Bronchiolar Walls Research Articles

Systemic inflammation and lung function

The current view on inflammation in COPD is foremost based on examinations of luminal samples and bronchial tissues. Inflammation in peripheral lung tissues has however remained relatively unexplored. Our research characterises structural alterations of the lung immune system (i.e. “immune remodelling”) in COPD. With focus on changes in lymphoid tissues and lymphatic vessels, immune remodelling was studied in patients with different severities of COPD and compared to never-smoking and smoking control subjects. The results confirmed an expansion of bronchiolar-associated lymphoid tissue (BALT) in COPD but also revealed increased lymphoid tissues in pulmonary vessels and the alveolar parenchyma. While the lymphoid structures in COPD had a leukocyte composition similar to controls, several leukocyte populations were activated, with e.g. increased expression of CXCL13 and ETS-1. In COPD lungs, increased numbers and size of lymphatic vessels were found in bronchiolar wall, pulmonary vessel, and alveolar compartments. Lymphatic vessels also displayed increased immunoreactivity for the cell traffic regulating chemokine CCL21. Altogether, our data suggest that in COPD all major lung compartments are subjected to immune remodelling with expansion and activation of lymphoid tissues and lymphatic vessels as significant features. These observations may have implications for the abnormal cell traffic and chronic inflammation in COPD.

Immune remodelling in peripheral lungs of COPD patients

The current view on inflammation in COPD is foremost based on examinations of luminal samples and bronchial tissues. Inflammation in peripheral lung tissues has however remained relatively unexplored. Our research characterises structural alterations of the lung immune system (i.e. “immune remodelling”) in COPD. With focus on changes in lymphoid tissues and lymphatic vessels, immune remodelling was studied in patients with different severities of COPD and compared to never-smoking and smoking control subjects. The results confirmed an expansion of bronchiolar-associated lymphoid tissue (BALT) in COPD but also revealed increased lymphoid tissues in pulmonary vessels and the alveolar parenchyma. While the lymphoid structures in COPD had a leukocyte composition similar to controls, several leukocyte populations were activated, with e.g. increased expression of CXCL13 and ETS-1. In COPD lungs, increased numbers and size of lymphatic vessels were found in bronchiolar wall, pulmonary vessel, and alveolar compartments. Lymphatic vessels also displayed increased immunoreactivity for the cell traffic regulating chemokine CCL21. Altogether, our data suggest that in COPD all major lung compartments are subjected to immune remodelling with expansion and activation of lymphoid tissues and lymphatic vessels as significant features. These observations may have implications for the abnormal cell traffic and chronic inflammation in COPD.

Rare pneumoconiosis induced by long‐term amorphous silica exposure: The histological characteristics and expression of cyclooxygenase‐2 as an antifibrogenic mediator in macrophages

Pneumoconiosis induced by non-crystalline silica is considered rare, although silicosis resulting from contact with crystalline silica is a well-known hazard associated with progressive pulmonary fibrosis. Here we describe a patient with pneumoconiosis induced by diatomaceous earth composed of amorphous silica detected by two-dimensional imaging of chemical elements. The histology revealed that the disease was characterized by a granulomatous reaction in the lung. A large number of macrophages laden with yellow and black pigments accumulated in alveolar spaces and were incorporated into the interstitial sites. Bronchiolar walls were destroyed by palisade macrophages, suggesting airflow obstruction. Packed macrophages adhering to and covering the denuded interstitium indicated that macrophages might be incorporated into pulmonary interstitium in this fashion. Immunohistochemistry showed that cyclooxygenase-2, an antifibrogenic mediator, was intensely expressed in the macrophages compared with macrophages in control lungs. No birefringent material was found in the tissues. When two-dimensional analysis of chemical elements was performed using an electron probe microanalyzer with a wavelength-dispersive spectrometer, the resultant fine mapping of silicon and oxygen on the tissue indicated that the pigments phagocytosed by macrophages corresponded to amorphous silica. In conclusion, two-dimensional analysis of elements is very useful for pathologists in correlating the presence of chemical elements with histological changes.

Attenuated Lung Fibrosis in Interleukin 6 Knock-out Mice after C-ion Irradiation to Lung

There is a great deal of evidence that a cyclic cascade of inflammatory cytokines, together with the activation of macrophages, is initiated very early after irradiation to develop lung fibrosis in a late phase. To understand the persistent effects of cytokines, the cytokine gene of knock out or transgenic mouse is one of the useful tools. In this study, we evaluated a role of a key molecule, interleukin-6 (IL-6), in the late-phase inflammatory response and subsequent fibrotic changes after irradiation using wild-type (WT) and IL-6 knock out (IL-6 KO) mice. The mice underwent thoracic irradiation with 10 Gy of C-ion beam or sham-irradiation and were examined by histology. Immunoreactivity for IL-6 was induced at the site of bronchiolar epithelium, in pneumocytes and in monocytes by C-ion irradiation. At 24 weeks after irradiation, the infiltration of macrophages, detected by positive immunohistological staining with Mac3 antibody, was observed in alveolar spaces both in WT and IL-6 KO mice. The thickening of bronchiolar and alveolar walls exhibited in WT mice, but not KO mice, and fibrotic changes detected by Masson-Trichrome staining, were observed only in the lungs of WT mice, while it was attenuated in IL-6 KO mice. These results indicated that IL-6 might not be essential for activating macrophages in the late phase, but plays an important role for fibrotic changes of the alveolar wall after irradiation.

T cell receptor heterodimer (alpha beta/gamma delta) expressions in diffuse panbronchiolitis

Several reports have indicated that T cells bearing gamma delta T cell receptor (TCR) are major effector cells in mucosal immunity of the murine intestinal tract. In humans, abnormal distribution of gamma delta + T cells has also been found in inflammatory bowel diseases. We studied TCR heterodimer expressions in lymphocytes infiltrating the peripheral airways in patients with diffuse panbronchiolitis (DPB), because DPB is histologically characterized by chronic inflammation in bronchioles and could be a model for investigation of the significance of gamma delta + T cells in persistent inflammation of the human respiratory tract. Open lung biopsy specimens were obtained from 7 patients and peripheral blood lymphocytes (PBL) from 9 patients. Immunohistochemically, we detected alpha beta and gamma delta TCR by avidin-biotin complex immunoperoxidase method, utilizing BMA 031 and TCR delta 1 monoclonal antibody, respectively, PBL were analyzed by flow cytometry. Histological analysis revealed that DPB lesions mainly involved the bronchiolar walls with marked infiltration of small round cells. Many T cells were distributed in the submucosal area, although few T cells infiltrated the epithelium. Most of the T cells in the bronchioles expressed alpha beta TCR (98.7%), whereas only 1.3% expressed gamma delta TCR. There was no significant difference in the percentage of gamma delta + T cells in PBL between DPB and age- and sex-matched controls (6.7% vs. 9.1%). These results suggest that the increase of T cells bearing alpha beta TCR played a major role. However, the possibility that the decrease of T cells bearing gamma delta TCR caused reduced mucosal defense against external antigens, leading to persistent inflammation of the lower respiratory tracts in DPB, is not excluded.

Persistent bronchiolar remodeling following brief ventilation of the very immature ovine lung

Children and adults who were mechanically ventilated following preterm birth are at increased risk of reduced lung function, suggesting small airway dysfunction. We hypothesized that short periods of mechanical ventilation of very immature lungs can induce persistent bronchiolar remodeling that may adversely affect later lung function. Our objectives were to characterize the effects of brief, positive-pressure ventilation per se on the small airways in very immature, surfactant-deficient lungs and to determine whether the effects persist after the cessation of ventilation. Fetal sheep (0.75 of term) were mechanically ventilated in utero with room air (peak inspiratory pressure 40 cmH2O, positive end-expiratory pressure 4 cmH2O, 65 breaths/min) for 6 or 12 h, after which tissues were collected; another group was studied 7 days after 12-h ventilation. Age-matched unventilated fetuses were controls. The mean basement membrane perimeter of airways analyzed was 548.6+/-8.5 microm and was not different between groups. Immediately after ventilation, 21% of airways had epithelial injury; in airways with intact epithelium, there was more airway smooth muscle (ASM) and less collagen, and the epithelium contained more mucin-containing and apoptotic cells and fewer proliferating cells. Seven days after ventilation, epithelial injury was absent but the epithelium was thicker, with greater cell turnover; there were increased amounts of bronchiolar collagen and ASM and fewer alveolar attachments. The increase in ASM was likely due to cellular hypertrophy rather than hyperplasia. We conclude that brief mechanical ventilation of the very immature lung induces remodeling of the bronchiolar epithelium and walls that lasts for at least 7 days; such changes could contribute to later airway dysfunction.

Non-Hodgkin's Lymphoma Accompanied by Pulmonary Involvement with Diffuse Ground-Glass Opacity on Chest CT: A Report of 2 Cases

We report 2 rare cases of non-Hodgkin's lymphoma accompanied by pulmonary involvement with diffuse ground-glass opacity. Histological examination of the lung revealed a diffuse large B-cell-type lymphoma within the bronchiolar wall and alveolar septum. Although this is a rare occurrence, diffuse large B-cell-type non-Hodgkin's lymphoma should be considered in the differential diagnosis of pulmonary diffuse ground-glass opacity in the chest CT scan.

FORMALDEHYDE-INDUCED DAMAGE IN LUNGS AND EFFECTS OF CAFFEIC ACID PHENETHYL ESTER: A LIGHT MICROSCOPIC STUDY

Aim: The aim of this study was to investigate the toxicity of formaldehyde on lung and protective effects of caffeic acid phenethyl ester against these toxic effects. Methods: For this purpose, 21 male Wistar rats were divided into three groups. The rats in Group I comprised the controls, while the rats in Group II were injected with formaldehyde (FA). The rats in Group III received CAPE daily while exposed to formaldehyde. After the treatment, lungs tissues were evaluated by microscopic examination. Results: In the microscopic examination of FA group, fatty and cellular infiltration in the pulmonary interstitium and thickening in the bronchiolar wall were evident. Dilatation and congestion were prominent in the alveolar septal vessels. In FA+CAPE group, dilatation of interalveolar septal vessels was less observed than FA group. Bronchial wall structures are similar with control. Conclusion: It was thought that FA exposure leads to inflammation and injury in lungs. CAPE shows protective and anti inflammatory activity against these adverse effects.

Diffuse Lymphoplasmacytic Bronchiolitis in Cartilage-Hair Hypoplasia

Three children with cartilage-hair hypoplasia presented with chronic obstructive symptoms and bronchiolar wall thickening on high-resolution computed tomography scanning. In all children, surgical lung biopsy demonstrated diffuse dilated lymphoplasmacytic bronchiolitis. The bronchiolar wall was infiltrated by a lymphocyte sheath with plasma cell differentiation and dispersed secondary follicles. Clarithromycin substantially improved respiratory symptoms and pulmonary function, allowing children to return home.

Lymphoid Interstitial Pneumonia Associated with Common Variable Immunoglobulin Deficiency

The patient was a 30-year-old woman with a disease of common variable immunodeficiency. She was admitted to our hospital because of abnormal findings on her chest radiographs in an annual health screening. Chest computed tomography showed multiple reticulonodular infiltrates in both lower lung fields. The surgical lung biopsy specimen demonstrated involvement of mature small lymphocytes with a mixture of other mononuclear cells in the lung parenchyma and bronchiolar walls. The patient was diagnosed to have lymphoid interstitial pneumonia. The patient was treated with prednisolone and intravenous supplement of immunoglobulin, resulting in radiographically and clinically stable disease.

Clinical/Pathologic Correlations in 553 Patients With Primary Centrilobular Findings on High-Resolution CT Scan of the Thorax

Clinical/pathologic correlations in patients with high-resolution CT (HRCT) scan findings presenting with two patterns of centrilobular opacity remain unclear. Chest HRCT scans in 553 patients with predominant centrilobular opacities or preferential centrilobular disease were retrospectively evaluated. In 141 patients who underwent biopsy, CT scan images were compared with actual specimens. Centrilobular nodules with a tree-in-bud appearance and bronchial wall thickening were observed in most patients who were carriers of human T-lymphotropic virus type 1 (88 patients and 57 of 99 patients, respectively), Mycoplasma pneumoniae pneumonia (44 patients and 45 of 52 patients, respectively), Mycobacterium tuberculosis (38 patients and 37 of 52 patients, respectively), Mycobacterium avium-intracellulare complex (22 patients and 27 of 37 patients, respectively), Mycobacterium kansasii (27 patients and 19 of 33 patients, respectively), allergic bronchopulmonary aspergillosis (6 patients and 7 of 9 patients, respectively), diffuse panbronchiolitis (12 patients and 10 of 12 patients, respectively), and diffuse aspiration bronchiolitis (12 patients and 12 of 13 patients, respectively). On the other hand, ill-defined centrilobular nodules of ground-glass attenuation were frequently seen in patients with subacute hypersensitivity pneumonitis (all 15 patients), metastatic calcification (all 4 patients), Churg-Strauss syndrome (4 of 12 patients), microscopic polyangiitis (27 of 48 patients), systemic lupus erythematosus (7 of 8 patients), and respiratory bronchiolitis-associated interstitial lung disease (all 8 patients). Pathologically, the tree-in-bud appearance correlated well with the plugging of small airways with mucous, pus, or fluid; dilated bronchioles; and bronchiolar wall thickening. Ill-defined centrilobular nodules represented peribronchiolar inflammation or the deposition of hemorrhagic materials. Knowledge of the two centrilobular patterns is of proven worth for generating differential diagnoses and is of particular value in suggesting a likely infectious etiology in cases with tree-in-bud appearance.

NASAL TOLERANCE WITH COLLAGEN V PROTEIN REVERTS BRONCHOVASCULAR AXIS REMODELING IN EXPERIMENTAL BRONCHIOLITIS OBLITERANS

The precise role of the remodeling process and possible therapies for bronchiolitis obliterans remain to be established. [corrected] In the present study, we sought to validate the importance of nasal collagen V tolerance to verify whether bronchovascular axis remodeling could be reverted by this therapeutic approach when compared to steroid treatment. Mice were randomly divided into 4 groups: control, bronchiolitis obliterans, collagen V tolerance, and prednisone groups. Morphometry was employed to evaluate bronchovascular axis dimensions, collagen density, and immune cell response. Collagen V nasal tolerance and steroid-treated mice showed significantly lower values of terminal bronchiole wall thickness and reduction in peribronchovascular cells; bronchioalveolar lymphoid tissue; and CD3+, CD4+, CD8+, and CD20+ lymphocytes. A significant decrease in CD68+ macrophage density was found in prednisone-treated mice. In addition, a strong quantitative relationship was found between collagen V tolerance, and reduction in density of immune cells and collagen. Our results indicate that bronchovascular axis remodeling in bronchiolitis obliterans can be reverted by collagen V nasal tolerance, possibly as the result of T-cell suppression. We concluded that the tolerance effects in this model were strongly related to the improvement in bronchovascular remodeling, and these may be an appropriate targets for further prospective studies on nasal collagen V tolerance.

Keratinocyte Growth Factor Gene Transduction Ameliorates Acute Lung Injury And Mortality in Mice

At present there is no known effective pharmacological therapy for acute lung injury (ALI). Because keratinocyte growth factor (KGF) promotes epithelial cell growth, intratracheal administration of KGF has the possibility of restoring lung tissue integrity in injured lungs and improving patient outcomes. However, treatment using recombinant KGF protein is limited by its short effective duration. Thus, we investigated the effectiveness of intratracheal KGF gene transduction using adenoviral vector in ALI. We constructed an adenoviral vector expressing mouse KGF (mKGF), and 1.0 x 10(9 ) plaque-forming units of mKGF cDNA-expressing (Ad-KGF) and control (Ad-1w1) adenoviral vector was intratracheally instilled, using a MicroSprayer, into anesthetized BALB/c mice. Three days later, the mice were exposed to >90% oxygen for 72 hr, and the effect of KGF on hyperoxia-induced lung injury was examined. In the Ad-KGF group, KGF was strongly expressed in the airway epithelial cells, while peribronchiolar and alveolar inflammation caused by adenoviral vector instillation was minimal. The KGF overexpression not only induced proliferation of surfactant protein C-positive cuboidal cells, especially in the terminal bronchiolar and alveolar walls, but also prevented lung injury including intraalveolar exudation/hemorrhage, albumin permeability increase, and pulmonary edema. The arterial oxygen tension and the survival rate were significantly higher in the KGF-transfected group. These findings suggest that KGF gene transduction into the airway epithelium is a promising potential treatment for ALI.

Epithelioid sarcoma presenting as pulmonary cysts with cancer antigen 125 expression

A 39-year-old Japanese woman presented with a swollen right hand and a right-sided pneumothorax. Chest CT revealed bilateral multiple pulmonary thin-walled cysts measuring<or=1 cm in diameter and small nodules. An initial skin biopsy led to a misdiagnosis of metastatic adenocarcinoma, as tumour cells were positive for cytokeratin, epithelial membrane antigen, carcinoembryonic antigen and cancer antigen 125. However, chemotherapy proved ineffective, and the skin biopsy was repeated. A final diagnosis of epithelioid sarcoma (ES) was made. Open lung biopsy showed that the pulmonary nodules represented metastases of ES. Although the pulmonary cyst walls did not contain tumour cells, bronchiolar wall adjacent to the cysts had been infiltrated by tumour cells. These findings suggested that pulmonary cysts, a rare form of pulmonary metastases from soft tissue sarcomas, had developed through a ball-valve effect of metastatic tumour in small airways. However, presence of cancer antigen 125 hindered obtaining a correct diagnosis of ES.

Rheumatoid arthritis, Pyrexia of Unknown Origin (PUO) and pancytopenia

A 61-yr-old previously fit lorry driver was referred by his general practitioner in October 1999 to an orthopaedic clinic with a 6-month history of painful hands, shoulders and feet. His general practitioner had treated him with ibuprofen without much improvement. He admitted to a recent history of loss of appetite with loss of two stones (12.7 kg) in weight. His joint pains had been increasing in severity with visible swelling of his fingers and knees. He had no relevant family history. He was an ex-smoker and drank little alcohol. Physical examination revealed a healthy-looking man with signs of synovitis in the symptomatic joints. The orthopaedic surgeon referred him to the rheumatologist (K.C.). The preliminary blood tests showed haemoglobin of 10.4 g/dl with normal haematocrit, leucocyte and platelet counts and normal serum vitamin B12 and red-cell folate levels. His serum ferritin was 468 g/l (normal range 18–400 g/l). He also had transient random hyperglycaemia, which was followed by a normal glucose tolerance test. His rheumatoid factor was elevated at 1:2560. His chest X-ray was normal except for some thickening of the bronchiolar wall. He was seen in the rheumatology clinic 2 months later, in December 1999, with classical symptoms and signs of a symmetrical inflammatory polyarthritis suggestive of rheumatoid disease. His knees were drained and injected with methyl prednisolone and local anaesthetic. He was also given intramuscular methyl prednisolone (120mg) to induce remission of active disease. Investigations revealed haemoglobin 10.3 g/dl, white cell count 6.4 10/l, platelet count 449 l0/l and ESR of 100mm in the first hour. The biochemical screens were all normal, including liver, renal and bone panels. The rheumatoid factor was 2460 IU (normal range 30 IU) and CRP was elevated at 85.1mg/dl (normal range <10mg/dl). The X-rays of his hands and feet showed no obvious erosions. The option of commencing methotrexate as a second-line drug was discussed but he preferred to wait until he returned from a planned Christmas holiday in Spain. Soon after his return from holiday he developed sudden severe cramp-like pains associated with numbness in his legs. He was virtually unable to walk. An MRI scan of his whole spine was done on the advice of the neurosurgeons, and, as the scans were normal, he was referred to the neurologists, who performed a lumbar puncture to exclude acute infective polyneuritis. The neurologists also noted a skin rash on his legs associated with left foot drop (Fig. 1). An autoimmune disease was suspected and the rheumatologist (K.C.) was consulted. On examination he had a vasculitic rash with peripheral neuropathy. There was no lymphadenopathy or organomegaly. Given the recent diagnosis of seropositive rheumatoid arthritis (RA), systemic rheumatoid vasculitis (SRV) seemed to be the most plausible diagnosis. Investigations at this time revealed haemoglobin 9.0 g/dl, white cell count 12.1 10/l and neutrophils 9.6 10/l with normal platelet and lymphocyte count. The ESR was 110mm in the first hour and CRP was 121mg/dl (normal range <5mg/dl). The biochemical, serological and microbiological screens including hepatitis A, B and C were all normal/negative. His anti nuclear antibodies, anti DNA antibodies, extractable nuclear antigens, anti cardiolipin antibodies, anti neutrophil cytoplasmic antibodies and cryoglobulins were all negative. Echocardiogram was normal. A cerebrospinal fluid study showed a mild increase in cerebrospinal fluid protein but no oligoclonal band or albumino-cytological dissociation. Electromyography showed severe sensorimotor polyneuropathy of the axonal type with some denervation changes in the peroneal muscles. A skin biopsy confirmed active necrotizing vasculitis, consistent with SRV (Fig. 2). He was commenced on pulse intravenous methyl prednisolone (500mg) and cyclophosphamide (500mg) with some symptomatic improvement, and was discharged home on a 2-weekly regime.

A Reliable Method for Intratracheal Instillation of Materials to the Entire Lung in Rats

A novel method for intratracheal instillation of rats is described by which an operator can confidently administer a liquid sample into the tracheal lumen, with direct observation of the entrance to the trachea. To confirm its efficacy, indigo carmine was administered with or without air to investigate optimal conditions for exposure of the whole lung. After administration of 0.5 ml of indigo carmine and an equal volume of air simultaneously by intratracheal instillation, sections through the whole lung demonstrated positive staining with the dye. For histological examination, 0.5 ml of saline containing iron oxide followed by an equal volume of air was administered intratracheally. Iron particles were observed in the wall of bronchioles and alveolar macrophages of whole lung. The method allows reliable intratracheal administration to large numbers of rats within a short period and should, therefore, prove useful for assays of toxicity in the respiratory tract.

Acute Pulmonary Toxicity Caused by Exposure to Colloidal Silica: Particle Size Dependent Pathological Changes in Mice

To compare the pulmonary toxicity between ultrafine colloidal silica particles (UFCSs) and fine colloidal silica particles (FCSs), mice were intratracheally instilled with 3 mg of 14 nm UFCSs and 230 nm FCSs and pathologically examined from 30 minutes to 24 hour postexposure. Histopathologically, lungs exposed to both sizes of particles showed bronchiolar degeneration and necrosis, neutrophilic inflammation in alveoli with alveolar type II cell swelling and particle-laden alveolar macrophage accumulation. UFCSs, however, induced extensive alveolar hemorrhage compared to FCSs from 30 minutes onwards. UFCSs also caused more severe bronchiolar epithelial cell necrosis and neutrophil influx in alveoli than FCSs at 12 and 24 hours postexposure. Laminin positive immunolabellings in basement membranes of bronchioles and alveoli of UFCSs treated animals was weaker than those of FCSs-treated animals in all observation times. Electron microscopy demonstrated UFCSs and FCSs on bronchiolar and alveolar wall surface as well as in the cytoplasm of alveolar epithelial cells, alveolar macrophages and neutrophils. Type I alveolar epithelial cell erosion with basement membrane damage in UFCSs treated animals was more severe than those in FCSs-treated animals. At 12 and 24 hours postexposure, bronchiolar epithelial cells in UFCSs-treated animals showed more intense vacuolation and necrosis compared to FCSs-treated animals. These findings suggest that UFCSs have greater ability to induce lung inflammation and tissue damages than FCSs.

Chronische Bronchitis, COPD

Chronic bronchitis is part and precursor of COPD, a complex disease triggered mostly by exposure to cigarette smoke. However COPD develops only in patients with specific susceptibility probably determined by genetic factors or additional risk factors. A specific type of inflammation resides in the bronchial and bronchiolar walls, that infers damage not only to airway structure but also to surrounding alveolar attachments and thus to the lung parenchyma. Chronic bronchitis, fibrosing bronchiolitis and emphysema constitute the three main stems of pathology of the disease but may coexist with varying extent. The clinical picture is therefore quite variable. Treatment exists largely in bronchodilation combining different mechanisms and using long acting drugs usually applied by inhalation. Acute exacerbations promote progression of the disease, which must be counteracted by adaptation and intensification of therapy, in some cases including non invasive or invasive ventilation. Several non-pharmacologic measures such as smoking cessation, rehabilitation, nutritional support, long term oxygen therapy, lung volume reduction and possibly lung transplantation may be available for appropriate patients and have to be considered.

Inhalation of cadmium, lead or its mixture: Effects on the bronchiolar structure and its relation with metal tissue concentrations

The human population in the industrialized world is constantly exposed to chemical mixtures of pollutants such as metals; information about the consequences of the interactions of these compounds on health is scarce. The current study examines the effects of the inhalation of lead (Pb), cadmium (Cd) and Pb–Cd mixture in mice models analyzing the metal concentrations in lung, and the morphological modifications in the bronchiolar epithelium identified by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) after 4 weeks of inhalation. Our results showed that metal concentrations in lung were higher compared to controls; however, Pb concentrations drastically decrease with the mixture. This reduction was also observed in the inhalation chamber. These data correlate with the morphological alterations observed, which consisted of flattened and decreased number of nonciliated bronchiolar cells (NCBC), bald ciliated cells and bundles of NCBC. These modifications were mainly given by Cd, alone or in combination with Pb. The clusters formed by NCBC cells suggest cell proliferation which probably means that after metal inhalation, the cells enhance their proliferative capacity in order to repopulate the bronchiolar wall.

Prior Bordetella pertussis infection modulates allergen priming and the severity of airway pathology in a murine model of allergic asthma.

It has been proposed that T helper (Th)2-driven immune deviation in early life can be countered by Th1 inducing childhood infections and that such counter-regulation can protect against allergic asthma. To test whether Th1-inducing infection with Bordetella pertussis protects against allergic asthma using well-characterized murine models. Groups of mice were sensitized to ovalbumin (OVA) in the presence or absence of B. pertussis, a well-characterized Th1 inducing respiratory infection. Immunological, pathological and physiological parameters were measured to assess the impact of infection on immune deviation and airway function. We demonstrate that OVA sensitization does not affect the development of B. pertussis-specific immune responses dominated by IgG2a and IFN-gamma and does not impair Th1-mediated clearance of airway infection. In contrast, B. pertussis infection at the time of sensitization modulated the response to OVA and significantly reduced total serum and OVA-specific IgE. The pattern of cytokine responses, in particular OVA-specific IL-5 responses in the spleen was also modulated. However, B. pertussis did not cause global suppression as IL-10 and IL-13 levels were enhanced in OVA-stimulated spleen cell cultures and in lavage fluid from infected co-sensitized mice. Histopathological examination revealed that B. pertussis infection prior to OVA sensitization resulted in increased inflammation of bronchiolar walls with accompanying hyperplasia and mucous metaplasia of lining epithelia. These pathological changes were accompanied by increased bronchial hyper-reactivity to methacholine exposure. Contrary to the above premise, a Th1 response induced by a common childhood infection does not protect against bronchial hyper-reactivity, but rather exacerbates the allergic asthmatic response, despite modulation of immune mediators.