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Indium oxide (In2O3) is a technologically important semiconductor essentially used, doped with tin oxide, to form indium tin oxide (ITO). It is poorly soluble in all so far tested physiologic media. After repeated inhalation, In2O3 particles accumulate in the lungs. Their mobilization can cause significant systemic exposure over long periods of time. An increasing number of cases of severe lung effects (characterized by pulmonary alveolar proteinosis, emphysema and/or interstitial fibrosis) in workers of the ITO industry warrants a review of the toxicological hazards also of In2O3. The database on acute and chronic toxicity/carcinogenicity/genotoxicity/reproductive toxicity as well skin/eye irritation and sensitization is very limited or even lacking. Short-term and subchronic inhalation studies in rats and mice revealed persistent alveolar proteinosis, inflammation and early indicators of fibrosis in the lungs down to concentrations of 1 mg/m3. Epidemiological and medical surveillance studies, serum/blood indium levels in workers as well as data on the exposure to airborne indium concentrations indicate a need for measures to reduce exposure at In2O3 workplaces.

Introduction: Pulmonary alveolar proteinosis (PAP) is a diffuse pulmonary disease characterized by the intra-alveolar accumulation of formless, proteinaceous material. Lipids and proteins materials with specific staining appearance in the alveoli impair pulmonary gas transfer in PAP. The severity of this condition ranges from an asymptomatic clinical presentation to respiratory failure and death. PAP is an extremely rare disorder, occurring worldwide with an estimated prevalence of 0.1 per 100000 individuals. Although the pathogenesis of PAP has remained unknown, most investigators have considered this condition to be caused by the impaired clearance of lipids and surfactant proteins from the airspaces. These functions are known to be performed by alveolar macrophages and type 2 epithelial cells. It is likely that granulocyte macrophage-colony stimulating factor (GM-CSF) dysfunction on macrophages is responsible for PAP. Primarily, in most adult patients with PAP, antibodies against GM-CSF have been observed with dysfunction of macrophages. Secondly, alveolar macrophage dysfunction plays a role in the impaired secretion of surfactant in this disease. It has been noted that both impaired secretion of surfactant and impaired phagocytosis are responsible for disease pathogenesis. Case Report: A 40-year-old man who had suffered from a cough with sputum for more than 2 years, with no associated fever, referred to our clinic. He had been diagnosed with pneumonia and treated unsuccessfully with antibiotics. His past medical history showed that he had a chronic history of a cough, easy fatigability and shortness of breath upon mild exertion. Computed tomography (CT) imaging of the chest revealed bilateral diffuse reticulonodular opacities and a crazy-paving pattern, which was suggestive of alveolar proteinosis. Conclusion: PAP is a generalized pulmonary disorder caused by the collection of formless, proteinaceous material with specific staining appearance in the alveolus.

We tested the role of Stat5 in dendritic cell (DC) and alveolar macrophage homeostasis in the lung using CD11c-cre mediated deletion (Cre+5f/f). We show that Stat5 is required for CD103+ dendritic cell (DC) and alveolar macrophage development. We found that fetal monocyte maturation into alveolar macrophages was impaired in Cre+5f/f mice, and we also confirmed impaired alveolar macrophage development of progenitor cells using mixed chimera experiments. In the absence of Stat5 signaling in alveolar macrophages, mice developed alveolar proteinosis with altered lipid homeostasis. In addition, loss of Stat5 in CD11c+ cells was associated with exaggerated LPS-induced inflammatory responses and vascular leak. In Cre+5f/f mice, there was loss of immune-dampening effects on epithelial cells, a key source of CCL2 that serves to recruit monocytes/macrophages. These findings demonstrate the critical importance of Stat5 signaling in maintaining lung homeostasis and underscore the importance of resident macrophages in moderating tissue damage and excess inflammation.

PAP is a rare disease characterized by the accumulation of surfactant materials in the alveolar spaces due to the imbalance of surfactant homeostasis (production and clearance). We herein report a case of an 8-year-old girl who developed PAP after BMT from her mother for the treatment of DBA. The anemia was improved by BMT; however, respiratory dysfunction due to graft-versus-host disease gradually progressed. She eventually underwent right single LDLLT from her mother when she was 14 years old. A pathological examination of the excised lung confirmed the finding of diffuse bronchiolitis obliterans and unexpectedly revealed widespread alveolar proteinosis. Interestingly, the GGO of her native left lung on chest X-ray was improved after LDLLT. We present the very unique clinical course of this patient and discuss the mechanisms underlying the development of PAP after BMT and its improvement after LDLLT from the same donor.

Tissue‐resident macrophages (MΦ(TR)) originate from at least two distinct waves of erythro‐myeloid progenitors (EMP) arising in the yolk sac (YS) at E7.5 and E8.5 with the latter going through a liver monocyte intermediate. The relative potential of these precursors in determining development and functional capacity of MΦ(TR) remains unclear. Here, we studied development of alveolar macrophages (AM) after single and competitive transplantation of different precursors from YS, fetal liver, and fetal lung into neonatal Csf2ra (−/−) mice, which lack endogenous AM. Fetal monocytes, promoted by Myb, outcompeted primitive MΦ (pMΦ) in empty AM niches and preferentially developed to mature AM, which is associated with enhanced mitochondrial respiratory and glycolytic capacity and repression of the transcription factors c‐Maf and MafB. Interestingly, AM derived from pMΦ failed to efficiently clear alveolar proteinosis and protect from fatal lung failure following influenza virus infection. Thus, our data demonstrate superior developmental and functional capacity of fetal monocytes over pMΦ in AM development and underlying mechanisms explaining replacement of pMΦ in fetal tissues.

Airspace predominant diseases characterized by accumulation in the alveoli of various substations, such as protein and lipid complexes (alveolar proteinosis, lipoid pneumonia), calcium phosphorus calcinates (alveolar microlithiasis), blood (alveolar hemorrhages). These diseases can have a long chronic course (alveolar proteinosis, alveolar microlithiasis), and be life-threatening, accompanied by acute respiratory failure (diffuse alveolar hemorrhage). The chapter discusses the specific signs of these diseases, the risks factors and possible causes of development, the principles of differential diagnosis and treatment approaches.

A modern approach to the diagnosis of diffuse pulmonary diseases (DPDs) is based on a multidisciplinary discussion (MDD) among clinicians, pathologists, and radiologists. Many rare pulmonary diseases have very clear and specific HRCT signs, and there is often no need for invasive diagnostic approaches to obtain histological material. For example, in cases of idiopathic pulmonary fibrosis, lymphangioleiomyomatosis, alveolar microlithiasis, and alveolar proteinosis as well as others, chest HRCT can be a definitive diagnostic method; in other cases, it can narrow the range of possible diagnoses so that additional laboratory tests or patient history can conclude the diagnostic quest satisfactorily. Thus knowledge of the basic interpretation of HRCT signs of DPDs is a prerequisite for the professional competence of a chest physician. In this chapter, we will overview the main HRCT signs of DPDs, which will be discussed in more detail in subsequent chapters that describe the radiological picture of individual DPDs. In addition, we provide basic information on probe-based confocal laser endomicroscopy (pCLE) of the lower respiratory tract, a relatively new method, which, similar to HRCT, is aimed at structural assessment of the lung tissue; however, unlike HRCT, pCLE does not utilize X-ray radiation but analyzes reflected laser beam from intraacinar structures and inclusions that have taking autofluorescence properties. In this monograph, we also present our own data and conclusions regarding the prospects for the use of this technology based on our accumulating experience in pCLE for patients with DPDs.

Occupational lung disease secondary to inhalation of silica particles is variable and potentially life-threatening. As the artificial stone industry has grown over the last two decades, the development of silicosis has been seen to accelerate and behave differently to chronic silicosis. In this case report, we present two patients who underwent lung transplantation for silicosis at the Alfred Hospital, both with predominantly artificial stone masonry exposure. We have identified the presence of both fibrotic/nodular silicosis and conspicuous alveolar proteinosis within the same lung parenchyma of both patients. We then demonstrate the radiological and histopathological correlates of disease; the first time this has been shown clearly in the literature.

Probe-based confocal laser endomicroscopy (pCLE) provides a valuable information in patients with interstitial lung diseases (ILDs). Aim: to determine the correlations between pCLE and HRCT lung patterns in ILDs in corresponding zones. Methods: pCLE and HRCT were compared in 51 patients with ILDs: sarcoidosis 23, nonspecific interstitial pneumonia 8, idiopathic pulmonary fibrosis 6, cystic diseases 4, hypersensitivity pneumonitis 2, alveolar proteinosis 6, lipoid pneumonia 1. The following HRCT signs were analyzed: reticular changes, foci, ground-glass opacity (GGO), consolidation areas (CA), air traps, honeycomb lung, cysts. pCLE images were assessed on following criteria: size and quantity of alveolar macrophages (AM) and floating intraalveolar substances (FIS), alveolar and microvessels diameter, elastic fibers thickness, fluorescence intensity, etc. Results: The most expressed correlations at reticular changes, foci, GGO, CA were with elastic fibers thickness, amount of FIS and AM, their fluorescence intensity. Air traps, honeycomb lung, cysts and cavities had correlations with the alveolar size and interalveolar septa thickness. Pathologic pCLE findings were also detected in unchanged lung parenchyma according to HRCT. Conclusions: There are strong correlation between some pCLE with HRCT findings. pCLE can be used as additional diagnostic method of ILDs, revealing pathologic changes both in the presence and in the absence of HRCT signs.

Pulmonary alveolar proteinosis (PAP) is characterized by the massive accumulation of lipoproteinaceous material within alveoli, which results in progressive respiratory failure. The abnormalities in surfactant clearance are caused by defective pulmonary macrophages, whose terminal differentiation is GM-CSF-dependent. In hereditary PAP, the rupture of GM-CSF signaling is because of mutations in the GM-CSF receptor genes. This review focus on the innovative technologies of gene-correction proposed for the development of new therapeutic strategies, for hereditary PAP patients.Hematopoietic stem cell gene therapy has been successfully experimented in murine models to restore the expression of the GM-CSF receptor, however, a therapeutic approach based on bone marrow transplantation requires a preconditioning, which could be hazardous in PAP patients, who are highly susceptible to pulmonary infections. Gene-corrected pulmonary macrophages, administered directly to the lung, could represent an improved approach. Finally, patient-derived induced pluripotent stem cells seem to be promising to overcome the limited availability of primary patient cells and to generate gene-corrected macrophages, able to recover pulmonary surfactant clearance.WLL is the gold standard therapy for PAP. However, its use in hereditary PAP is limited by the difficulty of performing this technique in paediatric patients and by its purely symptomatic efficacy. The recent advances in genome engineering could provide efficacious strategies for clinical application.

Occupational inhalation of indium compounds can cause the so-called "indium lung disease". Most affected individuals show pulmonary alveolar proteinosis (PAP) and fibrotic interstitial lung disease. In animal experiments, inhalation of indium tin oxide or indium oxide has been shown to cause lung damage. However, the mechanisms by which indium compounds lead to indium lung disease remain unknown. In this study, we constructed a mouse model of indium lung disease and analyzed gene expression in response to indium exposure. Indium oxide (In2O3, 10 mg/kg, primary particle size

Tissue-resident macrophages can derive from yolk sac macrophages (YS-Macs), fetal liver monocytes (FL-MOs), or adult bone-marrow monocytes (BM-MOs). The relative capacity of these precursors to colonize a niche, self-maintain, and perform tissue-specific functions is unknown. We simultaneously transferred traceable YS-Macs, FL-MOs, and BM-MOs into the empty alveolar macrophage (AM) niche of neonatal Csf2rb(-/-) mice. All subsets produced AMs, but in competition preferential outgrowth of FL-MOs was observed, correlating with their superior granulocyte macrophage-colony stimulating factor (GM-CSF) reactivity and proliferation capacity. When transferred separately, however, all precursors efficiently colonized the alveolar niche and generated AMs that were transcriptionally almost identical, self-maintained, and durably prevented alveolar proteinosis. Mature liver, peritoneal, or colon macrophages could not efficiently colonize the empty AM niche, whereas mature AMs could. Thus, precursor origin does not affect the development of functional self-maintaining tissue-resident macrophages and the plasticity of the mononuclear phagocyte system is largest at the precursor stage.

Pulmonary alveolar proteinosis is a rare lung disease in which lipoproteinaceous material accumulates within the alveoli, interfering with gas exchange. The disease is classified into congenital, secondary, and acquired. The congenital form includes inborn errors of surfactant metabolism, lysinuric protein intolerance and mutations in the components of granulocyte-macrophage colony-stimulating factor receptor. The main symptoms are non-specific. The radiologic appearance of pulmonary alveolar proteinosis is bilateral, symmetric and perihilar airspace consolidation. Bronchoalveolar lavage is crucial for diagnosis of the disease. There is only one ten-year-old patient with diagnosed congenital form in Croatia. What makes him different from other children in the world is that since the ninth month of his life he has been mechanically ventilated. Diagnosis of postnatal alveolar proteinosis should be considered in every infant with respiratory distress with diffuse alveolar and interstitial infiltrate.

International audience; Pulmonary alveolar proteinosis (PAP) is a rare form of chronic interstitial lung disease, characterised by the intra-alveolar accumulation of lipoproteinaceous material. Numerous conditions can lead to its development. Whereas the autoimmune type is the main cause in adults, genetic defects account for a large part of cases in infants and children. Even if associated extra-respiratory signs may guide the clinician during diagnostic work-up, next-generation sequencing panels represent an efficient diagnostic tool. Exome sequencing also allowed the discovery of new variants and genes involved in PAP. The aim of this article is to summarise our current knowledge of genetic causes of PAP.

Alveolar proteinosis is a rare pulmonary disease characterized by intra-alveolar accumulation of surfactant composed of lipoproteinaceous material, related to a lack of surfactant resorption by alveolar macrophages. Crazy paving pattern is characteristic, but not specific. The multinodular forms of this affection remain exceptional.

Nanomaterial (NM) characteristics may affect the pulmonary toxicity and inflammatory response, including specific surface area, size, shape, crystal phase or other surface characteristics. Grouping of TiO2 in hazard assessment might be challenging because of variation in physicochemical properties. We exposed C57BL/6 J mice to a single dose of four anatase TiO2 NMs with various sizes and shapes by intratracheal instillation and assessed the pulmonary toxicity 1, 3, 28, 90 or 180 days post-exposure. The quartz DQ12 was included as benchmark particle. Pulmonary responses were evaluated by histopathology, electron microscopy, bronchoalveolar lavage (BAL) fluid cell composition and acute phase response. Genotoxicity was evaluated by DNA strand break levels in BAL cells, lung and liver in the comet assay. Multiple regression analyses were applied to identify specific TiO2 NMs properties important for the pulmonary inflammation and acute phase response. The TiO2 NMs induced similar inflammatory responses when surface area was used as dose metrics, although inflammatory and acute phase response was greatest and more persistent for the TiO2 tube. Similar histopathological changes were observed for the TiO2 tube and DQ12 including pulmonary alveolar proteinosis indicating profound effects related to the tube shape. Comparison with previously published data on rutile TiO2 NMs indicated that rutile TiO2 NMs were more inflammogenic in terms of neutrophil influx than anatase TiO2 NMs when normalized to total deposited surface area. Overall, the results suggest that specific surface area, crystal phase and shape of TiO2 NMs are important predictors for the observed pulmonary effects of TiO2 NMs.

International audience; Background: Whole lung lavage is the current standard therapy for pulmonary alveolar proteinosis (PAP) that is characterized by the alveolar accumulation of surfactant. Rituximab showed promising results in auto-immune PAP (aPAP) related to anti-GM-CSF antibody.Methods: We aimed to assess efficacy of rituximab in aPAP in real life and all patients with aPAP in France that received rituximab were retrospectively analyzed.Results: Thirteen patients were included. No patients showed improvement 6 months after treatment, but, 4 patients (30%) presented a significant decrease of alveolar-arterial difference in oxygen after 1 year. One patient received lung transplantation and one patient was lost of follow-up within one year. Although a spontaneous improvement cannot be excluded in these 4 patients, improvement was more frequent in patients naive to prior specific therapy and with higher level of anti-GM-CSF antibodies evaluated by ELISA. No serious adverse event was evidenced. Conclusions: These data do not support rituximab as a second line therapy for patients with refractory aPAP.

Background: Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by deposition of lipoproteinaceous material within alveoli, with a variable clinical course. Here, we report an experience of management of PAP at our center. A systematic review of previously reported cases from India is also included in the article. Materials and Methods: This study included patients with primary PAP managed at our center from 2009 to 2015. Diagnosis of primary PAP was based on histopathologic diagnosis on bronchoalveolar lavage or transbronchial lung biopsy and absence of causes of secondary PAP. For systematic review of Indian publications, the literature search was performed using PubMed and EMBASE databases using the terms “pulmonary alveolar proteinosis'” or “alveolar proteinosis” and “India” or “Indian.” Results: During the above-specified period, five patients with diagnosis of PAP were admitted at our center. Median age of patients was 32 years (interquartile range [IQR] 30.5–59); 80% were female. Mean duration (± standard deviation) of symptoms was 6.2 (±1.79) months. Anti-granulocyte-macrophage colony stimulating factor (GM-CSF) antibodies were elevated in 4 out of 5 patients (80%). For management, whole lung lavage (WLL) was done for four patients with median volume of 32.5 (IQR 18–74) L per patient. All the patients showed significant symptomatic as well as improvement in physiological parameters. Subcutaneous GM-CSF and ambroxol were given to 3 patients and 1 patient, respectively. The median follow-up of all patients was 18 (IQR 5–44) months. A systematic review of all Indian studies of PAP revealed thirty publications. Conclusions: WLL is the most common, effective, and safe therapy in patients with PAP. GM-CSF administration is an efficacious treatment for patients with incomplete response after WLL.

Background: DLPD are frequently detected and better evaluated by means of current diagnostic guidelines. Methods: Prospective assessment of patients with DLPD referred to a regional reference center in Germany using clinical, functional and radiological parameters, and results of bronchoscopic or surgical results. The diagnosis was made after a multidisciplinary discussion (MDD). Results: Between January and June of 2016 342 patients were admitted to the hospital for diagnosis and therapy of DPLD (144 women, average age 63,5 years), on average with a mild restrictive ventilatory defects (O VC 76,1 %, O DLCOcSB 61,1 %). IPF was the subgroup detected with the lowest DLCOcSB (O 46,7 %), pneumoconiosis showed the highest results (O 87,2 %); alveolar proteinosis showed the lowest VC (O 63,0 %), LAM showed the highest VC (O 93,3 %). 50 patients were diagnosed with the help of clinical and radiological findings. 292 patients underwent a bronchoscopy, in 133 cases a transbronchial cryobiopsy was performed. A surgical lung biopsy for the diagnosis of DPLD was performed in 20 patients. In 323 cases a precise diagnose could be obtained after MDD (94,4%): IPF (n= 59), sarcoidosis (n=50), hypersensitivity pneumonitis (n=47), collagen vascular disease (n=36), organizing pneumonia (n=32), nonspecific interstitial pneumonia (n=23), pneumoconiosis (n=14), other DLPD DLPD (n=62). In 19 cases a specific diagnose could not be obtained. Conclusion: Using a standardised approach including bronchoscopic assessment and the MDD, a specific diagnosis of DPLD can be made in 94 % of cases. A robust histological result could be obtained in 63% of patients using transbronchial cryobiopsies. The most prevalent DLPD are IPF, sarcoidosis and hypersensitivity pneumonitis.

This report describes the general characteristics, objectives and organizational aspects of the registries of rare respiratory diseases included in the National Registry of Rare Diseases of the Research Institute for Rare Diseases (ISCIII), in order to publicize their existence and encourage the participation of professionals. Information is collected on the following conditions: alpha-1 antitrypsin deficiency, idiopathic tracheal stenosis, adult pulmonary Langerhans' cell histiocytosis, lymphangioleiomyomatosis, alveolar proteinosis, and sarcoidosis.

Paraquat poisoning is characterized by multi-organ failure and pulmonary fibrosis with respiratory failure, resulting in high mortality and morbidity. To serious paraquat patients, the effectiveness of conventional treatments is unsuccessful. Whole lung lavage is a technique that was developed in the 1960s with the purpose of removing lipoproteinaceous material that accumulates in the bronchi of patients with alveolar proteinosis, leading to clinical and functional improvement. Pneumoconioses are characterized as irreversible, progressive respiratory diseases. No effective therapy exists to prevent progression of these diseases. Whole lung lavage might limit the rate of disease progression through the removal of dust, inflammatory cells, and cytokines. Whole lung lavage is also used successfully to treat other lung diseases such as endogenous lipoid pneumonia and mineral oil lipoid pneumonia. Paraquat poisoning could not be controlled by only one method and combined therapies are needed. So, we hypothesized that whole lung lavage will provide a new therapy of acute lung injury caused by paraquat. On the base of conventional therapy for paraquat poisoning, whole lung lavage could be considered in the early time of poisoning and then followed by glucocorticoid for patients with moderate to severe paraquat poisoning. Key words: Paraquat, poisoning, acute lung injury, whole lung lavage.