A Comprehensive Outlook on Pulmonary Alveolar Proteinosis-A Review.

Pulmonary alveolar proteinosis (PAP) is an ultra-rare disease caused by impaired pulmonary surfactant clearance due to the dysfunction of alveolar macrophages or their signaling pathways. PAP is categorized into autoimmune, congenital, and secondary PAP, with autoimmune PAP being the most prevalent. This article aims to present a comprehensive review of PAP classification, pathogenesis, clinical presentation, diagnostics, and treatment. The literature search was conducted using the PubMed database and a total of 67 articles were selected. The PAP diagnosis is usually based on clinical symptoms, radiological imaging, and bronchoalveolar lavage, with additional GM-CSF antibody tests. The gold standard for PAP treatment is whole-lung lavage. This review presents a summary of the most recent findings concerning pulmonary alveolar proteinosis, pointing out specific features that require further investigation.

Inhaled recombinant GM-CSF reduces the need for whole lung lavage and improves gas exchange in autoimmune pulmonary alveolar proteinosis patients.

RATIONALE: Whole lung lavage (WLL) is a widely accepted palliative treatment for autoimmune pulmonary alveolar proteinosis (aPAP) but does not correct myeloid cell dysfunction or reverse the pathological accumulation of surfactant. In contrast, inhaled recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) is a promising pharmacological approach that restores alveolar macrophage functions including surfactant clearance. Here, we evaluate WLL followed by inhaled rGM-CSF (sargramostim) as therapy of aPAP. METHODS: 18 patients with moderate-to-severe aPAP were enrolled, received baseline WLL, were randomised into either the rGM-CSF group (receiving inhaled sargramostim) or control group (no scheduled therapy) and followed for 30 months after the baseline WLL. Outcome measures included additional unscheduled "rescue" WLL for disease progression, assessment of arterial blood gases, pulmonary function, computed tomography, health status, biomarkers and adverse events. Patients requiring rescue WLL were considered to have failed their assigned intervention group. RESULTS: The primary end-point of time to first rescue WLL was longer in rGM-CSF-treated patients than controls (30 versus 18 months, n=9 per group, p=0.0078). Seven control patients (78%) and only one rGM-CSF-treated patient (11%) required rescue WLL, demonstrating a 7-fold increase in relative risk (p=0.015). Compared to controls, rGM-CSF-treated patients also had greater improvement in peripheral arterial oxygen tension, alveolar-arterial oxygen tension difference, diffusing capacity of the lungs for carbon monoxide and aPAP biomarkers. One patient from each group withdrew for personal reasons. No serious adverse events were reported. CONCLUSIONS: This long-term, prospective, randomised trial demonstrated inhaled sargramostim following WLL reduced the requirement for WLL, improved lung function and was safe in aPAP patients. WLL plus inhaled sargramostim may be useful as combined therapy for aPAP.

[Congenital pulmonary alveolar proteinosis in a neonate]. / æ–°ç”Ÿå„¿å ˆå¤©æ€§è‚ºæ³¡è›‹ç™½æ²‰ç§¯ç—‡1例.

The male patient was referred to the hospital at 44 days old due to dyspnea after birth and inability to wean off oxygen. His brother died three days after birth due to respiratory failure. The main symptoms observed were respiratory failure, dyspnea, and hypoxemia. A chest CT scan revealed characteristic reduced opacity in both lungs with a "crazy-paving" appearance. The bronchoalveolar lavage fluid (BALF) showed periodic acid-Schiff positive proteinaceous deposits. Genetic testing indicated a compound heterozygous mutation in the ABCA3 gene. The diagnosis for the infant was congenital pulmonary alveolar proteinosis (PAP). Congenital PAP is a significant cause of challenging-to-treat respiratory failure in full-term infants. Therefore, congenital PAP should be considered in infants experiencing persistently difficult-to-treat dyspnea shortly after birth. Early utilization of chest CT scans, BALF pathological examination, and genetic testing may aid in early diagnosis.

Pulmonary storage.

Interstitial lung diseases (ILDs) are not just a matter of scarring or inflammation in the lung tissue. The lungs can also serve as a repository for products that can be produced in excessive amounts in the human body as a result of disease. Geneticaly based dysfunctions of lysosomal enzymes, which leads to an unefficient degradation and transport of various macromolecules from lysosomes, are considered to be storage diseases sensu stricto. ILDs were described in patients with Gaucher disease, Niemann-Pick disease and Fabry disease. In a broader context, however, the accumulation of various substances in the lung tissue is also encountered in cases of pediatric pulmonary interstitial glycogenosis (PIG), alveolar lipoproteinosis or pulmonary amyloidosis. The cause of PIG is not clear. The disease was first described in 2002 and a lung tissue sample is required to establish this diagnosis. Even though PIG usually goes well in childhood and the patients difficulties spontaneously subside over time, the long-term prognosis of the patients is unknown. Alveolar lipoproteinoses can be acquired (e.g. after massive exposure to silica dust), autoimmune, but also genetically determined. Unlike lysosomal storage diseases, in the case of pulmonary alveolar lipoproteinosis, accumulation of abnormal macromolecules occurs only in the lungs of affected individuals. Similarly, amyloidosis is not a single disease, but a group of diseases with different etiopathogenesis, as a result of which amyloid - a group of different proteins with a distinctvive conformation, which can be deposited in various organs, including the lungs - is formed. The diagnosis of pulmonary alveolar lipoproteinosis is based on the typical appearance and biochemical composition of the fluid obtained by bronchoalveolar lavage, the diagnosis of amyloidosis is histological.

Pulmonary effects of exposure to indium and its compounds: cross-sectional survey of exposed workers and experimental findings in rodents.

BACKGROUND: Many studies have shown that occupational exposure to indium and its compounds could induce lung disease. Although animal toxicological studies and human epidemiological studies suggest indium exposure may cause lung injury, inflammation, pulmonary fibrosis, emphysema, pulmonary alveolar proteinosis, and even lung cancer, related data collected from humans is currently limited and confined to single workplaces, and the early effects of exposure on the lungs are not well understood. OBJECTIVES: This study combined population studies and animal experiments to examine the links of indium with pulmonary injury, as well as its mechanism of action. A cross-sectional epidemiological study of indium-exposed workers from China was conducted to evaluate associations between occupational indium exposure and serum biomarkers of early effect. This study also compares and analyzes the causal perspectives of changes in human serum biomarkers induced by indium compound exposure and indium exposure-related rat lung pathobiology, and discusses possible avenues for their recognition and prevention. METHODS: This is a study of 57 exposed (at least 6 h per day for one year) workers from an indium ingot production plant, and 63 controls. Indium concentration in serum, urine, and airborne as exposure indices were measured by inductively coupled plasma-mass spectrometry. Sixteen serum biomarkers of pulmonary injury, inflammation, and oxidative stress were measured using ELISA. The associations between serum indium and 16 serum biomarkers were analyzed to explore the mechanism of action of indium on pulmonary injury in indium-exposed workers. Animal experiments were conducted to measure inflammatory factors levels in bronchoalveolar lavage fluid (BALF) and lung tissue protein expressions in rats. Four different forms of indium compound-exposed rat models were established (intratracheal instillation twice per week, 8 week exposure, 8 week recovery). Model I: 0, 1.2, 3, and 6 mg/kg bw indium tin oxide group; Model II: 0, 1.2, 3, and 6 mg/kg bw indium oxide (In2O3) group; Model III: 0, 0.523, 1.046, and 2.614 mg/kg bw indium sulfate (In2(SO4)3) group; Model IV: 0, 0.065, 0.65, and 1.3 mg/kg bw indium trichloride (InCl3) group. Lung pathological changes were assessed by hematoxylin & eosin, periodic acid Schiff, and Masson's staining, transmission electron microscopy, and the protein changes were determined by immunohistochemistry. RESULTS: In the production workshop, the airborne indium concentration was 78.4 µg/m3. The levels of serum indium and urine indium in indium-exposed workers were 39.3 µg/L and 11.0 ng/g creatinine. Increased lung damage markers, oxidative stress markers, and inflammation markers were found in indium-exposed workers. Serum indium levels were statistically and positively associated with the serum levels of SP-A, IL-1ß, IL-6 in indium-exposed workers. Among them, SP-A showed a duration-response pattern. The results of animal experiments showed that, with an increase in dosage, indium exposure significantly increased the levels of serum indium and lung indium, as well as the BALF levels of IL­1ß, IL­6, IL­10, and TNF­α and up-regulated the protein expression of SP-A, SP-D, KL-6, GM-CSF, NF-κB p65, and HO-1 in all rat models groups. TEM revealed that In2(SO4)3 and InCl3 are soluble and that no particles were found in lung tissue, in contrast to the non-soluble compounds (ITO and In2O3). No PAS-staining positive substance was found in the lung tissue of In2(SO4)3 and InCl3 exposure groups, whereas ITO and In2O3 rat models supported findings of pulmonary alveolar proteinosis and interstitial fibrosis seen in human indium lung disease. ITO and InCl3 can accelerate interstitial fibrosis. Findings from our in vivo studies demonstrated that intra-alveolar accumulation of surfactant (immunohistochemistry) and characteristic cholesterol clefts granulomas of indium lung disease (PAS staining) were triggered by a specific form of indium (ITO and In2O3). CONCLUSIONS: In indium-exposed workers, biomarker findings indicated lung damage, oxidative stress and an inflammatory response. In rat models of the four forms of indium encountered in a workplace, the biomarkers response to all compounds overall corresponded to that in humans. In addition, pulmonary alveolar proteinosis was found following exposure to indium tin oxide and indium oxide in the rat models, and interstitial fibrosis was found following exposure to indium tin oxide and indium trichloride, supporting previous report of human disease. Serum SP-A levels were positively associated with indium exposure and may be considered a potential biomarker of exposure and effect in exposed workers.

First Documented Case of Pulmonary Alveolar Proteinosis with Atopy Presenting Secondary to CSFR2B Mutation.

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. It is essential to gain a better understanding of the signs to clinically diagnose PAP and include PAP among the differential diagnoses of interstitial pulmonary diseases or other diseases with similar manifestations. We describe a 2.5-year patient with atopy who presented with pulmonary infiltration, recurrent wheezing, and cough despite steroid and salbutamol administration via inhalation. High-resolution computed tomography revealed crazy-paving patterns in both lungs, suggesting PAP. An open lung biopsy revealed intra-alveolar granular amphophilic material, which was strongly positive on periodic acid-Schiff staining. The results of pulmonary-associated surfactant protein B and C gene analyses were normal. However, granulocyte-macrophage colony-stimulating factor receptor beta-protein was not detected in leucocytes, and a novel mutation was identified in the CSF2RB gene. The patient was diagnosed with PAP and treated with whole-lung lavage. Key Words: Pulmonary alveolar proteinosis, Child, Atopy, Wheezing.

N-acetylcysteine alleviates pulmonary alveolar proteinosis induced by indium-tin oxide nanoparticles in male rats: involvement of the NF-κB signaling pathway.

Indium-tin oxide (ITO) was previously found to have a toxic effect on lung tissues, and oxidative stress and the inflammatory response are two important mechanisms of ITO­induced lung injury. N-acetylcysteine (NAC) has been found to exhibit antioxidant and anti­inflammatory properties. The current study aimed to evaluate the possible protective effects of NAC against ITO nanoparticle (Nano-ITO)-induced pulmonary alveolar proteinosis (PAP) in adult male Sprague-Dawley rats, especially via modulation of nuclear factor-kappa B (NF-κB) signaling. For this purpose, 50 rats were randomly allocated into five groups (10 rats each) as follows: (1) control group; (2) saline group; (3) NAC (200 mg/kg) group; (4) PAP model group receiving a repeated intratracheal dose of Nano-ITO (6 mg/kg); and (5) PAP model+NF-κB inhibitor (NAC) group pre-treated intraperitoneally with NAC (200 mg/kg) twice per week before the administration of an intratracheal dose of Nano-ITO (6 mg/kg). Rats were then euthanized under anesthesia, and their lungs were removed for histopathological and biochemical investigations. A 6 mg/kg dose of Nano-ITO markedly altered the levels of some oxidative stress biomarkers. The histological examination of Nano-ITO-exposed rats demonstrated diffused alveolar damage that involved PAP, cholesterol crystals, alveolar fibrosis, pulmonary fibrosis, and alveolar emphysema. The immunohistochemical results of Nano-ITO-exposed rats revealed strongly positive NF-κB p65 and inhibitory kappa B kinase (IKK)-ß and weakly positive inhibitor of kappa-B subunit alpha (IκB-α) staining reactivity in the nuclei of cells lining the epithelium of the bronchioles and alveoli. Moreover, Nano-ITO activated the NF-κB pathway. However, pre-treatment with NAC significantly attenuated Nano-ITO-evoked alterations in the previously mentioned parameters, highlighting their antioxidant, anti-inflammatory, and anti-apoptotic potential. The results indicated that the degree of pulmonary fibrosis and proteinosis in the NAC­treated group was improved compared with that in the Nano-ITO-induced PAP model group. The level of malondialdehyde was also decreased overall in the NAC-treated group compared with that in the Nano-ITO-induced model group, indicating that the pulmonary fibrosis degree and oxidation levels were decreased. The present study also demonstrated that NAC increased the activity of antioxidant enzyme superoxide dismutase and total antioxidant capacity, indicating that it could alleviate oxidative stress in the lung tissue of Nano-ITO­exposed rats. In addition, NAC reduced the production of pro­inflammatory cytokines interleukin (IL)­1ß, IL­6, and tumor necrosis factor (TNF)­α, and increased the levels of anti­inflammatory factor IL­10. The current study demonstrated that NAC can effectively attenuate Nano-ITO­induced lung injury by reducing oxidative damage and the inflammatory response.

Autoimmune Pulmonary Alveolar Proteinosis.

Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease characterized by myeloid cell dysfunction, abnormal pulmonary surfactant accumulation, and innate immune deficiency. It has a prevalence of 7-10 per million; occurs in individuals of all races, geographic regions, sex, and socioeconomic status; and accounts for 90% of all patients with PAP syndrome. The most common presentation is dyspnea of insidious onset with or without cough, production of scant white and frothy sputum, and diffuse radiographic infiltrates in a previously healthy adult, but it can also occur in children as young as 3 years. Digital clubbing, fever, and hemoptysis are not typical, and the latter two indicate that intercurrent infection may be present. Low prevalence and nonspecific clinical, radiological, and laboratory findings commonly lead to misdiagnosis as pneumonia and substantially delay an accurate diagnosis. The clinical course, although variable, usually includes progressive hypoxemic respiratory insufficiency and, in some patients, secondary infections, pulmonary fibrosis, respiratory failure, and death. Two decades of research have raised autoimmune PAP from obscurity to a paradigm of molecular pathogenesis-based diagnostic and therapeutic development. Pathogenesis is driven by GM-CSF (granulocyte/macrophage colony-stimulating factor) autoantibodies, which are present at high concentrations in blood and tissues and form the basis of an accurate, commercially available diagnostic blood test with sensitivity and specificity of 100%. Although whole-lung lavage remains the first-line therapy, inhaled GM-CSF is a promising pharmacotherapeutic approach demonstrated in well-controlled trials to be safe, well tolerated, and efficacious. Research has established GM-CSF as a pulmonary regulatory molecule critical to surfactant homeostasis, alveolar stability, lung function, and host defense.

A case series of pulmonary alveolar proteinosis: Response differently to whole lung lavage.

Pulmonary alveolar proteinosis (PAP) is a rare disease and its prognosis can be improved by whole lung lavage (WLL). Herein, we present three cases with idiopathic PAP treated successfully with either single or double WLL in the same setting. All three of them presented with exertional dyspnoea with radiographic findings of pulmonary infiltrates. They showed a marked clinical and physiologic improvement post WLL. Two of them were in remission. These three cases were diagnosed using different lung biopsy modalities, including video-assisted thoracoscopic lung biopsy, computed tomography-guided percutaneous transthoracic tru-cut needle lung biopsy, and transbronchial forceps lung biopsy (TBLB), respectively. The current cases have shown that TBLB may provide adequate diagnostic yield, and the invasive surgical lung biopsy may not be necessary to achieve a definitive diagnosis.

Case Report: The first reported case of pulmonary alveolar proteinosis with myasthenia gravis in a 27-year-old patient.

Background: Pulmonary alveolar proteinosis is a very rare diffuse lung disease characterized by the accumulation of amorphous and periodic acid Schiff-positive lipoproteinaceous material in the alveolar spaces due to impaired surfactant clearance by alveolar macrophages. Three main types were identified: Autoimmune, secondary and congenital. Pulmonary alveolar proteinosis has been previously reported to be associated with several systemic auto-immune diseases. Accordingly, we present the first case report of pulmonary alveolar proteinosis associated with myasthenia gravis. Case: A 27-year-old female patient, ex-smoker, developed a dyspnea on exertion in 2020. The chest X-ray detected diffuse symmetric alveolar opacities. Pulmonary infection was ruled out, particularly COVID-19 infection. The chest scan revealed the "crazy paving" pattern. The bronchoalveolar lavage showed a rosy liquid with granular acellular eosinophilic material Periodic acid-Schiff positive. According to the lung biopsy results, she was diagnosed with pulmonary alveolar proteinosis. The granulocyte macrophage colony-stimulating factor autoantibodies were negative. Nine months later, she was diagnosed with bulbar seronegative myasthenia gravis, confirmed with the electroneuromyography with repetitive nerve stimulation showing significant amplitude decrement of the trapezius and spinal muscles. She was treated with pyridostigmine, oral corticosteroids and azathioprine. Given the worsening respiratory condition of the patient, a bilateral whole lung lavage was performed with a partial resolution of symptoms. Thus, this previously unreported association was treated successfully with rituximab, including improvement of dyspnea, diplopia and muscle fatigability at six months of follow-up. Conclusions: This case emphasizes on the possible association of auto-immune disease to PAP, which could worsen the disease course, as the specific treatment does not exist yet. Hence, further studies are needed to establish clear-cut guidelines for PAP management, particularly when associated to auto-immune diseases.

A 30-Year-Old Immune Deficient Woman With Persistent Cough and Shortness of Breath.

CASE PRESENTATION: A 30-year-old woman was referred with increasing shortness of breath and cough in the setting of GATA2 deficiency. She initially presented 9 years previously with recurrent episodes of pneumonia and sinusitis. Genetic testing revealed a heterozygous GATA2 mutation (c.988C>T). She has since had multiple infections that have included necrotizing fasciitis of the right thumb, recurrent pilonidal infections (which required 23 procedures), esophageal candidiasis, and human papillomavirus-positive high-grade squamous intraepithelial lesion of the cervix. Serial bone marrow biopsy specimens showed persistent hypocellularity (20% to 60%) with intermittent erythroid atypia and variable detection of trisomy 8, which were concerning for evolving myelodysplastic syndrome. One year before the current admission, she was diagnosed with disseminated Mycobacterium avium complex and was treated with rifabutin, ethambutol, and azithromycin. She was taking voriconazole, acyclovir, and trimethoprim-sulfamethoxazole prophylaxis.

Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10-12), followed by an additional independent risk allele at HLA-DPß1 amino acid position 8 (OR = 0.28; P = 3.4 × 10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (ß = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.

Indium oxide nanoparticles induce lung intercellular toxicity between bronchial epithelial cells and macrophages.

Concerns have been raised over the safety and health of industrial workers exposed to indium oxide nanoparticles (IO-NPs) when working. IO-NPs were previously shown in vitro and in vivo to be cytotoxic, but the mechanism of pathogenesis was unclear. In this study, the effects of IO-NPs on lung cells associated with respiratory and immune barriers and the toxic effects of intercellular cascades were studied. Here IO-NPs had acute toxicity to Wistar rats over a time course (5 days post-intratracheal instillation). Following treatment epithelial cells (16HBE) or macrophages (RAW264.7) with IO-NPs or IO fine particles (IO-FPs), the damage of 16HBE cells caused by IO-NPs was serious, mainly in the mitochondrial and rough endoplasmic reticulum. The lactate dehydrogenase level also showed that cytotoxicity in vitro was more serious for IO-NPs compared with IO-FPs. The level of In3+ (examined by inductively coupled plasma mass spectrometry) in 16HBE cells was 10 times higher than that in RAW cells. In3+ , releasing from IO-NPs absorbed by 16HBE cells, could not only significantly inhibit the phagocytosis and migration of macrophages (P < .0001), but also stimulate RAW cells to secrete high levels of inflammatory cytokines. IO-NPs can directly damage pulmonary epithelial cells. The In3+ released by epithelial cells affect the phagocytosis and migration of macrophages, which may be a new point for the decrease in the clearance of alveolar surfactants and the development of IO-related pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis.

PAP is an ultra-rare disease in which surfactant components, that impair gas exchange, accumulate in the alveolae. There are three types of PAP. The most frequent form, primary PAP, includes autoimmune PAP which accounts for over 90% of all PAP, defined by the presence of circulating anti-GM-CSF antibodies. Secondary PAP is mainly due to haematological disease, infections or inhaling toxic substances, while genetic PAP affects almost exclusively children. PAP is suspected if investigation for ILD reveals a crazy-paving pattern on chest CT scan, and is confirmed by a milky looking BAL that gives a positive PAS reaction indicating extracellular proteinaceous material. PAP is now rarely confirmed by surgical lung biopsy. WLL is still the first-line treatment, with an inhaled GM-CSF as second-line treatment. Inhalation has been found to be better than subcutaneous injections. Other treatments, such as rituximab or plasmapheresis, seem to be less efficient or ineffective. The main complications of PAP are due to infections by standard pathogens (Streptococcus, Haemophilus and Enterobacteria) or opportunistic pathogens such as mycobacteria, Nocardia, Actinomyces, Aspergillus or Cryptococcus. The clinical course of PAP is unpredictable and spontaneous improvement can occur. The 5-year actuarial survival rate is 95%.

A Case of Autoimmune Pulmonary Alveolar Proteinosis with Pulmonary Fibrosis and Asbestosis-Like Features.

A 78-year-old man who had worked in the building industry visited our hospital because of groundglass opacity with smoothly thickened, intralobular interstitial lines and interlobular septal lines on chest high-resolution computed tomography (HRCT). HRCT image also showed a focal area of reticulation and pleural thickening. Lung specimens obtained by surgical lung biopsy showed accumulations of intra-alveolar periodic acid-Schiffpositive materials, usual interstitial pneumonia (UIP)-like subpleural lung fibrosis and asbestos bodies (1 body/cm2 in high-power field, ×400). Serum granulocyte-macrophage colony stimulating factor autoantibody was positive. The patient was diagnosed as having autoimmune pulmonary alveolar proteinosis (PAP) and needed differential diagnosis from secondary PAP caused from pulmonary asbestosis and UIP. Careful observation of the manifestations of pulmonary asbestosis and the progression of fibrosis using HRCT will be necessary in this patient.

The early onset and persistent worsening pulmonary alveolar proteinosis in rats by indium oxide nanoparticles.

Workplace inhalation exposure to indium compounds has been reported to produce 'indium lung disease' characterized by pulmonary alveolar proteinosis (PAP), granulomas, and pulmonary fibrosis. However, there is little information about the pulmonary toxicity of nano-sized indium oxide (In2O3), which is widely used in various applications such as liquid crystal displays. In this study, we evaluated the time-course and dose-dependent lung injuries by In2O3 nanoparticles (NPs) after a single intratracheal instillation to rats. In2O3 NPs were instilled to female Wistar rats at 7.5, 30, and 90 cm2/rat and lung injuries were evaluated at day 1, 3, 7, 14, 30, 90, and 180 after a single intratracheal instillation. Treatment of In2O3 NPs induced worsening diverse pathological changes including PAP, persistent neutrophilic inflammation, type II cell hyperplasia, foamy macrophages, and granulomas in a time- and dose-dependent manner. PAP was induced from day 3 and worsened throughout the study. The concentrations of interleukin-1ß, tumor necrosis factor-α, and monocyte chemoattractant protein-1 in bronchoalveolar lavage fluid (BALF) showed dose- and time-dependent increases and the levels of these inflammatory mediators are consistent with the data of inflammatory cells in BALF and progressive lung damages by In2O3 NPs. This study suggests that a single inhalation exposure to In2O3 NPs can produce worsening lung damages such as PAP, chronic active inflammation, infiltration of foamy macrophages, and granulomas. The early onset and persistent PAP even at the very low dose (7.5 cm2/rat) implies that the re-evaluation of occupational recommended exposure limit for In2O3 NPs is urgently needed to protect workers.