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In common variable immunodeficiency, lung manifestations are related to different mechanisms: recurrent pneumonias due to encapsulated bacteria responsible for diffuse bronchiectasis, diffuse infiltrative pneumonia with various patterns, and lymphomas, mostly B cell extranodal non-Hodgkin type. The diagnosis relies on significant serum Ig deficiency and the exclusion of any primary or secondary cause. Histopathology may be needed. Immunoglobulin (IgG) replacement is crucial to prevent infections and bronchiectasis. IgG4-related respiratory disease, often associated with extrapulmonary localizations, presents with solitary nodules or masses, diffuse interstitial lung diseases, bronchiolitis, lymphadenopathy, and pleural or pericardial involvement. Diagnosis relies on international criteria including serum IgG4 dosage and significantly increased IgG4/IgG plasma cells ratio in pathologically suggestive biopsy. Respiratory amyloidosis presents with tracheobronchial, nodular, and cystic or diffuse interstitial lung infiltration. Usually of AL (amyloid light chain) subtype, it may be localized or systemic, primary or secondary to a lymphoproliferative process. Very rare other diseases due to nonamyloid IgG deposits are described. Among the various lung manifestations of dysregulated states of humoral immunity, this article covers only those associated with the common variable immunodeficiency, IgG4-related disease, amyloidosis, and pulmonary light-chain deposition disease. Autoimmune connective-vascular tissue diseases or lymphoproliferative disorders are addressed in other chapters of this issue., (© 2017 S. Karger AG, Basel.)

Sarcoidosis is a systemic disease, with lung involvement in almost all cases. Abnormal chest radiography is usually a key step for considering diagnosis. Lung impact is investigated through imaging; pulmonary function; and, when required, 6-minute walk test, cardiopulmonary exercise testing, or right heart catheterization. There is usually a reduction of lung volumes, and forced vital capacity is the most accurate parameter to reflect the impact of pulmonary sarcoidosis with or without pulmonary infiltration at imaging. Various evolution patterns have been described. Increased risk of death is associated with advanced pulmonary fibrosis or cor pulmonale, particularly in African American patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The 1930 International Labour Office Conference on silicosis in Johannesburg was a turning point in the history of silicosis and in the recognition of the associated pathologic patterns. Since 1930, pneumoconioses such as silicosis have become much rarer in developed countries and can now be diagnosed at an early stage based on clinical and radiologic criteria. However, in spite of these advances, pathologists must remember to look for silica in tissues, particularly when clinical and radiologic findings are more uncertain. Furthermore, nowadays pathologists essentially observe silicotic lesions as incidental findings adjacent to lung cancers. In addition to identifying the characteristic lesions, pathologists must also try to identify their causative agent, in the case of crystalline silica firstly by using polarized light examination, followed as appropriate by more sophisticated devices. Finally, pathologists and clinicians must always keep in mind the various implications of exposure to silica compounds in a wide range of diseases., (© 2015 Wiley Periodicals, Inc.)

Accidental exposure by inhalation to alpha-emitting particles from mixed oxide (MOX: uranium and plutonium oxide) fuels is a potential long-term health risk to workers in nuclear fuel fabrication plants. For MOX fuels, the risk of lung cancer development may be different from that assigned to individual components (plutonium, uranium) given different physico-chemical characteristics. The objective of this study was to investigate late effects in rat lungs following inhalation of MOX aerosols of similar particle size containing 2.5 or 7.1% plutonium. Conscious rats were exposed to MOX aerosols and kept for their entire lifespan. Different initial lung burdens (ILBs) were obtained using different amounts of MOX. Lung total alpha activity was determined by external counting and at autopsy for total lung dose calculation. Fixed lung tissue was used for anatomopathological, autoradiographical, and immunohistochemical analyses. Inhalation of MOX at ILBs ranging from 1-20 kBq resulted in lung pathologies (90% of rats) including fibrosis (70%) and malignant lung tumors (45%). High ILBs (4-20 kBq) resulted in reduced survival time (N = 102; p < 0.05) frequently associated with lung fibrosis. Malignant tumor incidence increased linearly with dose (up to 60 Gy) with a risk of 1-1.6% Gy for MOX, similar to results for industrial plutonium oxide alone (1.9% Gy). Staining with antibodies against Surfactant Protein-C, Thyroid Transcription Factor-1, or Oct-4 showed differential labeling of tumor types. In conclusion, late effects following MOX inhalation result in similar risk for development of lung tumors as compared with industrial plutonium oxide.

Adenocarcinomas (AC), squamous cell carcinomas (SCC) and adenosquamous carcinomas (ASC) are three histological subtypes of non-small-cell lung carcinomas (NSCLC). ASC are morphologically mixed tumours that contain the two cell components AC and SCC. To understand if they are a "simple" mix of AC and SCC or if they present molecular specificities, as compared with the molecular characterization of both components, we performed a comparative transcriptome analysis on a series of nine ASC, five AC and five SCC induced in rats by radon exposure. We found that 72, 40 and 39 genes were differentially expressed when comparing AC&#95;SCC, ASC&#95;SCC and AC&#95;ASC, respectively. Moreover, when classifying the three histological subtypes, using genes that discriminated AC and SCC, we observed that all ASC were classified as intermediate between the AC and SCC, some being closer to AC, others to SCC. These results indicated that, regarding gene expression, ASC could be considered as a mix of AC and SCC, both in various proportions. However, they also exhibit molecular specificities since we found specific genes discriminating ASC&#95;SCC and AC&#95;ASC. In conclusion, the ASC mixed lung tumours are more complex than simple mixes of AC and SCC components. Neuroendocrine differentiation and ERK proliferation pathways seemed preferentially deregulated in ASC compared to AC and SCC respectively, pathways that are worthy of being explored because they could partially explain the high clinical aggressiveness of ASC., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

It has been assumed for a long time that except for limited areas close to respiratory bronchioles or their satellite arteries, there is no evidence of lymphatic vessels deep in the pulmonary lobule. An immunohistochemical study using the D2-40 monoclonal antibody was performed on normal pulmonary samples obtained from surgical specimens, with particular attention to the intralobular distribution of lymphatic vessels. This study demonstrated the presence of lymphatics not only in the connective tissue surrounding the respiratory bronchioles but also associated with intralobular arterioles and/or small veins even less than 50 mum in diameter. A few interlobular lymphatic vessels with a diameter ranging from 10 mum to 20 mum were also observed further away, in interalveolar walls. In conclusion, this study, using the D2-40 monoclonal antibody, demonstrated the presence of small lymphatic channels within the normal human pulmonary lobules, emerging from interalveolar interstitium, and around small blood vessels constituting the paraalveolar lymphatics. This thin intralobular lymphatic network may play a key pathophysiological role in a wide variety of alveolar and interstitial lung diseases and requires further investigation.

The inter-alpha-trypsin inhibitor (ITI) family is a group of plasma proteins built up from heavy (HC1, HC2, HC3) and light (bikunin) chains synthesized in the liver. In this study we determined the distribution of ITI constitutive chains in normal and cancerous lung tissues using polyclonal antibodies. In normal lung tissue, H2, H3, and bikunin chains were found in polymorphonuclear cells, whereas H1 and bikunin proteins were found in mast cells. Bikunin was further observed in bronchoepithelial mucous cells. In lung carcinoma, similar findings were obtained on infiltrating polymorphonuclear and mast cells surrounding the tumor islets. Highly differentiated cancerous cells displayed strong intracytoplasmic staining with H1 and bikunin antiserum in both adenocarcinoma and squamous cell carcinoma. Moreover, weak but frequent H2 expression was observed in adenocarcinoma cells, whereas no H3-related protein could be detected in cancer cells. Local lung ITI expression was confirmed by RT-PCR. Although the respective role of inflammatory and tumor cells in ITI chain synthesis cannot be presently clarified, these results show that heavy chains as well as bikunin are involved in malignant transformation of lung tissue.(J Histochem Cytochem 47:1625-1632, 1999)

For diagnostic purposes, mineralogical analysis was performed in bronchoalveolar lavage fluid and lung tissue from a 58-year-old patient previously exposed to asbestos and rare earth dusts. No significant retention of asbestos was demonstrated in lung tissue by light microscopy (asbestos bodies) or transmission electron microscopy analysis (uncoated fibers). Particles containing rare earth (cerium, lanthanum) and phosphorus were identified in alveolar macrophages in bronchoalveolar lavage fluid, and cerium-containing particles accounted for 70% of particles observed in the lung tissue. Ultrastructural analysis of lung tissue revealed the presence of particles containing cerium and phosphorus in interstitial macrophages and elastic fibers. These results suggest that rare earth is metabolized and should be considered as biopersistent in the human respiratory tract, since occupational inquiries revealed that exposure to cerium oxide abrasive powder had ceased at least 15 years earlier.

To evaluate the incidence of air-blood barrier lesions in the course of chronic interstitial lung diseases, we studied by electron microscopy open lung biopsy specimens from patients with sarcoidosis or chronic hypersensitivity pneumonitis, and compared the distribution of ultrastructural air-blood barrier lesions (including swelling or destruction of epithelial and endothelial cells, type II cell hyperplasia, and basement membrane disruption) with the type of histopathologic abnormalities present (including inflammation, inflammation and fibrosis, or fibrosis alone). Ultrastructural lesions of the air-blood barrier were frequently observed in sarcoidosis as well as hypersensitivity pneumonitis. Their nature and distribution were highly dependent on the histologic pattern of lung tissue in which they were present: epithelial and/or endothelial injury was more frequently observed in inflammatory areas (90 to 100% of all lung specimens displaying inflammation alone), whereas type II cell hyperplasia was mainly identified in fibrotic tissues (83 to 100% of all lung specimens displaying fibrosis alone). Strikingly, in lung tissue considered as normal by light microscopy, air-blood barrier was frequently found to be damaged (50 to 62% of apparently normal lung specimens), suggesting that alveolar lesions may constitute an early phenomenon in the course of pulmonary inflammatory processes. The air-blood barrier alterations observed in this study may provide an anatomic basis for the modifications of alveolar permeability described in pulmonary sarcoidosis and hypersensitivity pneumonitis.

Calbindin-D9K (CaBP9K) is classically considered to be the molecular expression of 1,25-dihydroxyvitamin D3. The hormone is known to regulate the rat CaBP9K gene in duodenal tissue at transcriptional and posttranscriptional levels. This study shows that the CaBP9K gene is expressed in the rat lung, and that this expression is probably not vitamin D- or estrogen-dependent. The CaBP9K gene is not expressed in alveolar macrophages, but CaBP9K messenger RNA (mRNA) was localized by in situ hybridization in alveolar epithelial cells. CaBP9K mRNA was detected as early as the 20th day of gestation. The quantity of CaBP9K mRNA gradually increased during growth, from 1-77 days after birth, whereas the CaBP9K concentration dramatically increased from day 19 to day 20 of gestation. Vitamin D-deficient male rats (8 weeks old) were given a single injection of 1,25-dihydroxyvitamin D3 (650 pmol/100 g body wt) and killed 1 h and 24 h after injection. The hormonal treatment resulted in a rise in duodenal CaBP9K mRNA, but no significant change in lung extracted CaBP9K mRNA. Mature ovariectomized rats were injected with 17 beta-estradiol (0.5 microgram/100 g body wt) and killed 24, 48, and 72 h later. The CaBP9K mRNA concentration in the uterus was markedly dependent on estrogen; that of the lung was not. The factors regulating the CaBP9K gene expression in the lung remain to be determined.

The pulmonary toxicity of antineoplastic drugs may be either direct or mediated by hypersensitivity. The aim of this study was to determine whether the mechanism by which cyclophosphamide (CY) damages the lung is direct and immediate or is the result of delayed immune toxicity. Pulmonary and immune changes following intraperitoneal injection of either CY (50 mg/kg) or NaCl (0.9%) in rats were assessed repeatedly over a period of 31 days by semi-quantitative histological studies, by measuring the pulmonary water/body weight ratio, dry lung weight/body weight ratio, heart weight and by assessing the transfer of [125I]-albumin in lung tissue. Lung damage was delayed and greatest at 11 (D11) and 14 (D14) days after CY injection. The pulmonary lesions were: (i) an infiltration of lymphocytes, plasma cells and histiocytes surrounding blood vessels and small airways, (ii) an alveolitis composed of macrophages, lymphocytes, a few neutrophils and a lymphoid infiltration of alveolar septa. Pulmonary water/body weight and dry lung weight/body weight ratios also increased and peaked at D11-D14 in CY-treated rats. No significant increase in [125I]-albumin in lung tissue or in heart weight was observed. It can be concluded that the mechanism by which CY induces a lymphoid lung infiltration is not direct and immediate but is the result of a delayed immune toxicity.

Pneumocystis carinii (PC) has been recognized as frequently responsible for most opportunistic pulmonary infections occurring in immunocompromised AIDS and non-AIDS patients. Moreover, these patients can be considered at risk for secondary pulmonary alveolar proteinosis. Therefore, we have investigated the occurrence of associated secondary alveolar proteinosis and PC pneumonitis in AIDS and non-AIDS immunocompromised patients. In a series of 26 bronchoalveolar lavages (BAL) in patients with PC pneumonitis (19 AIDS and seven non-AIDS patients), we observed on light microscopy, in addition to the honeycombed material, areas of an extracellular material that had a different pattern which was suggestive of that described in alveolar proteinosis. A systematic ultrastructural study of these 26 BAL fluid samples demonstrated in each of them an accumulation of phospholipid surfactantlike extracellular material mixed or not with the PC cysts. In nine cases, the observation of lipoproteinaceous material on light microscopy and abundant phospholipid material with myelinlike and myelin tubular laminated structures on electron microscopy was highly suggestive of an associated pulmonary alveolar proteinosis (PAP). Such an accumulation of extracellular material was not observed in the 11 BAL fluid samples collected in immunocompromised patients (seven AIDS and four non-AIDS patients) without PC pneumonitis. These findings demonstrated a particular frequency of associated PAP with PC pneumonitis. These results raise important questions concerning (1) the consequence of such an alveolar accumulation of lipoproteinaceous material on the clinical status and prognosis of the pneumonitis, and (2) the mechanisms responsible for this accumulation.

The case reported concerned a patient 44 years old, affected by a systemic lupus erythematosus for 18 years and admitted for an acute respiratory distress due to a bronchopulmonary infection. After this episode an interstitial chronic lung disease is diagnosed (reticulonodular pattern on the chest X-ray, functional restrictive syndrome). The study of the transbronchial lung biopsy by electron microscopy revealed interstitial electron dense deposits. This observation focussed on the interest of this technic of morphological study mainly in chronic lung interstitial diseases.

The rat and guinea pig are widely used in experimental models dealing with immuno allergic bronchoreactivity. The present study was designed to compare the distribution and heterogeneity of the mast cell population in the respiratory tract of the Sprague-Dawley rat and Hartley guinea pig. Mast cells were identified according to the sequential Alcian blue/safranin O staining method. From the trachea to the peripheral conductive airways, the density of mast cells increased in the guinea pig whereas it decreased in the rat. Although mast cells were observed in the interalveolar septa of the guinea pig, none were found in the rat. In the lung of the rat, three types of mast cells were observed: in the wall of the trachea and large bronchi, safranin-positive, mixed and Alcian-blue-positive mast cells were found, whereas only Alcian-blue-positive mast cells were observed in the small conductive airways. In contrast, only Alcian-blue-positive mast cells were observed in the lung of the guinea pig. These results show that the types and localization of the mast cell populations are distinctly different in these two species. Consequently, experimental models of bronchoreactivity in these species are testing different cellular systems.

The permeability of the blood-air barrier to antiperoxidase (HRP) IgG antibodies (160,000 daltons), F(ab')2 fragments (100,000 daltons) and Fab fragments (50,000 daltons) was studied in the normal rat. The use of isologous and heterologous immunoglobulin G or IgG fragments injected intravenously allowed a sequential study. It was shown that these proteins transfer from the vascular bed towards to interstitium. Evidence was obtained that these proteins crossed the endothelium through interendothelial spaces or structures suggesting transendothelial channels. The alveolar epithelium was found to be an efficient barrier for heterologous and isologous proteins, raising the question of the origin of serum proteins found in the alveolar surface material. Heterologous anti-HRP IgG antibodies and their Fab fragments were also administered intraalveolarly. The alveolar epithelium was found permeable to Fab fragments but not to IgG molecules, suggesting that some serum proteins present in the alveolar lining fluid can be transepithelially reabsorbed.

Paraquat intoxication in both the initial and late stages is responsible for a decrease in lung volumes and lung elasticity. In this study, we tried to separate these two stages with analysing the quasi-static pressure-volume curves (P-V) obtained both during inflation and deflation of the lungs. Three groups of rats were studied: group I: control (n = 9), group II: 11 animals studied 48 h after intraperitoneal injection of paraquat (24 mg X kg-1), group III: 6 animals studied 9 days after the administration of paraquat. Groups II and III, when compared to group I, were characterized by a significant decrease of 1) functional residual capacity (p less than 0.001), 2) the lung volume obtained for a 3 kPa distending pressure, and 3) the slope of the P-V curve during deflation (p less than 0.001). In group II, there was a clear increase in the hysteresis of the P-V loop due to an inflection of the inflation P-V limb. Such a shape is the only characteristic of the P-V curves which separates groups II and III. By contrast, the P-V curve during deflation, even when analysed with an exponential fitting, does not separate these two groups which were clearly different in their morphological aspect: alveolar edema (group II), interstitial pneumonitis (group III).

Immunization of rabbits with soluble elastin peptides (kappa 1-elastin) in complete Freund's adjuvant resulted in morphological and biochemical modifications in aorta and in lung arterioles. The elastic fibers of both tissues appeared fragmented at the light microscopical and ultrastructural levels. The presence of IgG at the site of lysed elastic fibers could be evidenced by immunological techniques. In agreement with these findings, a significantly increased elastase-type protease activity could be demonstrated in aorta extracts from the immunized animals as compared to those obtained from control animals. The biosynthetic activities of aorta explants of rabbits immunized with kappa 1-elastin maintained in organ culture conditions were considerably reduced, as shown by the decrease of incorporation of [14C]lysine and [14C]glucosamine in aorta macromolecules. These results show that anti-elastin antibodies may well be involved in the pathological modifications of the arterial wall and especially in the triggering of the degradation of elastic lamellae.

Following the intravenous injection of complete Freund's adjuvant, changes in the rat lung were studied with the electron microscope. Interstitial granulomas were produced and whereas on light microscopy these appeared to consist mainly of epitheloid cells, electron microscopy showed that the granulomas were largely made up of macrophages. Epithelioid cells were in fact few in number, atypical in appearance and limited to the periphery of some granulomas. Fenestrated capillaries were also found at the edge of the granulomas. The alveolar macrophages were increased in number and size but marked cytoplasmic vacuolation and a paucity of lysosomes are consistent with our previous suggestion that the phagocytic and migratory properties of these cells are weakened or inhibited. Alterations were found in both types of alveolar epithelial cell with the appearance of intermediate cell forms.

Langerhans' cells are a defined subpopulation of the mononuclear phagocyte system known to accumulate in the lung in histiocytosis X, an interstitial lung disorder strongly linked to cigarette smoking. To evaluate the hypothesis that cigarette smoking itself may be associated with the accumulation of Langerhans' cells in the lung, normal nonsmokers (n = 5) and normal smokers (n = 10) were evaluated by bronchoalveolar lavage for the presence of Langerhans' cells as identified by the OKT6 monoclonal antibody and by transmission electron microscopy. While the OKT6 antibody identified 0.1 +/- 0.1% of the cells recovered from nonsmokers, it labeled 1.1 +/- 0.3% of those recovered from smokers (p less than 0.01). Furthermore, while electron microscopy demonstrated no Langerhans' cells among the lavage cells from nonsmokers, 0.4 +/- 0.1% of the cells recovered from normal smokers contained characteristic intracytoplasmic Birbeck granules, positively identifying them as Langerhans' cells. We conclude that cigarette smoking is associated with an expansion in the population of Langerhans' cells on the epithelial surface of the lower respiratory tract. While the mechanisms underlying this accumulation are unknown, it is possible that the properties of these cells contribute to the derangements of the pulmonary parenchyma found in cigarette smoking and establish a biologic link to the already observed epidemiologic association between histiocytosis X and cigarette smoking.

Serum macromolecules such as albumin or type G immunoglobulins are found in the film lining the alveolus, by virtue of techniques of broncho-alveolar lavage as well as demonstration by immunocytochemistry. Passage of such molecules may be studied experimentally by the use of tracers. Two barriers are found: a first at the level of the vascular endothelium which is relatively permeable and a second which is relatively impermeable at the site of the alveolar epithelium. Rupture of this barrier during non-hemodynamic oedema is responsible for massive passage of serum proteins to the alveolus, in particular of fibrinogen.