CD103hi Treg cells constrain lung fibrosis induced by CD103lo tissue-resident pathogenic CD4 T cells.

Tissue-resident memory T cells (TRM cells) are crucial mediators of adaptive immunity in nonlymphoid tissues. However, the functional heterogeneity and pathogenic roles of CD4+ TRM cells that reside within chronic inflammatory lesions remain unknown. We found that CD69hiCD103lo CD4+ TRM cells produced effector cytokines and promoted the inflammation and fibrotic responses induced by chronic exposure to Aspergillus fumigatus. Simultaneously, immunosuppressive CD69hiCD103hiFoxp3+ CD4+ regulatory T cells were induced and constrained the ability of pathogenic CD103lo TRM cells to cause fibrosis. Thus, lung tissue-resident CD4+ T cells play crucial roles in the pathology of chronic lung inflammation, and CD103 expression defines pathogenic effector and immunosuppressive tissue-resident cell subpopulations in the inflamed lung.

Inflammasome-Independent and Atypical Processing of IL-1ß Contributes to Acid Aspiration-Induced Acute Lung Injury.

Inflammation plays a pivotal role in the pathophysiology of gastric aspiration-induced acute lung injury (ALI). However, its mechanism remains unclear. In this study, we investigated the role of NLRP3 inflammasome-driven IL-1ß production in a mouse model of acid aspiration-induced inflammation and ALI. Acid aspiration-induced inflammatory responses and ALI in wild-type mice were significantly attenuated in IL-1ß-/- mice, but not NLRP3-/- mice. In vitro experiments revealed that severe acidic stress (pH 1.75) induced the processing of pro-IL-1ß into its 18-kDa mature form (p18-IL-1ß), which was different from the caspase-1-processed 17-kDa form (p17-IL-1ß), in human THP-1 macrophages and primary murine macrophages. Deficiency of NLRP3 and caspase-1 had no effect on acidic stress-produced IL-1ß. The production of IL-1ß by severe acidic stress was prevented by inhibitors of serine proteases [4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride], but not of cysteine proteases (E-64), cathepsin G, or inflammasome. The cathepsin D inhibitor pepstatin A inhibited IL-1ß production induced by mild acidic stress (pH 6.2) or lactic acid, but not severe acidic stress. Using mass spectrometry and processing-site mutants of pro-IL-1ß, we identified D109 as a novel cleavage site of pro-IL-1ß in response to severe acidic stress and calculated the theoretical molecular mass of the mature form to be 18.2 kDa. The bioactivity of acidic stress-produced IL-1ß was confirmed by its ability to promote p38 phosphorylation and chemokine upregulation in alveolar epithelial cells. These findings demonstrate a novel mechanism of acid-induced IL-1ß production and inflammation independent of NLRP3 inflammasome and provide new insights into the therapeutic strategies for aspiration pneumonitis and ALI.

NLRP3 protein deficiency exacerbates hyperoxia-induced lethality through Stat3 protein signaling independent of interleukin-1ß.

Supplemental oxygen inhalation is frequently used to treat severe respiratory failure; however, prolonged exposure to hyperoxia causes hyperoxic acute lung injury (HALI), which induces acute respiratory distress syndrome and leads to high mortality rates. Recent investigations suggest the possible role of NLRP3 inflammasomes, which regulate IL-1ß production and lead to inflammatory responses, in the pathophysiology of HALI; however, their role is not fully understood. In this study, we investigated the role of NLRP3 inflammasomes in mice with HALI. Under hyperoxic conditions, NLRP3(-/-) mice died at a higher rate compared with wild-type and IL-1ß(-/-) mice, and there was no difference in IL-1ß production in their lungs. Under hyperoxic conditions, the lungs of NLRP3(-/-) mice exhibited reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, as well as increased and decreased expression of MMP-9 and Bcl-2, respectively. NLRP3(-/-) mice exhibited diminished expression and activation of Stat3, which regulates MMP-9 and Bcl-2, in addition to increased numbers of apoptotic alveolar epithelial cells. In vitro experiments revealed that alveolar macrophages and neutrophils promoted Stat3 activation in alveolar epithelial cells. Furthermore, NLRP3 deficiency impaired the migration of neutrophils and chemokine expression by macrophages. These findings demonstrate that NLRP3 regulates Stat3 signaling in alveolar epithelial cells by affecting macrophage and neutrophil function independent of IL-1ß production and contributes to the pathophysiology of HALI.

Physical activity in patients with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Physical activity is an important parameter in patients with chronic obstructive pulmonary disease, but has not been studied in detail in patients with interstitial lung disease. This study aimed to evaluate physical activity in patients with idiopathic pulmonary fibrosis (IPF). METHODS: Physical activity was monitored in 31 stable IPF patients using an accelerometer for 1 month. The following factors reflecting physical activity were measured: the number of steps, walking distance, the time spent at magnitude of movement (MM) 1-6, physical activity-related energy expenditure (PAEE) and total energy expenditure. We also measured the following clinical parameters: the modified Medical Research Council (MRC) scale, Krebs von den Lungen-6 (KL-6), pulmonary function parameters, 6-min walk test (6MWT) results and high-resolution computed tomography (HRCT) findings of the chest. We determined the relationship between these parameters and physical activity. RESULTS: We recorded 24 days of physical activity data. The time spent at MM < 1 was more than 10 h per day, whereas that at MM > 1 was approximately 1 h per day. The modified MRC scale, serum KL-6 levels, 6MWT distance, and the extent of honeycomb and reticular abnormality on HRCT were associated with several facets of physical activity. In particular, lower KL-6 levels were correlated with higher physical activity based on the number of steps, walking distance, the time spent at MM 1-4 and PAEE. CONCLUSIONS: The modified MRC scale, 6MWT distance, extent of fibrosis on HRCT and serum KL-6 levels are strongly associated with physical activity.

Temsirolimus induces surfactant lipid accumulation and lung inflammation in mice.

Interstitial lung disease (ILD) is a well-known adverse effect of mammalian target of rapamycin (mTOR) inhibitors. However, it remains unknown how lung toxicities are induced by mTOR inhibitors. Here, we constructed a mouse model of mTOR inhibitor-induced ILD using temsirolimus and examined the pathogenesis of the disease. Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus (3 or 30 mg·kg(-1)·wk(-1)) or vehicle. Temsirolimus treatment increased capillary-alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space, indicating alveolar epithelial and/or endothelial injury. It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols. Alveolar macrophage depletion is thought to cause surfactant lipid accumulation. To further examine whether temsirolimus has cytotoxic and/or cytostatic effects on alveolar macrophages and alveolar epithelial cells, we performed in vitro experiments. Temsirolimus inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells. Temsirolimus treatment caused some signs of pulmonary inflammation, including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates, and an increase in lymphocytes in the bronchoalveolar lavage fluid. These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation, resulting in pulmonary inflammation. This is the first study to focus on the pathogenesis of mTOR inhibitor-induced ILD using an animal model.

Novel therapeutic strategies targeting bypass pathways and mitochondrial dysfunction to combat resistance to RET inhibitors in NSCLC.

RET fusion is an oncogenic driver in 1-2 % of patients with non-small cell lung cancer (NSCLC). Although RET-positive tumors have been treated with multikinase inhibitors such as vandetanib or RET-selective inhibitors, ultimately resistance to them develops. Here we established vandetanib resistance (VR) clones from LC-2/ad cells harboring CCDC6-RET fusion and explored the molecular mechanism of the resistance. Each VR clone had a distinct phenotype, implying they had acquired resistance via different mechanisms. Consistently, whole exome-seq and RNA-seq revealed that the VR clones had unique mutational signatures and expression profiles, and shared only a few common remarkable events. AXL and IGF-1R were activated as bypass pathway in different VR clones, and sensitive to a combination of RET and AXL inhibitors or IGF-1R inhibitors, respectively. SMARCA4 loss was also found in a particular VR clone and 55 % of post-TKI lung tumor tissues, being correlated with higher sensitivity to SMARCA4/SMARCA2 dual inhibition and shorter PFS after subsequent treatments. Finally, we detected an increased number of damaged mitochondria in one VR clone, which conferred sensitivity to mitochondrial electron transfer chain inhibitors. Increased mitochondria were also observed in post-TKI biopsy specimens in 13/20 cases of NSCLC, suggesting a potential strategy targeting mitochondria to treat resistant tumors. Our data propose new promising therapeutic options to combat resistance to RET inhibitors in NSCLC.

Significance of Persistent Systemic Support in the Clinical Course of Delayed Post-hypoxic Leukoencephalopathy Following Severe Coronavirus Disease 2019.

A 45-year-old woman was hospitalized with severe coronavirus disease 2019 pneumonia. Following cytokine storm-induced multiorgan failure and lethal arrhythmia, the patient developed a sustained coma with flaccid quadriplegia. A cerebrospinal fluid examination excluded infectious and immunogenic encephalopathies, and diffusion-weighted magnetic resonance imaging demonstrated high-intensity areas in the white matter with a cortex-sparing distribution, suggesting delayed post-hypoxic leukoencephalopathy. As a result of intensive cardiopulmonary support for a month, the neurological function gradually recovered. Based on the reversible clinical course noted in this patient, accurate diagnosis and persistent medical approaches are important for the management of coronavirus disease 2019-related delayed post-hypoxic leukoencephalopathy.

Clinical significance of interleukin 33 (IL-33) in patients with eosinophilic pneumonia.

BACKGROUND: Interleukin 33 (IL-33) works as a functional mediator in allergic disease by enhancing the activity of eosinophils and inducing expression of T helper 2 (Th2)-associated cytokines. However, the role of IL-33 in pulmonary eosinophilia has not been elucidated. We investigated the levels of IL-33 in eosinophilic pneumonia (EP) together with associated cytokines, and discussed the clinical significance of IL-33 in EP. METHODS: Sera and bronchoalveolar lavage fluid (BALF) were obtained from 16 patients with EP, including acute eosinophilic pneumonia (AEP) and chronic eosinophilic pneumonia (CEP). Twelve patients with acute respiratory distress syndrome (ARDS) were also included for comparison. The concentration of IL-33 and Th2 cytokines (IL-4, IL-5, IL-13) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The concentration of serum IL-33 was significantly higher in patients with AEP than in CEP. In CEP, only patients with atopic factors showed mild increase of serum IL-33. The concentration of BALF IL-33 was also significantly elevated in AEP, however, it remained quite low in CEP. Among Th2 cytokines, IL-5 was significantly increased in both serum and BALF in AEP, and the level of IL-5 was positively correlated with that of IL-33. ARDS showed no increase of serum and BALF IL-33. CONCLUSIONS: The remarkable increase of BALF IL-33 in AEP indicated the local production of IL-33 in lungs. IL-33 is considered to be a local key molecule for triggering pulmonary eosinophilia, together with IL-5. BALF IL-33 appears to be a useful marker for discriminating AEP from CEP and ARDS.

[Clinical evaluation of inpatients with tuberculosis diagnosed after admission--comparison of characteristics of patients diagnosed with and without the acid-fast bacillus test].

PURPOSE: To evaluate the clinical characteristics of patients in whom tuberculosis was not suspected before admission but was diagnosed after admission. METHODS: We enrolled 39 inpatients who were diagnosed with tuberculosis between April 2007 and March 2011 at Jichi Medical University Hospital. The patients were divided into 2 groups as follows: those who underwent a preadmission acid-fast bacillus (AFB) test (AFB group) and those who did not (non-AFB group). We retrospectively evaluated the clinical characteristics of these 2 groups of patients. RESULTS: A total of 22 patients and 17 patients comprised the non-AFB and AFB groups, respectively. The prevalence rates of malignancy (9 vs. 2 patients, p = 0.04), extrapulmonary tuberculosis without pulmonary tuberculosis (9 vs. 2 patients, p = 0.04), and smear-negative tuberculosis (16 vs. 7 patients, p = 0.04) were higher in the non-AFB group than in the AFB group. In contrast, the computed tomographic findings of the patients with pulmonary tuberculosis revealed that compared with the AFB group, the non-AFB group had less consolidation (2 vs. 11 patients, p < 0.01) and fewer cavitary lesions (0 vs. 6 patients, p < 0.01) and more nodular lesions (8 vs. 2 patients, p < 0.01). We then divided the inpatients into groups with and without malignancy and compared their clinical characteristics. The mean interval from admission to diagnosis of tuberculosis was significantly longer in the patients with malignancy as an underlying disease than in those without malignancy (23.5 vs. 10.5 days; p < 0.01). CONCLUSION: Malignancy was the most frequent underlying disease in the tuberculosis inpatients in the non-AFB group and could be the reason for the delayed diagnosis of tuberculosis.

Patient-derived spheroids and patient-derived organoids simulate evolutions of lung cancer.

Cancer cells harbor many genetic mutations and gene expression profiles different from normal cells. Patient-derived cancer cells (PDCC) are preferred materials in cancer study. We established patient-derived spheroids (PDSs) and patient-derived organoids (PDOs) from PDCCs isolated from the malignant pleural effusion in 8 patients. The morphologies suggested that PDSs may be a model of local cancer extensions, while PDOs may be a model of distant cancer metastases. The gene expression profiles differed between PDSs and PDOs: Gene sets related to inflammatory responses and EMT were antithetically regulated in PDSs or in PDOs. PDSs demonstrated an attenuation of the pathways that contribute to the enhancement of transforming growth factor beta (TGF-ß) induced epithelial mesenchymal transition (EMT), while PDOs demonstrated an attenuation of it. Taken together, PDSs and PDOs have differences in both the interaction to the immune systems and to the stroma. PDSs and PDOs will provide a model system that enable intimate investigation of the behavior of cancer cells in the body.

A case of pulmonary tuberculosis with false negative QuantiFERON TB-2G Test.

A 57-year-old man was admitted to our hospital with a high fever and productive cough. He had a previous history of total gastrectomy and splenectomy at the age of 45 years due to gastric cancer. He also showed severe macrocytic anemia with low vitamin B12, and an infiltrative shadow was found in the right lung on an X-ray. Sputum examination on admission revealed no significant pathogenic bacteria, and an acid-fast stain and a M. tuberculosis PCR test were negative. QuantiFERON TB-2G Test (QFT) was negative on admission. Because pneumococcal antigen in the urine was positive, we initially diagnosed pneumococcal pneumonia and treatment with antibiotics was started. However, symptoms were not resolved with several antibiotics, finally, a thoracoscopic lung biopsy under general anesthesia was performed for a definitive diagnosis. The biopsy showed epithelioid cell granuloma in the alveolar spaces, and the 8 weeks culture of sputum taken on admission revealed M. tuberculosis. Finally, a pulmonary tuberculosis was diagnosed and treatment with four drugs of HERZ was begun. We have encountered a case of pulmonary tuberculosis combined with a lobar pneumococcal pneumonia, and negative for QFT. In general, splenectomy is known as a risk factor of pneumococcal infection. And vitamin B12 deficiency due to gastrectomy is one of the risk factors for cellular immunity impairment and was possibly to the false negative QFT and development of TB.

Virulent Pseudomonas aeruginosa pneumonia in an immunocompetent adult associated with a home whirlpool bath: A case report.

We present a case of life-threatening pneumonia caused by Pseudomonas aeruginosa (P. aeruginosa) in a healthy 67-year-old man. Rapid disseminated infection resulted in the right hemorrhagic pneumonia and bacteremia. Antimicrobial therapy had limited effects, radical pneumonectomy eventually resolved the prolonged infection. Concurrently, we explored the environmental factors responsible for fulminant P. aeruginosa infection. Multi-locus sequence typing demonstrated that P. aeruginosa isolated from the patient was identical to that collected from home whirlpool bath by the common virulent factor gene. Massive inhalation of contaminated aerosol and pathogen virulence may have synergistically contributed to the severity in this case.

Characterization of ST2 transgenic mice with resistance to IL-33.

IL-33, a member of the IL-1 family, activates MAPK and NF-kappaB through its receptor ST2L and IL-1RAcP. ST2, a member of the IL-1R superfamily, is a secreted form of ST2 gene products, which has been shown to act as a decoy receptor for IL-33 and to inhibit the IL-33/ST2L/IL-1RAcP signaling pathway. In this work, we generated ST2 transgenic mice. In control mice, intraperitoneal administration of IL-33 caused an increased number of eosinophils in blood and in peritoneal cavity, an increased number of peritoneal M Phi, splenomegaly, accumulation of periodic acid-Schiff-positive material in the lung, and high concentrations of serum IL-5 and IL-13. However, these alterations were hardly detectable in ST2 Tg mice. In peritoneal M Phi from IL-33-stimulated mice, mRNA expression of M2 M Phi marker genes were increased compared with thioglycollate-elicited peritoneal M Phi. The IL-33-stimulation also increased the secretion of IL-6 from M Phi. However, when the IL-33 was preincubated with ST2 prior to its addition to the M Phi cultures, the secretion of IL-6 was attenuated. These data suggest that, though IL-33 induced the Th2-type immune responses and infiltration of M2 type M Phi into the peritoneal cavity, ST2 can downregulate these reactions both in vivo and in vitro.

[Interstitial pneumonia with anti-PL-7 antibody difficult to distinguish from rheumatoid lung].

A 63-year-old woman had abnormal shadows on a chest radiograph taken on a medical examination during treatment for rheumatoid arthritis. The chest radiograph showed linear and reticular shadows and ground glass opacities in the bibasilar lung fields. Though we considered rheumatoid arthritis due to joint disorder and a positive reaction for serum anti-CCP antibody, there were no bone lesions or articular narrowing on radiographs of the fingers. We diagnosed antisynthetase syndrome after we obtained a positive reaction for serum anti-PL-7 antibody. Antisynthetase syndrome demonstrates findings similar to those of rheumatoid arthritis, and this disease should be taken into consideration if chest computed tomography demonstrates consolidation with predominant patchy and irregular bronchovascular bundle thickening with a subpleural distribution.

A comparative study of the Parker Flex-Tip tube versus standard portex tube for oral fiberoptic intubation in bronchoscopy performed by pulmonologists with limited experience.

BACKGROUND: Fiberoptic tracheal intubation (FTI) in bronchoscopy is widely performed with a conventional Portex tracheal tube (PTT). Occasionally, it is difficult for pulmonologists with limited experience to insert a tube beyond the vocal cords and advance it into the trachea. A new endotracheal tube, the Parker Flex-Tip tube (PFT), was recently designed. We compared the usefulness and safety of PFT versus PTT for FTI in bronchoscopy performed by pulmonologists with limited experience. METHODS: Forty consecutive patients were enrolled and randomly assigned to either the PFT group (n = 20) or PTT group (n = 20). The time required for the tip of the endotracheal tube to pass from the mouth to the carina, the number of vomiting reflexes, the number of attempts to pass the tube through the vocal cords during intubation, complications, and technical difficulty of intubation were evaluated. RESULTS: Both the PFT and PTT groups exhibited high intubation success rates (100% vs. 90%, respectively). The PFT group was intubated faster than the PTT group (11.5 [5-45] s vs. 22.5 [8-270] s, respectively, p < 0.01). The PFT group showed fewer vomiting reflexes and tube impingements than the PTT group (p < 0.05). Operators felt it was easier to intubate with PFT versus PTT (p < 0.01). Complications were not significantly different between the two groups. CONCLUSION: For pulmonologists with limited experience who perform FTI in bronchoscopy, intubation using PFT versus PTT is faster and easier, without an increase in complications.

Highly sensitive detection of driver mutations from cytological samples and cfDNA in lung cancer.

BACKGROUND: Bronchoscopy is a minimally invasive procedure for establishing the diagnosis of lung cancer. It sometimes fails to obtain tissue samples but readily collects cytological samples. METHODS: We developed PNA-LNA dual-PCR (PLDP), which amplified mutant sequences by a high-fidelity DNA polymerase in the presence of a peptide nucleic acid (PNA) oligomer having a wild-type sequence. Mutations are detected either by locked nucleic acid (LNA) probes for quick detection of a limited number of mutations, which are EGFR, KRAS, and BRAF mutations in the current study, or by direct sequencing for a comprehensive screening. In a total of 233 lung cancer samples, the results for cytological samples by PLDP were compared with those for tissue samples by cobas® EGFR mutation test (cobas) or by the PNA-LNA PCR clamp method (P-LPC). Moreover, the performance of PLDP using cell-free DNA (cfDNA) was investigated. RESULTS: Peptide nucleic acid-LNA dual-PCR was able to detect each synthesized mutant sequence with high sensitivity. PLDP detected EGFR mutations in 80 out of 149 clinical samples, while the cobas or the P-LPC detected in 66 matched. The correctness of PLDP was confirmed both by clinical response and by the results of sequencing using a next-generation sequencer. PLDP detected mutations from cfDNA in approximately 70% of patients who harbors mutations in the tumor. CONCLUSIONS: Peptide nucleic acid-LNA dual-PCR exhibited an excellent performance, even using cytological samples. PLDP is applicable for the investigation of cfDNA. The combination of bronchoscopy and PLDP is attractive and will expand the utility of bronchoscopy in clinical practice.

Cytological detection of metastatic chordoma cells in pleural effusions: A case report.

Cytological detection of chordoma cells in the serosal cavity is challenging because of its rare presentation. Herein, we report a case of chordoma showing malignant pleural effusion accompanied by pleuropulmonary metastases in a 68-year-old woman. Cytological analysis was performed using pleural fluid obtained following thoracentesis. Conventional cytological staining demonstrated few clusters of large, atypical cells characterized by epithelial cell-like connectivity and rich cytoplasm with foamy and/or multivacuolar changes. The nuclei of these atypical cells were large and either round or oval with no conspicuous irregularities in the nuclear membrane. Periodic acid-Schiff staining of these atypical cells revealed fine granules in the cytoplasm. Giemsa staining showed foamy and/or multivacuolar cytoplasm in these cells, with metachromatic mucoid stroma in the surroundings. Immunocytochemistry analysis using cellblock showed these cells to be positive for broad cytokeratins, epithelial membrane antigen, S100 protein, vimentin, and Brachyury. To the best of our knowledge, this is the first case report in which chordoma cells were cytologically detected in pleural effusions. Our findings also suggest that conventional cytology combined with cellblock immunocytochemistry can increase the accuracy of chordoma cell detection in the serosal cavity.

[Role of IL-33 in bronchial asthma].

IL-33 is a member of the IL-1 family and has been identified as an agonist of ST2L. IL-33 drives the production of Th2-associated cytokines and IgE, and IL-33 administration induces eosinophilia and hypertrophy of bronchial epithelial cells, as well as mucus secretion in vivo. Such changes resemble pathological findings in bronchial asthma (BA). In this study, we investigated the relationship between IL-33 and BA by evaluating serum IL-33 levels. Serum was obtained from BA patients (n = 20), emphysema patients (n = 5) and from non-smoking healthy controls (n = 8). IL-33 levels were assayed by enzyme-linked immunosorbent assay. Then, we divided BA patients according to 5 factors; (1) IgE concentration, (2) eosinophil count, (3) current treatment, (4) classification of severity, and (5) smoking status. Atopic BA patients showed significantly higher IL-33 levels than non-atopic patients. IL-33 was significantly higher in untreated patients, and in the moderate and severely affected groups. Smoking BA and emphysema patients had lower levels than nonsmoking BA patients. Eosinophil counts were not related to IL-33 levels. The present study suggests that IL-33 is closely associated with IgE levels and the exacerbation of BA. We speculated that IL-33 elevation is responsible for the maintenance of airway inflammation and hypersensitivity. It is possible that low IL-33 levels in smokers are caused by the deterioration of the airway epithelium and endothelium.

A case of lymphocytic interstitial pneumonia presenting with a ground glass nodule as an initial finding.

A 65-year-old woman had a ground glass nodule, which was suspicious for lung cancer, in her right lung S6 by chest computed tomography. For diagnosis, video-assisted thoracoscopic surgery was performed, and the specimen showed a pathological pattern of lymphocytic interstitial pneumonia (LIP). Four years after surgery, new localized ground glass shadows gradually increased on the base of the lung. However, because she had no respiratory symptoms and had normal respiratory function, she was observed with no medication. Subsequently, no other underlying diseases associated with LIP developed. The ground glass nodule was the initial lesion of LIP.