Kinetic changes in serum KL-6 levels predict disease progression in patients with systemic sclerosis-associated interstitial lung disease.

BACKGROUND: The clinical course of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable. The Krebs von den Lungen-6 (KL-6) glycoprotein is a promising biomarker for reflecting epithelial injury. However, serum KL-6 and its association with the progression of SSc-ILD have been understudied. METHODS: We reviewed 77 consecutive patients with SSc-ILD seen from 2004 to 2016. A longitudinal study of forced vital capacity (FVC), serum KL-6 levels, and changes in KL-6 levels from baseline (ΔKL-6) was conducted. The progression of ILD was defined as ≥10% relative decline in FVC predicted or 5%-10% decline in FVC predicted along with radiological progression on chest computed tomography. The risk factors for ILD progression were assessed by univariate and multivariate regression. RESULTS: During a 5-year follow-up period, 10 (13%) patients showed rapid progression of ILD within 2 years, 39 (51%) showed overall progression during the 5 years, and 28 (36%) had stable disease. Most patients with progressive ILD showed elevations in serum KL-6 levels over the initial 1-year follow-up period. The best cut-off value for ΔKL-6 that predicted progression of ILD was 193 U/mL (sensitivity 81.6%, specificity 92.9%). Multivariate analysis adjusted by age, sex, smoking status, and immunosuppressant use found that diffuse cutaneous SSc (hazard ratio [HR] 4.51; 95% confidence interval [CI] 1.56-13.04) and ΔKL-6 > 193 U/mL from baseline (HR 7.19; 95% CI 3.30-15.69) were independent predictors for progression of SSc-ILD. CONCLUSION: Changes in the KL-6 level can be useful for predicting disease progression in patients with SSc-ILD.

Fractional analysis of bronchoalveolar lavage in systemic sclerosis-associated interstitial lung disease.

BACKGROUND: The utility of bronchoalveolar lavage (BAL) in the evaluation of systemic sclerosis-associated interstitial lung disease (SSc-ILD) remains controversial. Fractional analysis of BAL (FBAL) is a technique that can analyze small airways and alveolar compartments separately and has proven informative in other ILDs. The aim of this study was to explore FBAL characteristics across the spectrum of SSc-ILD severity. METHODS: We retrospectively reviewed patients with SSc-ILD who underwent bronchoscopy with FBAL using three 50 mL aliquots of saline solution. These aliquots were analyzed separately for differential cell composition (FBAL-1, -2, and -3). We compared the FBAL cell composition to the progression of ILD and end-stages of ILD using Cox proportional hazards models. RESULTS: Sixty-eight patients with SSc-ILD were enrolled in this study. The percentage of neutrophils and eosinophils was lower in FBAL-3 compared to FBAL-1. In contrast, the percentage of macrophages and lymphocytes was higher in FBAL-3. Neutrophils in FBAL-2, -3, and the estimated total FBAL cell fraction (FBAL-total) were negatively correlated with the forced vital capacity % predicted (r=-0.420, -0.362, -0.409, respectively). Although FBAL-total was not linked to the progression and end-stage of ILD, a high percentage of neutrophils in FBAL-3 was significantly associated with the development of end-stage ILD (HR 1.093, 95% CI: 1.003-1.190). CONCLUSIONS: A higher percentage of neutrophils in FBAL-3 is correlated with development of end-stage ILD in SSc-ILD as well as mortality.

Surfactant protein D: a useful marker for differentiation of drug-induced pneumonia and bacterial pneumonia.

BACKGROUND: Drug-induced pneumonia (d-pneumonia) and bacterial pneumonia (b-pneumonia) are often difficult to differentiate; therefore, this study examined the possibility of differentiating them using serum biomarkers. METHODS: The study included 22 and 16 patients diagnosed with b- and d-pneumonia, respectively, at our institution or affiliated institutions. For d-pneumonia, the causative drug was minocycline hydrochloride in four patients, gefitinib in two patients, nivolumab in two patients, pembrolizumab in two patients, sulfasalazine in two patients, loxoprofen in one patient, Bouiougitou in one patient, edoxaban tosilate hydrate in one patient, and abemaciclib in one patient. White blood cell (WBC), C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-D, and SP-A levels were measured in each patient and compared between the groups. RESULTS: Significant differences were noted in the WBC and SP-D levels between the two groups (P < 0.05, P < 0.001), but not in the CRP, KL-6, or SP-A levels. CONCLUSION: The study results suggest that SP-D is a useful marker for differentiating b-pneumonia and d-pneumonia.

Lung cancer in connective tissue disease-associated interstitial lung disease: clinical features and impact on outcomes.

BACKGROUNDS: Lung cancer (LC) adversely impacts survival in patients with idiopathic pulmonary fibrosis. However, little is known about LC in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). The aim of this study was to evaluate the prevalence of and risk factors for LC in CTD-ILD, and the clinical characteristics and survival of CTD-ILD patients with LC. METHODS: We conducted a single-center, retrospective review of patients with CTD-ILD from 2003 to 2016. Patients with pathologically diagnosed LC were identified. The prevalence, risk factors, and clinical features of LC and the impact of LC on CTD-ILD patient outcomes were observed. RESULTS: Of 266 patients with CTD-ILD, 24 (9.0%) had LC. CTD-ILD with LC was more likely in patients who were older, male, and smokers; had rheumatoid arthritis, a usual interstitial pneumonia pattern, emphysema on chest computed tomography scan, and lower diffusing capacity of the lung carbon monoxide (DLco)% predicted; and were not receiving immunosuppressive therapy. Multivariate analysis indicated that the presence of emphysema [odds ratio (OR), 8.473; 95% confidence interval (CI), 2.241-32.033] and nonuse of immunosuppressive therapy (OR, 8.111; 95% CI, 2.457-26.775) were independent risk factors for LC. CTD-ILD patients with LC had significantly worse survival than patients without LC (10-year survival rate: 28.5% vs. 81.8%, P<0.001). CONCLUSIONS: LC is associated with the presence of emphysema and nonuse of immunosuppressive therapy, and contributes to increased mortality in patients with CTD-ILD.

Immunoglobulin G4-related disease preceded by lung involvement: A case report.

RATIONALE: Immunoglobulin G4-related disease (IgG4-RD) is a systemic condition involving various organs and vessels including the pancreas, bile duct, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, and aorta. Recently, some cases of IgG4-RD have been reported, in which only pulmonary lesions were present. It is not known whether IgG4-RD can be diagnosed on the basis of pulmonary lesions only, because increases in serum IgG4 levels and infiltration of IgG4-positive plasma cells into the lung tissue also occur in other inflammatory conditions. A case of IgG-RD that was followed-up for 7 years after onset is described. PATIENT CONCERNS: Initially, only pulmonary lesions were present; however, other lesions in the submandibular glands, pancreas, periarterial region, and other areas occurred over time, with a gradual increase in serum IgG4 levels. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Histopathology results from the patient's submandibular gland confirmed the diagnosis of IgG4-RD. Following diagnosis, the patient was treated with corticosteroids immediately, and his symptoms disappeared rapidly. LESSONS: Because other diseases, including malignancies, mimic IgG4-RD in clinical and histopathological features, an absolute diagnosis is necessary to avoid missing the presence of underlying diseases. This case more provides insight into the clinical pathology of IgG4-RD.

Imatinib ameliorates bronchiolitis obliterans via inhibition of fibrocyte migration and differentiation.

BACKGROUND: Imatinib, a tyrosine kinase inhibitor, has been proposed as a potential anti-fibrotic agent for fibroproliferative diseases, including bronchiolitis obliterans (BO). However, the underlying anti-fibrotic mechanisms of the agent remain unclear. We evaluated whether bone (BM)-derived progenitor cells, fibrocytes, might be a target of imatinib in the attenuation of BO. METHODS: We used a murine BO model induced by heterotopic tracheal transplantation and assessed the origin of fibroblasts by using green fluorescent protein-BM chimeric mice. We also evaluated the effects of imatinib on luminal obstruction and fibrocyte accumulation. The effects of imatinib on fibrocyte migration and differentiation were assessed by culturing fibrocytes in vitro. RESULTS: In the murine BO model, tracheal allografts showed epithelial injury and developed complete luminal occlusion 28 days after transplantation. Most of the mesenchymal cells that had accumulated in the tracheal allograft were derived from BM cells. Imatinib treatment ameliorated the airway luminal occlusion and significantly reduced the number of fibrocytes in the allografts. In vitro studies showed that imatinib inhibited migration of cultured blood fibrocytes via the platelet-derived growth factor/platelet-derived growth factor receptor axis. Imatinib also inhibited differentiation of fibrocytes via suppression of c-Abl activity that was essential for the differentiation of monocytes to fibrocytes. CONCLUSIONS: Imatinib prevents airway luminal obstruction by inhibiting the migration and differentiation of fibrocytes. Fibrocytes may be a novel target in the prevention and treatment of BO.

Patients with End-stage Interstitial Lung Disease may have More Problems with Dyspnea than End-stage Lung Cancer Patients.

INTRODUCTION: Patients with end-stage interstitial  lung disease (ILD) do not appear to receive adequate palliative care despite apparent suffering before death. The aim of this study was to evaluate their signs, symptoms, and treatment received before death. METHODS: Patients with ILD and lung cancer (LC) who were hospitalized and died in our hospital were enrolled retrospectively. Signs and symptoms and treatments at 7 days, 3 days, and 1 day before death were evaluated and compared between the two groups of patients. RESULTS: A total of 23 patients with ILD and 59 patients with LC group were eligible for participation. Significantly more LC patients had loss of consciousness than ILD patients on 7 days (ILD: LC = 1 [5.6%]:24 [41%], P = 0.013), 3 days (1 [5.6%]:33 [56%], P < 0.001). Significantly more ILD patients had dyspnea than LC patients on 3 days (16 [89%]:38 [64%], P = 0.047) 1 day before death (21 [91%]:33 [56%], P = 0.001). On 1 day before death, significantly more LC patients received morphine than ILD patients (2 [8.7%]: 14 [24%], P = 0.015). More ILD patients received sedation (11 [48%]: 11 [19%], P = 0.007). CONCLUSIONS: End-stage ILD patients may experience dyspnea more frequently than terminal LC patients, and they need sedation. Morphine should be administered to ILD patients who have dyspnea. Additional prospective studies are needed.

Antisynthetase syndrome: Pulmonary computed tomography findings of adult patients with antibodies to aminoacyl-tRNA synthetases.

OBJECTIVES: To describe the pulmonary CT findings in patients with anti-ARS-antibody-positive interstitial lung disease (anti-ARS-ILD) METHODS: The CT findings of 64 patients with anti-ARS-ILD were retrospectively reviewed. The images were retrospectively reviewed independently by 2 chest radiologists, and the final decision on the CT findings was made by a third chest radiologist. RESULTS: There were 16 male and 48 female patients, aged 54.2±13.4 years. Sixteen patients had anti Jo-1, 24 had anti-EJ, 9 had anti-PL-7, 7 had anti-PL-12, 5 had anti-KS, and 3 had anti-OJ antibodies. Overall, 63 patients (98.4%) had CT findings predominantly in the lower lobe; 61 patients (95.3%) showed peripheral opacities, and 47 patients (73.4%) showed peribronchovascular opacities. Ground-glass attenuation, consolidation, and reticulation showed similar distribution patterns. Regarding detailed CT findings, 89.1% of patients had lower volume loss, 76.6% had interlobular septal thickening, and 67.2% had thickening of bronchovascular bundles. The final radiologic diagnoses were as follows: inconsistent with usual interstitial pneumonia (UIP) in 63 patients (98.4%), which included nonspecific interstitial pneumonia (NSIP) in 35 patients (55.6%), organizing pneumonia (OP) in 4 patients (6.3%), and OP with fibrosis in 22 patients (34.9%). CONCLUSIONS: The characteristic CT findings of patients with anti-ARS-ILD were areas of ground-glass attenuation and reticulation, predominantly distributed as lower and peribronchovascular lesions, which is compatible with NSIP. One-third of patients showed OP with fibrosis.

Pleuroparenchymal fibroelastosis: Distinct pulmonary physiological features in nine patients.

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia defined by pleural and subpleural parenchymal fibrosis predominantly in the upper lobes. Although the radiological and pathological characteristics of PPFE have become increasingly recognized, its pulmonary physiological features are not well understood. METHODS: We reviewed nine patients with radiologically and histologically proven PPFE, and evaluated pulmonary physiological data. RESULTS: Of the nine patients, six were male and three were female. The median age at presentation was 61 years. Common symptoms were dyspnea on exertion, weight loss, and nonproductive cough. Recurrent pneumothorax was found in eight patients and pneumonia in four. Median pulmonary function test results were as follows: forced vital capacity, 55.4% predicted; total lung capacity (TLC), 67.1% predicted; residual volume (RV), 102.3% predicted; and RV/TLC, 143.6% predicted. RV/TLC was increased without evidence of small airway disease according to clinico-radiologic-pathologic evaluation. The median partial pressure of oxygen in arterial blood and the alveolar-arterial gradient of oxygen were within normal limits, although there was a slightly elevated partial pressure of carbon dioxide in arterial blood (PaCO2). PPFE progressed in all patients despite treatment with pirfenidone, corticosteroids, and immunosuppressive agents. Seven patients died during the follow-up, five because of hypercapnic respiratory failure. CONCLUSIONS: PPFE is characterized by severe mechanical restriction with high RV/TLC, causing increased PaCO2 and eventual hypercapnic respiratory failure. These physiological findings may be useful as an adjunct in the diagnosis of PPFE.

Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma.

We report the case of a 52-year-old woman with lung adenocarcinoma treated with EGFR tyrosine kinase inhibitor (TKI) therapy. After disease progression, histological examination of a secondary biopsy specimen revealed small-cell lung cancer (SCLC) that was sensitive to standard SCLC treatment. Tumor markers, including ProGRP and NSE, were elevated. Transformation to SCLC is a mechanism for acquired resistance to EGFR-TKI therapy. Secondary biopsy is important for evaluation of genetic and histological changes and selection of appropriate treatment. Furthermore, ProGRP and NSE may be useful for early detection of SCLC transformation in cases resistant to EGFR-TKI therapy.

Pulmonary manifestations of anti-ARS antibody positive interstitial pneumonia--with or without PM/DM.

BACKGROUND: Autoantibodies against aminoacyl-tRNA synthetases (ARS) have been found to be highly specific for polymyositis and dermatomyositis (PM/DM) and to correlate strongly with complicating interstitial pneumonia (IP). The aim of the present study was to compare the clinical presentations of anti-ARS antibody-positive IP patients with or without manifestations of PM/DM. METHODS: We retrospectively examined 36 IP patients with anti-ARS antibodies. Sixteen patients presented with and 20 without the features of PM/DM. They were divided into PM/DM-IP and idiopathic-IP (IIP) groups. Clinical symptoms, findings on physical examination, laboratory data, pulmonary function, computed tomography (CT), and bronchoalveolar lavage fluid (BALF) cell counts were compared. RESULTS: Skin findings, myalgia, and elevation of serum creatinine kinase were found in the PM/DM-IP group. Features common to both groups included: volume loss in lower bilateral lobes; ground-glass opacities, reticular shadows and traction bronchiectasis on chest CT; high percentage of lymphocytes (IIP: 44.0% ± 21.0% (mean ± SD), PM/DM-IP: 50.5% ± 23.5%) and low CD4/8 ratios (IIP: 0.36 ± 0.34, PM/DM-IP: 0.44 ± 0.42) in BALF; decreased pulmonary function, including percentage of predicted vital capacity (VC) (IIP: 80.1% ± 15.4%, PM/DM-IP: 73.6% ± 16.4%), residual volume (RV) (IIP: 70.7% ± 21.7%, PM/DM-IP: 71.5% ± 17.1%), total lung capacity (TLC) (IIP: 73.4% ± 13.6%, PM/DM-IP: 71.6% ± 13.0%), and diffusing capacity DLco (IIP: 57.5% ± 26.7%, PM/DM-IP: 46.4% ± 10.3%). Both groups achieved good responses to initial corticosteroid or immunosuppressant therapy. CONCLUSION: Patients with anti-ARS antibody-positive IP have common pulmonary manifestations regardless of the presence of PM/DM.

Successful treatment with chemotherapy and corticosteroids of pulmonary Mycobacterium abscessus infection accompanied by pleural effusion.

We describe a 50-year-old woman with rapidly progressive pulmonary Mycobacterium abscessus (M. abscessus) infection accompanied by pleural effusion and organizing pneumonia (OP). CT scan showed consolidation, centrilobular shadows, ground-glass opacity (GGO), and cavities. A transbronchial lung biopsy showed nonnecrotizing granuloma surrounded by infiltrative lymphocyte-dominant inflammatory cells, and lymphocytes in bronchoalveolar lavage fluid (BALF) were increased. We considered OP occurred secondary to M. abscessus infection because clarithromycin, amikacin, and imipenem/cilastatin administration resulted in partial improvement. We added corticosteroids to the regimen, which resulted in a remarkable improvement. We report a case of pulmonary M. abscessus infection involving pleural effusion that responded favorably to medical therapy including corticosteroids.

Pulmonary T-cell lymphoma with pulmonary arterial hypertension.

We report on a 73-year-old man with systemic lymphadenopathy and chest computed tomography (CT) findings of bilateral diffuse ground-glass opacities and interlobular septal thickening. He also had pulmonary arterial hypertension (PAH). Several lymph node biopsies were attempted, without a definitive diagnosis. A thoracoscopic lung biopsy was performed, and the specimen was diagnosed as peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Lymphoma cells had invaded lung vessels, resulting in PAH. We should include pulmonary lymphoma in the differential diagnosis of patients with PAH and chest CT findings of diffuse ground-glass opacities and interlobular septal thickening.

The specific chymase inhibitor TY-51469 suppresses the accumulation of neutrophils in the lung and reduces silica-induced pulmonary fibrosis in mice.

Chymase is a chymotrypsin-like serine protease that is present in mast cells. Its activities include various effects associated with inflammatory responses. But little is known about the effects of chymase in pulmonary fibrosis. The mouse silicosis model was induced by intratracheal injection of 10 mg silica. The Ashcroft pathological score and the hydroxyproline content of lungs were measured to evaluate the effect of a chymase inhibitor, 2-[4-(5-fluoro-3-methylbenzo[b]thiophen-2-yl)sulfonamido-3-methanesulfonylphenyl] thiazole-4-carboxylic acid (TY-51469). The cellular composition and cytokine levels in bronchoalveolar lavage fluid (BALF) were also examined. Following TY-51469 treatment, the lung fibrosis score and hydroxyproline level were significantly reduced, and the number of neutrophils and the levels of macrophage inflammatory protein-2, monocyte chemoattractant protein-1, and transforming growth factor-ß1 in BALF were reduced on day 21. The administration of TY-51469 at an early stage showed a greater reduction of fibrosis compared to administration at a later stage. The neutrophil number in BALF in mice treated with TY-51469 both at an early stage and late stage was significantly reduced. The level of mouse mast cell proteinase-4 mRNA increased with time in silica-induced fibrosing lung tissue. These results show that the chymase inhibitor TY51469 suppresses the migration of neutrophils, which results in the suppression of lung fibrosis.

A case of microscopic polyangiitis following mycoplasma infection in a patient with MPO-ANCA positive pulmonary fibrosis.

BACKGROUND: Microscopic polyangiitis is a vasculitic disease that may result in a pulmonary renal syndrome. Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis is strongly associated with infection. CASE SUMMARY: We describe a case of microscopic polyangiitis that developed in a patient with MPO-ANCA positive pulmonary fibrosis following infection with mycoplasma. A renal biopsy was undertaken following the detection of microscopic hematuria during follow-up but no abnormal findings were evident. The MPO-ANCA titer increased following infection with mycoplasma pneumonia and a second renal biopsy demonstrated crescentic glomerulonephritis. The degree of pulmonary fibrosis was unaffected. DISCUSSION: The present case suggests that the mycoplasma infection triggered the elevation of MPO-ANCA titer and provoked glomerulonephritis in a patient with MPO-ANCA positive IPF. This case indicates the importance of testing for MPO-ANCA at the time of initial diagnosis, performing urinalysis and examining the urine sediment during follow-up and being alert to the potential onset of vasculitis in cases of pulmonary fibrosis.

[A case of repeated bilateral pneumothorax associated with upper lobe predominant fibrosis in an aluminum processing worker].

A 39-year-old man, who had been working in an aluminum processing industry for 18 years, visited our hospital for right chest pain on March 2, 2007. A relapse of right pneumothorax was found, and he was hospitalized. As the pneumothorax did not improve with conservative treatment, video-assisted thoracoscopic biopsy and suturing of the right upper lobe were successfully performed. The pulmonary parenchyma had collapsed, there was pulmonary fibrosis, and lymphocytes had gathered in follicules. Based on elemental analysis results, we diagnosed aluminum lung. It was thought that overexpansion of the lower lobe with the predominant upper lobe fibrosis was caused by the aluminum deposition. We judged his condition to be serious and we started treatment with 25 mg/day prednisolone (PSL), and 120 mg/day cyclosporine (CyA). At the time of writing, he is an outpatient, and is being monitored on a regimen of 5 mg/day PSL and 160 mg/day CyA without any progression of pulmonary fibrosis or relapse of pneumothorax.

Sputum eosinophilia, airway hyperresponsiveness and airway narrowing in young adults with former asthma.

BACKGROUND: 30-80% of outgrown asthma subjects develop symptoms again later in life. We investigated inflammation and function of lower airway in adolescents with former asthma. METHODS: 326 never-smoking young adults (mean age 24.0 years) were interviewed with special emphasis on history of asthma. Diagnosis of asthma was based on GINA guidelines. Former asthma subjects consisted of ones with a history of physician-diagnosed childhood asthma, who had been free of asthma symptoms without the use of medication for at least 10 years prior to the study. Provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second (FEV(1))(PC(20)) and eosinophil percentage in induced sputum were measured. RESULTS: 31 subjects were former asthma subjects (FBA), 11 subjects were current asthma subjects (CBA) and 284 subjects had no history of asthma (non-BA). PC(20) and FEV(1)/FVC ratio were significantly lower in the FBA group than in the non-BA group (P < 0.01). Maximal mid-expiratory flow (MMF) was significantly lower in the FBA group than in the non-BA group (P < 0.05). Sputum eosinophil percentage was significantly increased in the FBA group compared with the non-BA group (P < 0.01). PC(20) was significantly lower in the CBA group than in the FBA and non-BA groups (P < 0.01). FEV(1), FEV(1)/FVC ratio and MMF were significantly lower in the CBA group than in the FBA group (P < 0.05, P < 0.05 and P < 0.05, respectively) and the non-BA group (P < 0.01, P < 0.01 and P < 0.05, respectively). Sputum eosinophils were significantly higher in the CBA group than in the FBA and non-BA groups (P < 0.01). CONCLUSIONS: This study shows that subjects with long-term outgrown asthma continue to have airway eosinophilic inflammation, airway hyperresponsiveness and airway narrowing.

Angiotensin II type 2 receptor antagonist reduces bleomycin-induced pulmonary fibrosis in mice.

BACKGROUND: The role of angiotensin II type 2 receptor (AT2) in pulmonary fibrosis is unknown. To evaluate the influence of angiotensin II type 1 receptor (AT1) and AT2 antagonists in a mouse model of bleomycin (BLM)-induced pulmonary fibrosis. METHODS: We examined effects of the AT1 antagonist (AT1A) olmesartan medoxomil (olmesartan) and the AT2 antagonist (AT2A) PD-123319 on BLM-induced pulmonary fibrosis, which was evaluated by Ashcroft's pathological scoring and hydroxyproline content of lungs. We also analyzed the cellular composition and cytokine levels in bronchoalveolar lavage fluid (BALF). RESULTS: With olmesartan, the lung fibrosis score and hydroxyproline level were significantly reduced, and lymphocyte and neutrophil counts and tumor necrosis factor (TNF)-alpha levels in BALF were reduced on day 7. On day 14, macrophage and lymphocyte counts in BALF were reduced, accompanied by a reduction in the level of transforming growth factor (TGF)-beta1. With PD-123319, the lung fibrosis score and hydroxyproline level were reduced. On day 7, macrophage, lymphocyte, and neutrophil counts in BALF were reduced, accompanied by reductions in TNF-alpha and monocyte chemoattractant protein (MCP)-1 levels. On day 14, macrophage, lymphocyte, and neutrophil counts in BALF were also reduced, accompanied by a reduction in the level of macrophage inflammatory protein (MIP)-2 level but not TGF-beta1. CONCLUSION: Both AT1 and AT2 are involved in promoting interstitial pneumonia and pulmonary fibrosis via different mechanisms of action.