Canary fancier's lung

A 54-year-old man presented with features consistent with extrinsic allergic alveolitis occurring after contact with his pet birds. Screening of the serum for avian precipitating antibody was negative but canary precipitins were present. Extrinsic allergic alveolitis to his pet canaries was confirmed by inhalation challenge.     

Soluble and participate activators of complement and granulomatous pulmonary reactions

In order to test the hypothesis that the histological changes of extrinsic allergic alveolitis result from non-specific activation of the complement cascade we studied pulmonary reactions to equivalent doses of soluble and particulate activators of complement in rats. A single intratracheal instillation of zymosan, a particulate activator of the complement system, produced a florid granulomatous pneumonitis which was maximal at 5 days. This granulomatous reaction did not appear to be associated with the development of hypersensitivity to zymosan. Complement depletion by cobra venom factor did not suppress the granulomatous reaction. Equivalent doses of soluble activators of complement failed to produce any inflammatory changes in the lung. Large doses of immune complex produced an acute, complement dependent, haemorrhagic alveolitis which was maximal at 8 hr and which resolved completely by 48 hr. We conclude that the late granulomatous pulmonary reaction to intra-tracheally administered zymosan is not due to an immune response, or a consequence of direct activation of the alternative pathway of complement, but is of ‘foreign body’ type. We urge caution in drawing conclusions regarding the pathogenesis of the allergic alveolitides on histological appearances alone.     

Increased expression of HLA-DR antigen on alveolar macrophages in pulmonary diseases

Summary The expression of HLA-DR antigen on alveolar macrophages obtained by bronchoalveolar lavage in healthy controls and patients with different diseases was investigated, using cytofluorographic analysis and phykoerythrin conjugated monoclonal mouse anti-human HLA-DR antibody. Alveolar macrophages in patients with extrinsic allergic alveolitis (n=4), idiopathic lung fibrosis (n=4), sarcoidosis (n=6), rheumatoid lung disease (n=6) and pulmonary infection (n=5) showed increased density of HLA-DR antigen expression compared to healthy control subjects (n=5). The increased expression of HLA-DR antigen on alveolar macrophages confirms the importance of these cells for recognition of antigens and immunological responses in different pulmonary diseases.Abbreviations BAL bronchoalveolar lavage - PBS phosphate buffered saline     

Methylation of membrane phospholipids of alveolar macrophages in pulmonary sarcoidosis and diffuse interstitial pulmonary fibrosis

Alveolar macrophage plays an important role in alveolitis pathogenesis and lung fibrosis process. Macrophages exhibit plasmic membrane biochemical modifications during cell activation. Phospholipid methylation is involved during plasmic membrane stimulation. Phosphatidylethanolamine methyltransferase I was measured in alveolar macrophage membrane from normal subjects and patients presenting with pulmonary sarcoidosis or interstitial lung fibrosis. We observed increased enzyme activity among sarcoidosis subjects with high intensity lung alveolitis and normal subjects receiving immunostimulating treatment (RU 41740). The role of membrane phospholipidic modifications in granulomatous process is discussed.     

Dendritic cells in muscle lesions of sarcoidosis

Sarcoidosis is a chronic systemic granulomatous disorder of unknown etiology. The precise mechanism by which granulomatous lesions form is still obscure. Dendritic cells (DCs) are the most efficient antigen presenting cells; however, pathologic investigations of dendritic cells in the affected lesions of sarcoidosis are quite limited. We immunohistochemically examined the localization and phenotypes of dendritic cells and the expressions of CD40 and CD40L (CD154), which are key molecules in dendritic cell activation, in the muscles of 5 patients with muscular sarcoidosis, 8 patients with muscular disorders without inflammation, and 4 patients with histologically normal muscles as controls. In muscular sarcoidosis, CD1c-positive myeloid dendritic cells were scattered mainly in the lymphocyte layers of granulomas and the endomysium around the granulomas. Double immunostaining revealed that some CD1c-positive cells expressed the mature dendritic cell marker CD83, but immature dendritic cell marker CD1a-positive cells were not found. Smaller numbers of Blood dendritic cell antigen (BDCA)-2-positive plasmacytoid dendritic cells were found in the lymphocyte layers of granulomas. In the controls, small numbers of CD1c-positive cells were seen in the endomysium, whereas BDCA-2-positive cells were not observed except in 1 case. In muscular sarcoidosis, CD40 was expressed on mononuclear cells, on the interstitium around the muscle fibers and granulomas, and on the endothelium of vessels. CD40L was positive on mononuclear cells scattered within and around granulomas in 3 of 5 patients. In the controls, CD40 was expressed on the endothelium of the vessels and sparse mononuclear cells in the lesions of muscle fiber necrosis, whereas CD40L was not seen in any. In muscular sarcoidosis, recruitment of myeloid dendritic cells and less plasmacytoid dendritic cells and up-regulation of the CD40/CD40L system in affected muscles suggest that myeloid dendritic cells may be mainly involved in granulomatous inflammation through antigen presentation in a Th1 immune milieu.     

Histochemical heterogeneity of human mast cells: disease-related differences in mast cell subsets recovered by bronchoalveolar lavage.

Fixation and staining characteristics were studied for mast cells recovered by bronchoalveolar lavage from 67 patients being investigated for lung disease. The number of toluidine blue stained mast cells in formaldehyde-fixed cytocentrifuge preparations was consistently less than in specimens fixed in Carnoy's solution, though the counts were highly dependent on the period of fixation or staining. The cellular histamine content closely correlated with total mast cell numbers in bronchoalveolar lavage fluid, but was not related to the relative proportions of mast cells which were sensitive or resistant to formaldehyde fixation when using a standard protocol. Compared with normal subjects, the numbers of formaldehyde-sensitive mast cells were significantly elevated in patients with bronchial carcinoma, sarcoidosis, extrinsic allergic alveolitis, cryptogenic fibrosing alveolitis, and mycobacterial infection and were particularly high in the cases of interstitial lung disease. An even greater increase in numbers of formaldehyde-resistant mast cells was observed in the patients with sarcoidosis and extrinsic allergic alveolitis. The associations of these mast cell subsets with disease may reflect relationships between the expansion of the formaldehyde-sensitive population and lymphocyte infiltration and between proliferation of formaldehyde-resistant mast cells and tissue fibrosis.     

Antibodies in some chronic fibrosing lung diseases

Autoantibodies to nuclear and cytoplasmic constitutents and to denatured γ-globulin have been studied in patients with different types of chronic fibrosing lung disease. The prevalence of these antibodies is increased in cryptogenic fibrosing alveolitis but the incidence in extrinsic allergic alveolitis is similar to previous published reports on random populations and a control group included in this series of asbestos workers with normal chest radiographs. In asbestosis there was a lesser increase in ANF and rheumatoid factors but no significant increase in antibodies to cytoplasmic constituents. No evidence of organ-specific autoantibodies to lung have been demonstrated in any group. The presence of non organ-specific autoantibodies cannot necessarily be attributed to a non-specific consequence of all types of chronic destructive pulmonary fibrosis because of their differential distribution in different lung diseases. Because ANF and RF but not precipitins to organic dust are positive in some 60% of patients with cryptogenic fibrosing alveolitis, and precipitins but not autoantibodies are found in chronic extrinsic allergic alveolitis, tests for these two groups of antibodies are complementary in the investigation of patients with widespread chronic radiographic shadows. Tissue antibodies were absent in 40% of patients with cryptogenic fibrosing alveolitis and a more detailed search for other types of antigen should be made in these cases.     

Acute inhibition of nitric oxide exacerbates airway hyperresponsiveness, eosinophilia and C-C chemokine generation in a murine model of fungal asthma

OBJECTIVE AND DESIGN: This study examined the role of nitric oxide in changes in airway physiology and inflammation in a murine model of fungal allergy induced by Aspergillus fumigatus (A. fumigatus) by treatment of A. fumigatus-sensitized mice with NG-nitro-L-arginine methyl ester (L-NAME) or D-NAME (8 mg/kg; i.p.). MATERIALS AND METHODS: Female CBA/J mice received A. fumigatus antigen dissolved in incomplete Freund's adjuvant (10 mg/100 ml i.p. and s.c.) followed 2 weeks later by A. fumigatus antigens (20 mg; i.n.) and a subsequent i.t. challenge 4 days later. Airway physiology and inflammation were examined (24 to 72 h) following i.t. challenge. RESULTS: L-NAME-treated mice had lower lung nitrite levels 24 h after A. fumigatus challenge, but higher airway hyperresponsiveness and inflammation compared to D-NAME controls. Airway inflammation in the L-NAME treatment group (72 h) was characterized by a greater bronchoalveolar lavage (BAL), peribronchial eosinophilia and augmented levels of CC chemokines compared to controls. CONCLUSIONS: These findings suggest that nitric oxide is an important modulator of airway hyperresponsiveness, inflammation and C-C chemokine generation during allergic airway responses to A. fumigatus.     

Takes your breath away--the immunology of allergic alveolitis

Extrinsic allergic alveolitis (synonym: hypersensitivity pneumonitis) is caused by inhaling antigenic aerosols which induce hypersensitivity responses in susceptible individuals. It is an interstitial inflammatory disease affecting the distal, gas-exchanging parts of the lung, in contrast to allergic asthma where the inflammation is more proximal, affecting the conducting airways. The aims of this review are to describe current concepts of the immunology of this model of lung inflammation, to describe some of the constitutional and environmental characteristics which affect disease susceptibility and development, and to describe topics for prospective study.     

Increased hyaluronan (hyaluronic acid) levels in bronchoalveolar lavage fluid after histamine inhalation

Hyaluronan (hyaluronic acid) appears in low concentrations in bronchoalveolar lavage fluid from healthy individuals, while increased amounts have been reported in lavage fluid from patients with interstitial lung diseases and allergic asthma. We have earlier reported a strong correlation between the appearance of lavage fluid mast cells and hyaluronan in patients with sarcoidosis and extrinsic allergic alveolitis. The central role of the mast cell in allergic asthma is well documented. In this study we have investigated if challenge with inhaled histamine, a major mast cell component, could influence the appearance of hyaluronan in bronchoalveolar lavage fluid. A more than twofold increase of hyaluronan was seen 24 h after challenge with histamine. This increase correlated with a less pronounced increase of albumin in lavage fluid. Histamine challenge also induced an increase of mast cells, lymphocytes, and granulocytes in the lavage fluid. The observed histamine effect on the hyaluronan recovery during lavage might be explained by a histamine-mediated leakage of interstitial fluid, rich in hyaluronan, to the alveolar space. Mast cell degranulation of histamine may partly underlie the appearance of increased amounts of hyaluronan in lavage fluid from patients with interstitial lung diseases and allergic asthma.     

In vivo responses to inhaled proteins. II. Induction of interstitial pneumonitis and enhancement of immune complex-mediated alveolitis by inhaled concanavalin A.

An animal model of environmental lung disease is described in which phytomitogen, antigen, or both, are administered in aerosol form to previously immunized or immunologically naive rabbits. Inhalation of concanavalin A alone induced an interstitial pneumonitis in nonimmunized rabbits. Inhalation of concanavalin A alone induced an interstitial pneumonitis in nonimmunized rabbits. Inhalation of bovine serum albumin (BSA) alone typically produced only focal eosinophilic granulomas in BSA-immunized animals, and no injury whatever in nonimmune animals. However, simultaneous administration of BSA-concanavalin A aerosol mixtures to BSA-immunized rabbits induced a severe interstitial pneumonitis and granulomatous vasculitis, together with areas of frank parenchymal necrosis. When repeated on a chronic basis over a 4- or 8-week interval, challenge with BSA-concanavalin A aerosols resulted in both acute necrotic lesions as well as areas of frank interstitial fibrosis. Necrotic foci in acutely injured lungs were associated with interstitial deposits of BSA, rabbit anti-BSA antibody, and complement. Electron microscopy revealed numerous neutrophils within the pulmonary interstitial spaces of these animals, often in association with collagen and elastin fibers. The pattern of injury in immune rabbits induced by antigen-concanavalin A aerosols, in its nonnecrotizing form, is consistent with that of an extrinsic allergic alveolitis. However, the severe, necrotizing form of acute injury closely resembles changes seen in Wegener's granulomatosis. Possible mechanisms of injury produced by antigen and phytomitogen inhalation are discussed.     

Selective suppression of granuloma formation and delayed hypersensitivity in rabbits

The relationship between dermal delayed hypersensitivity (DH) and granulomatous hypersensitivity was studied in rabbits sensitized with killed mycobacteria. Specific antigen challenge of sensitized animals resulted in extensive pulmonary granulomatous inflammation and induced suppression of both dermal DH and dermal granuloma formation. Whereas suppression of DH was concomitant with pulmonary granuloma formation, as is the case in a number of granulomatous diseases, a causal relationship between the two did not exist. Both DH and dermal granulomatous hypersensitivity were significantly suppressed whether or not the antigen challenge was of a granulomagenic (particulate) or nongranulomagenic (soluble) form. The data presented indicate that granulomatous hypersensitivity and DH are selectively suppressed with regard to different anatomical sites.     

Immunomodulation by Corynebacterium parvum. 1. Variable effects on anti-sheep erythrocyte antibody responses.

Corynebacterium parvum injected i.p. 1--16 days prior to i.p. antigen inoculation virtually abolished both IgM and IgG primary responses to 1 X 10(8) SRBC. The suppression was significantly marked at antigen doses ranging from 1 X 10(6)--1 X 10(9) SRBC but not at 5 X 10(9) SRBC. As little as 56 microgram C. parvum caused a marked suppression of the response to 1 X 10(8) SRBC. In secondary responses C. parvum given either one day before priming with 1 X 10(8) SRBC or one day before secondary challenge caused a dramatic suppression of both IgM and IgG PFC responses. In contrast with i.p. injected C. parvum, i.v. injection of the vaccine enhanced immune responses to i.p. or i.v. injected SRBC. Similarly C. parvum injected i.p. prior to i.v. immunization resulted in an augmented anti-SRBC response. An enhancement of anti-SRBC response was also noted when C. parvum was injected i.p. on the day of i.p. immunization. The suppressed responses in C. parvum injected animals could be explained partly by the reduced splenic localization of the antigen.     

Functional disturbances in patients with interstitial lung diseases without signs of restriction

Restriction is a typical functional abnormality in interstitial lung diseases (ILD) patients but not all of them represent this pattern. The aim of this study was to evaluate 164 patients with ILD in whom normal lung volumes (FVC and TLC > 80% predicted) were found. There were 111 patients with sarcoidosis (phase I--9, II--77, III--25 patients), 25 patients with pulmonary fibrosis, 12 patients with allergic alveolitis and 16 patients with disseminated radiological changes in the lungs of different etiology. Some patients (40%), mostly with fibrosis and allergic alveolitis, were treated with corticosteroids. Measured parameters included static compliance (Cst), transfer factor for CO (TLco and Kco) and maxima expiratory flow-volume curves (MEF50). 33% of patients had all examined functional parameters in normal range, 50% had decreased maximal expiratory flows (particularly in the sarcoidosis group), 46% decreased Cst and 24% decreased transfer factor. Decreased Cst was found in 31% of patients with sarcoidosis, in 67% of patients with allergic alveolitis and in 96% of patients with lung fibrosis. Decreased TLco or Kco was found only in 11% of patients with sarcoidosis, in 42% of patients with allergic alveolitis and in 60% of patients with pulmonary fibrosis. It seems that, these discussed tests are very helpful in detecting functional abnormalities in patients with ILD without signs of restriction. Increased lung elasticity and decreased transfer factor for CO indicate the existence of early or presisting functional disturbances (despite treatment) in patients with ILD and normal lung volumes.     

Pathomorphology of the lungs and microcirculatory bed of the lesser circulation in chronic experimental allergic alveolitis

Granulomatous lung lesions were produced in rats by 5 intravenous or intratracheal injections of the killed BCG suspension as an antigen. On the basis of immunocomplex and cell-mediated immunopathological reactions this condition may be considered as a chronic allergic form of alveolitis. Granulomas were formed along the arteries when the antigen was administered intravenously and along the bronchi after its intratracheal administration. In both cases there were single granulomas in the alveolar septa interstitium. The microcirculatory bed was studied in semithin sections and morphometrically in thick sections after impregnation with an Indian ink and 5% gelatin. The alveolar septa capillaries in control rats were shown to form a network the parameters ow which rather correspond to the "sheet-blow" model (Fung and Sobin, 1969). In chronic allergic alveolitis, a reduction of the capillary network develops at the zone of granulomatous inflammation while in the relatively normal zone a network type of the microcirculatory bed is preformed into the main one with the formation of predominant routes of circulation that provide the blood filling of the heart cavities.     

The route of antigen delivery determines the airway and lung tissue mechanical responses in allergic rats.

BACKGROUND: Previous results have shown tissue constriction in allergic animals following inhalation of an antigen. Further studies have demonstrated a differing response pattern in airway and parenchymal mechanics following inhaled (i.h.) or intravenous (i.v.) delivery of methacholine (MCh). OBJECTIVE: The purpose of this study was to compare the acute allergic response in airway and parenchymal mechanics following i.h. and i.v. antigen challenge. METHODS: Brown Norway rats were sensitized to ovalbumin (OVA). Rats were anaesthetized, paralysed, and thoracotomized, and lung input impedance (ZL) between 0.5 and 21 Hz was measured using small-amplitude pseudo-random oscillations at control, after saline, and for up to 1 h after either i.h. (n = 7) or i.v. (n = 5) administration of OVA. ZL was evaluated in terms of airway resistance (Raw) and inertance (Iaw), and a constant phase tissue parenchymal damping (G) and elastance (H). RESULTS: Following i.h. OVA challenge elevations were found in Raw [192 +/- 32 (SE) %], G (223 +/- 21%), and H (141 +/- 5%). Raw showed higher elevation after i.v. challenge (418 +/- 57%), whereas the elevation in G (278 +/- 30%) and H (130 +/- 4%) was approximately equal to those seen following inhalation of an antigen. CONCLUSIONS: Delivery (i.v.) of an antigen produces a significantly higher response in airway resistance, whereas inhaled antigen results in a mixed airway and parenchymal response.     

HLA-A, B, C and HLA-DR antigens in extrinsic allergic alveolitis (budgerigar fancier's lung disease)

Twenty-three patients with extrinsic allergic alveolitis due to an allergy to inhaled budgerigar serum protein (budgerigar fancier's lung disease) were typed for HLA-A, B, C and HLA-DR antigens. Antigen frequencies were compared with those found in 154 healthy control subjects. No statistically significant variation in the frequency of any HLA antigen was detected. Exclusion of two patients who had concurrent coeliac disease, and subdivision of the population into those with acute and chronic disease, failed to reveal any significant association with an HLA specificity. A non-significant increase in B8-DR3 amongst the patients with acute disease was noted. Possible reasons for the apparent HLA associations previously reported by others for extrinsic allergic alveolitis are discussed.     

Macrophages are necessary for maximal nuclear factor-kappa B activation in response to endotoxin

To define the role of macrophages in regulating the lung's response to Escherichia coli endotoxin (lipopolysaccharide [LPS]), depletion of macrophages was accomplished by administration of dichloromethylene diphosphonate (clodronate) delivered via intratracheal (i.t.) and/or intravenous (i.v.) routes. Clodronate reduced the number of macrophages in lung lavage 48 h after either i.t. or i.v. administration, but combined i.t. + i.v. clodronate achieved the most profound depletion (90%). Although i.t. clodronate alone had little effect on the evolution of lung inflammation, combined i.t. + i.v. clodronate treatment decreased neutrophilic alveolitis 4 h after exposure to aerosolized LPS by 80% compared with mice treated with empty liposomes. This decrease was associated with impaired activation of nuclear factor (NF)-kappa B and lower concentrations of tumor necrosis factor (TNF)-alpha in lung lavage fluid. Combined i.t. + i.v. clodronate markedly reduced lung NF-kappa B activation and the intensity of neutrophilic alveolitis after intraperitoneal (i.p.) LPS; however, i.v. clodronate alone had no effect on NF-kappa B activation in either liver or lung tissue or the development of neutrophilic alveolitis. We conclude that generalized macrophage depletion reduces NF-kappa B activation, generation of cytokines, and neutrophilic lung inflammation in response to gram negative bacterial endotoxin. These findings define the role of the macrophage as a critical component for initiation of the NF-kappa B-dependent innate immune response.     

Transbronchial biopsy in the diagnosis of sarcoidosis and certain other interstitial lung diseases

Results of transbronchial pulmonary biopsy studies of patients of different sex and age suffering from interstitial pulmonary lesion are presented. Different diagnostic value of transbronchial pulmonary biopsy (TBBP) is shown in relation to different lesions. In case of sarcoidosis its informative value, for example, is high, while in the diffuse processes such as cryptogenic fibrosing alveolitis, the data allow only suggestive diagnosis and recommendation of an open lung biopsy. In chronic nonspecific pulmonary diseases TBBP helps to clarify the character and the activity of the process involved. In some cases it is possible to reveal a latent cancer. It is suggested to use the term "allergic alveolitis" (indicating the mechanism of development of changes mentioned) when such changes as alveolitis, small granulemas and intraalveolar outgrowths are found in the biopsy specimens.     

The anti-inflammatory activity of intal and beta-carotene in a model of experimental granulomatous lung inflammation

A-25 sephadex-induced granulomatous inflammation of the lungs in rats was treated with beta-carotene and intal in inhalations. Both drugs showed antiinflammatory activity reducing the area of alveolitis and emphysema in the lungs, number of neutrophils and lymphocytes in the bronchoalveolar fluid. The experimental data allow to recommend further trial of intal and beta-carotene in granulomatous pulmonary diseases.