Pulmonary Structural Remodeling Research Articles

Tacrolimus alleviates pulmonary fibrosis progression through inhibiting the activation and interaction of ILC2 and monocytes

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous group of lung diseases with different etiologies and characterized by progressive fibrosis. This disease usually causes pulmonary structural remodeling and decreased pulmonary function. The median survival of IPF patients is 2–5 years. Predominantly accumulation of type II innate immune cells accelerates fibrosis progression by secreting multiple pro-fibrotic cytokines. Group 2 innate lymphoid cells (ILC2) and monocytes/macrophages play key roles in innate immunity and aggravate the formation of pro-fibrotic environment. As a potent immunosuppressant, tacrolimus has shown efficacy in alleviating the progression of pulmonary fibrosis. In this study, we found that tacrolimus is capable of suppressing ILC2 activation, monocyte differentiation and the interaction of these two cells. This effect further reduced activation of monocyte-derived macrophages (Mo-M), thus resulting in a decline of myofibroblast activation and collagen deposition. The combination of tacrolimus and nintedanib was more effective than either drug alone. This study will reveal the specific process of tacrolimus alleviating pulmonary fibrosis by regulating type II immunity, and explore the potential feasibility of tacrolimus combined with nintedanib in the treatment of pulmonary fibrosis. This project will provide new ideas for clinical optimization of anti-pulmonary fibrosis drug strategies.

Impact of COPD pulmonary structural remodeling on the prognosis of patients with advanced lung squamous cell carcinoma

BackgroundBy observing the changes of lung imaging airway structure in patients with advanced lung squamous cell carcinoma（ALUSC）, the relationship between the different types of COPD pulmonary structural remodeling and the prognosis of patients with ALUSC was analyzed. MethodsWe reviewed the medical records of 278 patients with ALUSC. The degree of emphysema and the percentage of bronchial wall thickness（WT%） on chest HRCT were calculated by Synapse3D software, Lung structural remodeling can be divided into there types: airway remodeling dominated, emphysema dominated, and mixed types. ResultsCompared with the diagnosis, the Goddard score increased, the proportion of airway remodeling dominated type decreased and the proportion of mixed type increased during the progression of ALUSC. In Kaplan-Meier analysis, whether with or without COPD, the mPFS and mOS of patients with mixed type were the shortest, and the difference was statistically significant. Univariate and multivariate Cox proportional hazard regression analysis showed that mixed type was an independent risk factor for poor PFS and OS in patients with ALUSC. ConclusionPatients with ALUSC all have varying degrees of lung structural remodeling, and patients with mixed lung structural remodeling have the worst prognosis. In addition, the aggravation of emphysema during tumor progression is more pronounced than the thickening of the airway wall, and the changes of emphysema was more powerful in predicting the progression of ALUSC.Clinicians must pay more attention to the changes of COPD (especially emphysema) in the process of diagnosis and treatment of ALUSC.

Correlation analysis between mechanical power, transforming growth factor-β1, and connective tissue growth factor levels in acute respiratory distress syndrome patients and their clinical significance in pulmonary structural remodeling.

Background:To identify the clinical correlations between mechanical power and transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) in acute respiratory distress syndrome (ARDS) patients, their clinical significance in pulmonary structural remodeling in ARDS patients was investigated.Methods:Ninety-five patients with moderate or severe ARDS, who required mechanical ventilation therapy, were randomly selected among hospitalized patients from January 2017 to February 2019. Their mechanical power was monitored and recorded, the TGF-β1 and CTGF levels were detected by enzyme-linked immunosorbent assay (ELISA), their relevance was analyzed, and the relationship between mechanical power and 28-day survival rate was investigated. According to the high-resolution computed tomography (HRCT) examination, the patients were divided into an ARDS group and an ARDS pulmonary fibrosis (ARDS-PF) group. The differences in mechanical power, TGF-β1, and CTGF between the 2 groups were compared, and the significance of TGF-β1 and CTGF in the diagnosis of ARDS pulmonary interstitial fibrosis were evaluated.Results:A significant positive correlation between mechanical power and serum TGF-β1 and CTGF in patients with ARDS was found and the correlation coefficients were 0.424 and 0.581, respectively. The difference between mechanical power and 28-day survival rate was statistically significant (P < .05), while the area under the receiver operating characteristic curves of TGF-β1 and CTGF for the diagnosis of ARDS pulmonary fibrosis was 0.838 and 0.884, respectively (P < .05).Conclusion:A significant correlation between mechanical power and serum fibrosis biomarkers TGF-β1 and CTGF in ARDS patients was found, and its level was related to the survival prognosis of patients. Mechanical power, TGF-β1, and CTGF were clinically evaluated for the assessment of lung structural remodeling, such as ARDS pulmonary fibrosis. This study has particular significance to the early prevention of ventilator-induced lung injury and pulmonary fibrosis in patients with ARDS receiving mechanical ventilation.

Bao Yuan decoction and Tao Hong Si Wu decoction improve lung structural remodeling in a rat model of myocardial infarction: Possible involvement of suppression of inflammation and fibrosis and regulation of the TGF-β1/Smad3 and NF-κB pathways.

Chronic heart failure (CHF) leads to pulmonary structural remodeling, which may be a key factor for poor clinical outcomes in patients with end-stage heart failure, and few effective therapeutic options are presently available. The aim of the current study was to explore the mechanism of action and pulmonary-protective effects of treatment with Bao Yuan decoction combined with Tao Hong Si Wu decoction (BYTH) on lung structural remodeling in rats with ischemic heart failure. In a model of myocardial infarction (MI) induced by ligation of the left anterior descending (LAD) artery, rats were treated with BYTH. Heart function and morphometry were measured followed by echocardiography, histological staining, and immunohistochemical analysis of lung sections. The levels of transforming growth factor-β1 (TGF-β1), type I collagen, phosphorylated-Smad3 (p-Smad3), tumor necrosis factor-α (TNF-α), toll-like receptor 4 (TLR4), active nuclear factor κB (NF-κB) and alpha smooth muscle actin (α-SMA) were detected using Western blotting. Lung weight increased after an infarct with no evidence of pulmonary edema and returned to normal as a result of BYTH. In addition, BYTH treatment reduced levels of type I collagen, TGF-β1, and α-SMA expression and decreased the phosphorylation of Smad3 in the lungs of rats after MI. BYTH treatment also reduced the elevated levels of lung inflammatory mediators such as TNF-α, TLR4, and NF-κB. Results suggested that BYTH could effectively improve lung structural remodeling after MI because of its anti-inflammatory and anti-fibrotic action, which may be mediated by suppression of the TGF-β1/Smad3 and NF-κB signaling pathways.

[The role of cellular retinol-binding protein-1 on pulmonary structural remodeling after rat myocardial infarction].

To observe the expression of cellular retinol-binding protein-1 (CRBP-1) in pulmonary tissues after rat myocardial infarction (MI) and uncover the role of CRBP-1 on the pulmonary structural remodeling. MI was produced in male Wistar rats by left coronary ligation. Rats were sacrificed to obtain the lung at the 3(rd), 6(th), 15(th), 30(th), and 45(th) day after operation. After weighted, the rat lungs were fixed in 4% formalin and embedded in paraffin. Sections were cut and stained with hematoxylin and eosin (HE), Masson's trichrome (MT), rabbit anti-CRBP-1 antibody. Thirty-nine Wistar rats survived and developed MI. Pulmonary tissue sections with HE and MT staining showed a remarkable lung structural remodeling. The content of pulmonary tissue collagen at the 30(rd) was higher than in the sham group (8.4% ± 3.6 vs 4.5% ± 2.6, P < 0.001). CRBP-1 expression was detected on the alveolar septa at the 3(rd) day after operation, and peaked at the 15(th) day (43.8 ± 7.4). Then the CRBP-1 expression decreased, and arrived at the level of the 3(rd) day. We demonstrate that CRBP-1 is expressed temporal on the alveolar septa after rat MI. It indicates a potential relationship between CRBP-1 and lung structure remodeling process after MI.

Effects of endogenous carbon monoxide on collagen synthesis in pulmonary artery in rats under hypoxia

To study the role of endogenous carbon monoxide (CO) in collagen metabolism during hypoxic pulmonary vascular remodeling, a total of 18 Wistar rats were used in the study and they were randomly divided into three groups: hypoxia group (n = 6), hypoxia with zinc protoporphyrin-IX (ZnPP-IX) group (n = 6) and control group (n = 6). The measurement of mean pulmonary artery pressure (mPAP) and carboxyhemoglobin (HbCO) formation in lung tissue homogenates was measured. A morphometric analysis of pulmonary vessels was performed, in which the percentage of muscularized arteries (MA); partially muscularized arteries (PMA) and nonmuscularized arteries (NMV) in small and median pulmonary vessels, relative medial thickness (RMT) and relative medial area (RMA) of pulmonary arteries were analyzed. Collagen type I and III and transforming growth factor-β 3 (TGF-β 3) expressions were detected by immunohistochemical assay. The expressions of procollagen type I and III and TGF-β 3 mRNA were detected by in situ hybridization. The results showed that ZnPP-IX significantly increased mPAP and markedly decreased HbCO formation in lung tissue homogenates in rats under hypoxia ( P<0.01). In the hypoxia rats treated with ZnPP-IX, the percentage of muscularized arteries of small and median pulmonary vessels was obviously increased, and RMT and RMA of intra-acinar muscularized pulmonary arteries were markedly increased compared with hypoxic rats. Ultrastructural changes, such as hyperplasia and hypertrophy of endothelial cells (ECs) and smooth muscle cells (SMCs) and the increased number of SMCs in synthetic phenotype were found in intra-acinar pulmonary muscularized arteries of hypoxic rats treated with ZnPP-IX. Meanwhile, ZnPP-IX promoted the expression of collagen type I and III and TGF-β 3 protein in pulmonary arteries of rats under hypoxia ( P<0.01). Furthermore, ZnPP-IX elevated obviously the expressions of procollagen type I and III mRNA, and TGF-β 3 mRNA in pulmonary arteries of rats under hypoxia ( P<0.01). The results of this study suggested that ZnPP-IX played an important role in promoting collagen synthesis in pulmonary arteries of rats with hypoxic pulmonary structural remodeling by increasing the expression of TGF-β 3. The above findings also suggested a possible role of endogenous CO in the pathogenesis of chronic hypoxic pulmonary hypertension.

Lung structural remodeling and pulmonary hypertension after myocardial infarction: complete reversal with irbesartan.

The severity of pulmonary hypertension associated with heart failure carries a poor prognosis. The lungs are very sensitive to the constrictive and proliferative effects of angiotensin-II and could represent a preferential target for this peptide. Rats with large myocardial infarcts or sham surgery received the angiotensin-II receptor antagonist irbesartan (40 mg/kg/day) or vehicle for 2 or 8 weeks (n=5 to 8 for each group). Hemodynamic and morphometric measurements were obtained followed by immunohistochemistry, immunofluorescence analysis and electron microscopic characterization of lung sections. The infarct groups developed progressive pulmonary hypertension and right ventricular hypertrophy with elevated left ventricular filling pressures (all P<0.01). Despite similar infarct size, filling pressures were lower (P<0.01) while pulmonary hypertension and right ventricular hypertrophy were completely normalized by irbesartan. Isolated lungs pressure-flow relationships were identical at 2 weeks. At 8 weeks it was steepest and shifted upward in the infarct group (P<0.001), and completely normalized by irbesartan. Lung weight doubled after infarct with no evidence of pulmonary edema and was also normalized by irbesartan. Important lungs structural remodeling evidenced by collagen and reticulin deposition, thickening of the alveolar septa and proliferation of cells with ultrastructural characteristics of myofibroblasts (pericytes) were identified after infarct. After large myocardial infarct there is important pulmonary structural remodeling in which myofibroblasts (pericytes) proliferation may play an important role. This initially protective mechanism against high filling pressures could eventually contribute to the development of pulmonary hypertension and right ventricular hypertrophy. Future studies are needed to determine if angiotensin-II directly modulates pulmonary remodeling after myocardial infarct.

The Role of Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 in Cryptogenic Organizing Pneumonia

The processes observed in interstitial lung disease are associated with the production, deposition, and proteolysis of the extracellular matrix (ECM), which may lead to irreversible pulmonary structural remodeling or to appropriate repair without fibrosis. Matrix metalloproteinases (MMPs) and a tissue inhibitor of metalloproteinases (TIMPs) are known to regulate remodeling of the ECM and thus to be important in the process of lung fibrosis. Pulmonary structures are extensively remodeled in usual interstitial pneumonia (UIP), whereas severe architectural remodeling is minimally present in cryptogenic organizing pneumonia (COP). However, not much is known about the roles of MMP-9 and/or TIMP-1 in COP. Levels of MMP-9, TIMP-1 and the molar ratio of MMP-9/TIMP-1 in BAL fluids were investigated in 11 patients with UIP, in 8 patients with COP, and in 10 control subjects. We checked the levels of MMP-9 and TIMP-1 by means of enzyme immunoassay, and the hydrolytic activity of MMP-9 in BAL fluids was measured by gelatin zymography. Further, we evaluated the expression of MMP-9 and TIMP-1 in lung tissue by immunohistochemistry. The concentrations of MMP-9 and TIMP-1 were significantly increased in patients with UIP and were even higher in patients with COP compared with control subjects. The levels of MMP-9 and TIMP-1 were significantly higher in patients with COP than in patients with UIP. The molar ratio of MMP-9/TIMP-1 was significantly higher in patients with COP than in control subjects. In patients with COP, the concentration of MMP-9 significantly correlated with the number of neutrophils and lymphocytes. Zymographic analysis revealed that the activity of the 92-kd pro-MMP-9 was increased in patients with UIP and was even higher in patients with COP, compared with control subjects. These data suggest that overproduction of MMP-9 and TIMP-1, and an imbalance between MMP-9 and TIMP-1, may have a role as diagnostic references in COP.

Mechanism of Structural Remodeling in Pulmonary Fibrosis

Idiopathic interstitial pneumonia is pathologically classified into acute interstitial pneumonia (AIP), usual interstitial pneumonia (UIP), bronchiolitis obliterans organizing pneumonia (BOOP), nonspecific interstitial pneumonia (NSIP), and so on.1 UIP is clinically progressive and has a bad prognosis. AIP is a severe disease, but some patients recover with a suitable therapy. BOOP and NSIP have a generally good prognosis. We analyzed the mechanism of pulmonary structural remodeling in patients with AIP, UIP, BOOP, and NSIP, especially in the process and characteristics of early fibrotic lesions.

Characteristic Elevation of Matrix Metalloproteinase Activity in Idiopathic Interstitial Pneumonias

Destruction of subepithelial basement membrane is a key event in the pathogenesis of idiopathic pulmonary fibrosis (IPF). To evaluate the role of matrix metalloproteinases (MMPs) in parenchymal remodeling in idiopathic interstitial pneumonia (IIP), we studied MMP-2 and -9 activity, in bronchoalveolar lavage fluid (BALF) by zymography and the expression of MMP-2 and -9 and TIMP-2 in lung tissue by immunohistochemistry. BALF and lung tissues were collected from 26 patients with usual interstitial pneumonia (IPF-UIP), 11 with nonspecific interstitial pneumonia (NSIP), and 6 with bronchiolitis obliterans organizing pneumonia (BOOP). IPF-UIP cases showed predominant expression of MMP-9, whereas NSIP and BOOP cases showed predominant MMP-2 expression in BALF and in tissues. In BALF samples from rapidly progressive IPF-UIP cases, neutrophil-derived MMP-9 activity, as well as MMP-9 active form were characteristically detected. Furthermore, the MMP-9 activity correlated significantly with an increase of neutrophils in BALF, whereas the MMP-2 activity associated with NSIP and BOOP correlated with an increase of lymphocytes. These results indicate that MMP-9 in IPF-UIP and MMP-2 in NSIP and BOOP may contribute to pulmonary structural remodeling through type IV collagenolytic activity. The characteristic contributions of matrix-degrading proteins may relate to the distinct prognostic features of these diseases.

[Pulmonary structural remodeling in interstitial lung disease].

[Pulmonary structural remodeling in interstitial lung disease].

Significance of early intra-alveolar fibrotic lesions and integrin expression in lung biopsy specimens from patients with idiopathic pulmonary fibrosis

To study the pulmonary structural remodeling in idiopathic pulmonary fibrosis (IPF), ultrastructural, immunohistochemical, and light microscopic morphometric observations were made on 11 pulmonary biopsy specimens from patients with IPF. The morphometric study was done using sequentially cut tissue sections stained for keratin-alcian blue periodic acid-Schiff (PAS), fibronectin, and type IV collagen-alcian blue PAS. Most of the early fibrotic lesions, which were alcian blue-and fibronectin-positive, were intra-alveolar in location. Intra-alveolar fibrosis is considered to be essential for the fusion of alveolar walls in IPF. A strong reaction for integrin α5β1 and vinculin was found in epithelial cells and mesenchymal cells in areas of intra-alveolar fibrosis. These findings show that these cells are active in adhesion to fibronectin in areas of early intra-alveolar fibrosis. Some of the epithelial cells, including cytoplasmic hyaline-laden cells, showed evidence of inadequate adhesion to the extracellular matrix, and this may constitute one of the mechanisms of progression of fibrosis in IPF.

Role of elastic fiber degradation in emphysema-like lesions of pulmonary lymphangiomyomatosis

To study the pulmonary structural remodeling in pulmonary lymphangiomyomatosis, electron microscopy and light and electron microscopic immunohistochemical observations for elastin and alpha 1-antitrypsin were performed on five open lung biopsy samples. Lung specimens showed emphysema-like changes in areas of abnormally accumulated smooth muscle cells. In the alveolar walls having accumulated smooth muscle cells, elastic fibers were decreased in number, disrupted, granular, and occasionally accumulated. Ultrastructurally, elastic fibers in areas of smooth muscle cell accumulation showed poorly outlined amorphous components and a few microfibrils, and occasionally showed electron-dense granular deposits in and around the amorphous components. Spiraling collagen fibrils were frequently found associated with these abnormal elastic fibers. Immunohistochemistry for elastin showed even staining of amorphous components of elastic fibers in the areas of smooth muscle cell accumulation. alpha 1-Antitrypsin was also detected evenly in amorphous components of elastic fibers in the areas of smooth muscle cell accumulation. It is proposed that the emphysema-like lesions of lymphangiomyomatosis are mediated by the degradation of elastic fibers, and these degraded elastic fibers are related to an imbalance of the elastase/alpha 1-antitrypsin system similar to the probable pathogenesis of emphysema.