalomyelitis (EAE). PA was localized exclusively to blood vessels. Vessels in the leptomeninges had maximum activity. A precipitous decrease in PA activity occured in recipient rats which coincided with onset of clinical neurologic signs. A subsequent return in activity occured in association with clinical remission of disease but remained well below the activity of normal rats for as long as the recipient animals were followed. Vessels containing perivascular cellular infiltrates of EAE had little or no detectable PA activity. Furthermore, PA could not be demonstrated to be associated with infiltrating inflammatory cells, including macrophages. These findings provide further support for involvement of the coagulation and fibrinolytic ssytems in the early clinical manifestation of EAE in Lewis rats.

Suppressed tuberculin reaction in guinea pigs following laser irradiation.

Tuberculin reactions were tested at the bilateral sites of the backs of sensitized guinea pigs. Laser irradiation at an energy fluence of 3.6 J at one site of reaction suppressed the reaction not only at the irradiated site but also at the contralateral nonirradiated site. These phenomena were observed when mononuclear cells were dominant in the perivascular cellular infiltration. The results indicate that local irradiation with a low-power laser has systemic inhibitory effects on delayed hypersensitivity reactions.

Canine parainfluenza virus-induced encephalitis in ferrets

Young seronegative ferrets were intracerebrally inoculated with a neurotropic strain of canine parainfluenza (CPI) virus and serially killed at intervals after infection for subsequent viral immuno-peroxidase, light microscopical and scanning electron microscopical evaluation. The CPI virus infection resulted in a self-limiting non-suppurative ependymitis and choroiditis with associated ependymal cell degeneration. These changes were accompanied by paraventricular and perivascular cellular infiltrates of lymphocytes and monocytes, predominantly in the fourth ventricle and the cervical sipinal cord and less frequently in the lateral ventricles and Sylvian duct. The inflammatory lesions were first detected on post-inoculation day (PID) 8 and had largely resolved after PID 22. Two animals showed multifocal axonal degeneration in the mesencephalon and vestibular nucleus, respectively. Immuno-histocytochemistry showed that virus replication was restricted to ependymal and subependymal cells and was most prominent on PID 4. No prominent residual lesions were present in convalescent animals. Virus-neutralizing CPI antibodies developed by PID 9 and increased slowly thereafter.

Perivascular infiltration in normal skin of patients with rheumatoid arthritis: association with rheumatoid factors and HLA-DR antigens.

The relation between immunohistological findings in biopsy specimens of apparently normal skin, HLA antigens, and rheumatoid factors (RF) was studied in 120 patients with rheumatoid arthritis (RA), selected for treatment with D-penicillamine. Perivascular infiltration (PVI) of more than three mononuclear cells was present in 77 (68%) of 114 patients, accompanied usually by the presence of IgM or C3, or both, in immunofluorescence studies. The number of perivascular cells was associated significantly with the titre of circulating RF. A weak relation of both perivascular cellular infiltration and RF with HLA-DR3 and DR4 did not reach statistical significance. It is concluded that the histological presence of perivascular inflammation is associated mainly with deposition of RF. It is suggested that the first is merely an epiphenomenon of the latter. PVI was not prognostic for the occurrence of the clinical syndrome of rheumatoid vasculitis. For practical purposes skin biopsies do not appear to be useful in the evaluation of individual patients with RA.

Nifedipine: a new treatment for perniosis

Perniosis consists of inflammatory cutaneous lesions, usually arising on acral sites as a result of an abnormal reaction to cold. Spontaneous resolution occurs, but some patients have chronic, recalcitrant and ulcerating lesions which persist into the summer. Although the aetiology is unknown, there are features suggesting a vasospastic component and since nifedipine is an effective treatment of Raynaud's phenomenon, we wondered whether it might also be beneficial in another cold-related disorder, perniosis. Twenty-five patients (23 female, two male) with severe recalcitrant perniosis were enrolled into an open study; 22 had idiopathic perniosis, three had associated anorexia nervosa.1 Nifedipine retard 20 mg was prescribed after onset of lesions and the dose was increased by increments of 20 mg every 3 days until a therapeutic dose was achieved or side-effects developed. Seventeen patients experienced rapid symptomatic relief on a modal dose of 60 mg daily with clearing of lesions after a mean of 14 days. A comparison of pre- and post-treatment biopsies showed resolution of the dermal oedema and diminution of the perivascular cellular infiltrate. Six patients who derived no benefit only achieved a dose of 30 mg daily because of side-effects and two patients were lost to follow-up. There was no correlation between the aetiology, clinical and histological features and response to treatment.

Coronary arteritis in mice after systemic injection of bacterial cell wall peptidoglycan.

We examined cell wall peptidoglycan (PGL) derived from group A streptococcus and other bacteria for possible induction of coronary arteritis in mouse strains. The histological finding of the main trunk of the coronary arteries of BALB/c, DBA/1J, C57BL/6 and DBA/2 mice, which were given an intravenous injection of sonicated PGL fragments of st. pyogenes at 500 micrograms per mouse 4 times at intervals of 1 week, showed diffuse cellular infiltration in the vascular wall as well as perivascular space. Marked hyperplasia of the endothelial cells was noted and necrosis of the medial smooth muscle of the coronary artery also was observed. The elastica stain clearly demonstrated fragmentation and degeneration of the elastic fibers. The histological change of the originating site of the aorta also noted swelling or hyperplasia of the endothelial cells and perivascular cellular infiltration. PGL fragments of st. mutans, st. sanguis and s. aureus did not cause any heart lesions. Coronary arteritis induced by st. pyogenes PGL could be very useful as an experimental animal model of Kawasaki's disease.

Blood levels of kinins in experimental allergic encephalomyelitis

The pathology of acute experimental allergic encephalomyelitis is characterized by perivascular cellular infiltrates in the central nervous system. Our hypothesis is that this immuno-pharmacological process can activate the circulating and tissular kallikrein-kinin systems. We studied 21 New Zealand rabbits inoculated with a homogenate of guinea-pig spinal cord in complete Freund's adjuvant. Each animal underwent radioimmunoassay for arterial blood bradykinin, des-Arg 9-bradykinin and des-Phe 8-des-Arg 9-bradykinin during the acute or subacute clinical phase of encephalomyelitis. Immediately after blood sampling, all animals had their complete central nervous system dissected out and prepared for staining and histological study. The number of hematoxylin-eosin-stained perivascular cellular infiltrates was counted at eight levels of the central nervous system, from the hypothalamic to sacral spinal segments. We demonstrated a positive significant ( P ⩽ 0.02) correlation ( r = 0.55) between the number of perivascular cellular infiltrates and blood level of the biologically active kinin bradykinin.

A spatial analysis of the blood-brain barrier damage in experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis was induced in young male Lewis rats. Following the development of neurological signs, the local distribution of perivascular inflammatory cellular infiltrates and the local blood-to-tissue transfer constants (K1) of alpha-aminoisobutyric acid (AIB) were determined, and these results were compared. Perivascular infiltrative lesions were generally found near areas of the CNS that normally lack an effective blood-brain barrier (BBB) such as the choroid plexus and the entry zones of the cranial and spinal nerve roots. This distribution pattern indicates that the entry of the causative agent into CNS tissue may be by way of the permeable microvessels of these structures. In tissue around inflamed veins, the mean transfer constant was slightly but significantly increased (2.8 +/- 1.5 microliter g-1 min-1) compared with uninvolved regions (0.9 +/- 0.2 microliter g-1 min-1) and similar areas in control animals (0.9 +/- 0.3 microliter g-1 min-1). Analysis of the autoradiographic method of determining transfer constants suggested that the AIB influx rate in the lesion areas may actually be manyfold larger than measured, that BBB permeability may be greatly increased at such sites, and that the areas of lymphocytic infiltration and increased K values may be virtually identical.

Comparison of the Histopathology of Immediate and Late Asthmatic and Cutaneous Responses in a Rabbit Model

The histopathologic changes in the skin and lung in the immunized rabbits are summarized in Table 1. At 30 minutes, cutaneous reaction sites and the submucosa of large airways displayed interstitial edema and vessel dilatation, while the small airways remained uninvolved. At 6 hours, both cutaneous reaction sites and the submucosa of large airways showed a moderate perivascular and interstitial cellular infiltrate with residual edema. In addition, the bronchiolar walls showed an intense, widespread mixed cellular infiltration. Similarly, there was widening of the vessel adventitia due to lymphatic dilatation and leukocyte infiltration. At 48 hours, while the edema had cleared, there was an increase in the mixed cellular infiltrate about both pulmonary and skin vessels and large and small airways. These observations showed that immunized rabbits challenged with antigen develop cutaneous and pulmonary inflammation. In conclusion, the immediate and late cutaneous responses in the rabbit model are similar to those described in the human skin. In this rabbit model, pulmonary changes are similar to those found in the skin. Thus, the pulmonary pathology in the rabbit model may be similar to the pathologic events that occur in allergic humans who have immediate and late asthmatic responses following an encounter with an antigen.

Accumulation of inflammatory cells in response to intracutaneous platelet activating factor (Paf-acether) in man.

Platelet activating factor (Paf-acether, AGEPC) is a family of ether-linked phospholipids known to be released from a range of inflammatory cell types. In vitro and in experimental animals, it seems to be a mediator of inflammation, and intradermal injection of Paf-acether in man elicits a biphasic inflammatory response, reminiscent of the dual response to allergen in sensitized individuals. In the present study, cutaneous histology was assessed in sequential skin biopsies from six normal volunteers after intradermal injection of 200 or 800 pmol Paf-acether. Paf-acether (200 pmol) induced intravascular accumulation of neutrophils, accompanied by a perivascular mixed cellular infiltrate which was composed predominantly of neutrophils at 4 and 12 hours, and lymphocytes and histiocytes at 24 hours. Control injections of lyso-Paf and normal saline induced no noteworthy histological changes. Paf-acether (800 pmol) resulted in vessel destruction, gross endothelial swelling and a perivascular infiltrate of mononuclear cells and neutrophils, accompanied by occasional evidence of leucocytoclasis. By virtue of its ability to induce inflammatory cell accumulation in human skin, Paf-acether should be considered as a potential mediator of inflammatory disorders such as psoriasis.

Blood-brain and blood-spinal cord barrier permeability during the course of experimental allergic encephalomyelitis in the rat

Experimental allergic encephalomyelitis (EAE) was induced in young male Lewis rats. Blood-brain barrier permeability to radiotracers of different molecular sizes was studied at intervals after induction using a tissue sampling technique. The results were correlated to the clinical picture and to the histological appearance of the central nervous system. Significant increase in blood-brain barrier permeability to small molecules was found to precede clinical symtoms by one day in the lumbar spinal cord and to coincide with the onset of clinical disease in other regions. In all regions, increased blood-brain barrier permeability preceded the occurrence of histological lesions (perivascular cellular infiltrates). No permeability increase to large molecules could be demonstrated.