OBJECTIVE: To investigate the common mechanisms among collagen-induced arthritis (CIA), bleomycin (BLM)-induced pulmonary fibrosis, and CIA+BLM to evaluate the therapeutic effect of triptolide (TP) on CIA+BLM. METHODS: Thirty-six male Sprague-Dawley rats were randomly assigned to 6 groups according to a random number table (n=6 per group): normal control (NC), CIA, BLM, combined CIA+BLM model, TP low-dose (TP-L, 0.0931 mg/kg), and TP high-dose (TP-H, 0.1862 mg/kg) groups. The CIA model was induced by intradermal injection at the base of the tail with emulsion of bovine type II collagen and incomplete Freund's adjuvant (1:1), with 200 µL administered on day 0 and a booster of 100 µL on day 7. Pulmonary fibrosis was induced via a single intratracheal injection of BLM (5 mg/kg). The CIA+BLM model combined both protocols, and TP was administered orally from day 14 to 35. After successful modeling, arthritis scores were recorded every 3 days, and pulmonary function was assessed once at the end of the treatment period. Lung tissues were collected for histological analysis (hematoxylin eosin and Masson staining), immunohistochemistry, measurement of hydroxyproline (HYP) content, and calculation of lung coefficient. In addition, HE staining was performed on the ankle joint. Total RNA was extracted from lung tissues for transcriptomic analysis. Differentially expressed genes (DEGs) were compared with those from the RA-associated interstitial lung diseases patient dataset GSE199152 to identify overlapping genes, which were then used to construct a protein-protein interaction network. Hub genes were identified using multiple topological algorithms. RESULTS: The successfully established CIA+BLM rat model exhibited significantly increased arthritis scores and severe pulmonary fibrosis (P<0.01). By intersecting the DEGs obtained from transcriptomic analysis of lung tissues in CIA, BLM, and CIA+BLM rats with DEGs from rheumatoid arthritis-interstitial lung disease patients (GSE199152 dataset), 50 upregulated and 44 downregulated genes were identified. Through integrated PPI network analysis using multiple topological algorithms, IGF1 was identified as a central hub gene. TP intervention significantly improved pulmonary function by increasing peak inspiratory flow (P<0.01), and reduced lung index and HYP content (P<0.01). Histopathological analysis showed that TP alleviated alveolar collapse, interstitial thickening, and collagen deposition in the lung tissues (P<0.01). Moreover, TP treatment reduced the expression of collagen type I and α-SMA and increased E-cadherin levels (P<0.01). TP also significantly reduced arthritis scores and ameliorated synovial inflammation (P<0.05). Both transcriptomic and immunohistochemical analyses confirmed that IGF1 expression was elevated in the CIA+BLM group and downregulated following TP treatment (P<0.05). CONCLUSION TP exerts protective effects in the CIA+BLM model by alleviating arthritis and pulmonary fibrosis through the inhibition of IGF1-mediated EMT.
Animals ; Pulmonary Fibrosis/complications* ; Bleomycin/adverse effects* ; Phenanthrenes/pharmacology* ; Male ; Rats, Sprague-Dawley ; Diterpenes/pharmacology* ; Epoxy Compounds/therapeutic use* ; Arthritis, Experimental/complications* ; Insulin-Like Growth Factor I/metabolism* ; Rats ; Lung/physiopathology*

Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease (ILD) of unknown causes, which is characterized by pulmonary fibrosis. The median survival period after diagnosis is about 2-4 years. In recent years, the incidence rate of lung cancer associated with IPF (IPF-LC) is increasing, and the prognosis is worse than that of IPF alone. Pulmonary fibrosis may be closely associated with the occurrence and development of lung cancer. Although the pathogenesis of IPF-LC is still unclear, the current research shows that there are similarities between the pathogenesis of these two diseases at molecular and cellular levels. At present, the research on the cellular and molecular mechanism of lung cancer related to pulmonary fibrosis has become the focus of researchers' attention. This article reviews the related literature, focusing on the latest status of the cellular and molecular mechanisms and treatment of IPF-LC, hoping to help clinicians understand IPF-LC.
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Humans ; Idiopathic Pulmonary Fibrosis/complications* ; Lung Neoplasms/complications*

BACKGROUND: Critical patients with the coronavirus disease 2019 (COVID-19), even those whose nucleic acid test results had turned negative and those receiving maximal medical support, have been noted to progress to irreversible fatal respiratory failure. Lung transplantation (LT) as the sole therapy for end-stage pulmonary fibrosis related to acute respiratory distress syndrome has been considered as the ultimate rescue therapy for these patients. METHODS: From February 10 to March 10, 2020, three male patients were urgently assessed and listed for transplantation. After conducting a full ethical review and after obtaining assent from the family of the patients, we performed three LT procedures for COVID-19 patients with illness durations of more than one month and extremely high sequential organ failure assessment scores. RESULTS: Two of the three recipients survived post-LT and started participating in a rehabilitation program. Pearls of the LT team collaboration and perioperative logistics were summarized and continually improved. The pathological results of the explanted lungs were concordant with the critical clinical manifestation, and provided insight towards better understanding of the disease. Government health affair systems, virology detection tools, and modern communication technology all play key roles towards the survival of the patients and their rehabilitation. CONCLUSIONS LT can be performed in end-stage patients with respiratory failure due to COVID-19-related pulmonary fibrosis. If confirmed positive-turned-negative virology status without organ dysfunction that could contraindicate LT, LT provided the final option for these patients to avoid certain death, with proper protection of transplant surgeons and medical staffs. By ensuring instant seamless care for both patients and medical teams, the goal of reducing the mortality rate and salvaging the lives of patients with COVID-19 can be attained.
Aged ; Betacoronavirus ; Coronavirus Infections ; complications ; mortality ; Extracorporeal Membrane Oxygenation ; Humans ; Lung Transplantation ; methods ; Male ; Middle Aged ; Pandemics ; Pneumonia, Viral ; complications ; mortality ; Pulmonary Fibrosis ; mortality ; surgery ; Respiratory Distress Syndrome, Adult ; mortality ; surgery

BACKGROUNDThe factors affecting the outcome of patients referred for lung transplantation (LTx) still have not been investigated extensively. The aim of this study was to characterize the patient outcomes and identify the prognostic factors for death while awaiting the LTx.

METHODSFrom January 2003 to November 2013, the clinical data of 103 patients with end-stage lung disease that had been referred for LTx to Department of Thoracic Surgery, Shanghai Pulmonary Hospital were analyzed retrospectively. The relationship between predictors and survival was evaluated using the Kaplan-Meier method and the Cox proportional hazards model.

RESULTSTwenty-five patients (24.3%) died while awaiting the LTx. Fifty patients (48.5%) underwent LTx, and 28 patients (27.2%) were still on the waitlist. Compared to the candidates with chronic obstructive pulmonary disease (COPD), patients with idiopathic pulmonary fibrosis (IPF) had a higher mortality while awaiting the LTx (40.0% vs. 12.3%, P = 0.003). Patients requiring mechanical ventilation (MV) had a higher mortality while waiting than others (50.0% vs. 20.2%, P = 0.038). Two variables, using MV and IPF but not COPD as primary disease, emerged as significant independent risk factors for death on the waitlist (hazard ratio [HR] = 56.048, 95% confidence interval [CI]: 3.935-798.263, P = 0.003 and HR = 14.859, 95% CI: 2.695-81.932, P = 0.002, respectively).

CONCLUSIONThe type of end-stage lung disease, pulmonary hypertension, and MV may be distinctive prognostic factors for death while awaiting the LTx.

Adult ; Aged ; Female ; Humans ; Hypertension, Pulmonary ; complications ; Idiopathic Pulmonary Fibrosis ; mortality ; Lung Diseases ; mortality ; Lung Transplantation ; statistics & numerical data ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive ; mortality ; Retrospective Studies ; Waiting Lists

OBJECTIVETo evaluate the characteristics of the serious complications of 17 cases with measles in ICU.

METHODSeventeen cases with measles with serious complications in ICU in Anhui Provincial Children's Hospital were recruited from May 2012 to May 2013. Clinical characteristics, image finding, and prognosis were analyzed retrospectively. IgM antibody was positive in all the 17 cases, which included 9 male cases, 8 female cases, and their age was from 2 months to 10 years.

RESULTAll the 17 patients received mechanical ventilation because of severe respiratory distress within 1 week of onset, of which 14 cases were complicated with acute respiratory distress syndrome (acute ARDS), 6 cases of tension pneumothorax, 3 cases were complicated with bronchitis, laryngeal obstruction III degrees, and totally 7 cases died. The survived 10 patients were followed up for 1 year, 1 patient with localized pneumothorax, bronchopleural fistula, 1 case of mild pulmonary fibrosis, 1 case of acute laryngitis with persistent hoarseness, and mild inspiratory dyspnea were found. The remaining 7 cases fully recovered. Fourteen cases failed to inoculate measles vaccine.

CONCLUSIONA higher risk of death and poor prognosis were found in children with measles who needed to be treated in PICU, especially for ARDS with pneumothorax. Laryngitis needed long time to cure and had weaning difficulties, and the case associated with pleural effusion or bronchopleural fistula must be treated with surgery, and the patients easily develop secondary bacterial infection.

Child ; Dyspnea ; Female ; Humans ; Intensive Care Units, Pediatric ; Lung Diseases ; etiology ; Male ; Measles ; complications ; Pleural Effusion ; Prognosis ; Pulmonary Fibrosis ; Respiration, Artificial ; Retrospective Studies

Humans ; Mediastinal Emphysema ; complications ; Paraquat ; poisoning ; Poisoning ; complications ; Pulmonary Fibrosis ; complications ; Subcutaneous Emphysema ; complications

BACKGROUNDCombined emphysema and pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF), is a distinct disorder described with upper-lobe emphysema and lower-lobe fibrosis on chest computed tomography. Smoking appears to be the predominant risk factor for this disorder. We aimed to compare clinical features, smoking history, physiological and radiological findings between IPF with and without emphysema.

METHODSA sample of 125 IPF patients over a period of 48 months were evaluated. High resolution CT scans were reviewed blinded to clinical data. The IPF patients with or without emphysema were classified accordingly.

RESULTSThe prevalence of emphysema in this IPF sample was 70/125. IPF with emphysema was significantly associated with smoking status (OR 63; 95% CI 4.4 to 915; P = 0.002) and smoking pack year (OR 1.1; 95% CI 1.05 to 1.13; P = 0.000). The patients with IPF and emphysema had a higher decrease in carbon monoxide diffusing capacity adjusted for alveolar volume ((58±19)% pred vs. (66±21)% pred; P = 0.021) and a higher prevalence of pulmonary hypertension (24/70 vs. 7/55; P = 0.006). The two groups of patients had similar forced and residual volumes. No significant differences were found in cell differentials of bronchoalveolar lavage or the scores of fibrosis on chest CT. Survival of the patients with emphysema was significantly less than that of patients with IPF alone.

CONCLUSIONSCigarette smoking induces IPF combined with emphysema. Emphysema further impairs physiological function and increases the prevalence of pulmonary hypertension that leads to poor prognosis. The inclusion of the patients with combined pulmonary fibrosis and emphysema in IPF clinical trials may lead to under evaluation of the effect of treatment in patients.

Aged ; Female ; Humans ; Idiopathic Pulmonary Fibrosis ; etiology ; physiopathology ; Male ; Middle Aged ; Pulmonary Emphysema ; complications ; physiopathology ; Smoking ; adverse effects

OBJECTIVETo review the studies investigating the increased risk of lung cancer in patients with idiopathic pulmonary fibrosis (IPF).

DATA SOURCESData cited in this review were obtained mainly from PubMed and Medline from 1999 to 2013 and highly regarded older publications were also included.

STUDY SELECTIONWe identified, retrieved and reviewed the information on the frequency, risk factors, anatomical features, histological types, clinical manifestations, computed tomography findings and underlying mechanisms of lung cancer in IPF patients.

RESULTSThe prevalence rates of lung cancer in patients with IPF (4.8% to 48%) are much higher than patients without IPF (2.0% to 6.4%). The risk factors for lung cancer in IPF include smoking, male gender, and age. Lung cancers often occur in the peripheral lung zones where fibrotic changes are predominant. Adenocarcinoma and squamous cell carcinoma are the most common types of lung cancer in patients with IPF. Radiologic features of these patients include peripherally located, ill-defined mass mimicking air-space disease. The underlying mechanisms of the development of lung cancer in patients with IPF have not been fully understood, but may include the inflammatory response, epithelial injury and/or abnormalities, aberrant fibroblast proliferation, epigenetic and genetic changes, reduced cell-to-cell communication, and activation of specific signaling pathways.

CONCLUSIONSThese findings suggest that IPF is associated with increased lung cancer risk. It is necessary to raise the awareness of lung cancer risk in IPF patients among physicians and patients.

Age Factors ; Female ; Humans ; Idiopathic Pulmonary Fibrosis ; complications ; epidemiology ; genetics ; Lung Neoplasms ; epidemiology ; etiology ; genetics ; Male ; Risk Factors ; Sex Factors

OBJECTIVETo explore the role of hypoxia-inducible factor 1alpha (HIF-1α) in early lung fibrosis of rats with acute paraquat (PQ) poisoning.

METHODSForty eight healthy SD rats were randomly divided into control group (6 rats) and paraquat poisoning group (42 rats). Control group was exposed to 1 ml normal solution by gastric gavage. The paraquat group was exposed to 1 ml paraquat solution (50 mg/kg) by gastric gavage for 2, 6, 12, 48, 72 and 120 h, respectively. The arterial blood gas analysis (PaO(2)) was detected. The pathological examinations of lung tissues were performed by HE and Mason staining. HIF-1α in lung tissues were measured by immunofluorescence. Western blot assay was used to detect the expression levels of HIF-1α protein in lung tissues.

RESULTSPaO2 of rats exposed to paraquat for 72 h was (62.33 ± 0.22) mm Hg, which was significantly lower than that (96.00 ± 5.20) of control group (P < 0.05). Pathological examination by HE staining indicated that the acute diffuse lesion appeared in the alveolar capillary endothelium, epithelia and interstitial tissues, and there was the inflammatory cell infiltration in the alveolar of rats exposed to paraquat at 2 h after exposure. At 12 h after exposure, the interstitial edema in lung tissues of rats decreased and the alveolar space became narrow. At 120 h after exposure, there were the alveolar structure derangement, abundant cicatrix, more fibroblasts and peripheral inflammation absorption. Pathological examination by Masson staining showed that there was obvious collagen deposition in the alveolar epithelia at 2h after exposure, the increased collagen fibrosis at 24 and 48 h after exposure and the obvious damage of alveolar tissues or much more fibrous connective tissue deposition at 120 h after exposure. The results of western blot and immunofluorescence assays exhibited that the expression levels of HIF-1α in lung tissues at 2, 24 and 48 h after exposure significantly increased, as compared with control group (P < 0.05), but there were no significant differences of HIF-1α expression among sub-groups at different time points after exposure.

CONCLUSIONThe results of present study shown that there were the pulmonary fibrosis and increased expression of HIF-1α in acute PQ poisoning rats at the early stage, and HIF-1α may be associated with pulmonary fibrosis.

Acute Lung Injury ; chemically induced ; complications ; metabolism ; Animals ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Male ; Paraquat ; poisoning ; Pulmonary Fibrosis ; etiology ; metabolism ; pathology ; Rats ; Rats, Sprague-Dawley

This study is to determine the preventive effect and mechanism of targeting IL-17A on pulmonary inflammation and fibrosis after acute lung injury. Mice were treated with anti-IL-17A antibody on the day 7 and sacrificed on the day 14 after bleomycin lung injury. The pulmonary inflammatory status and the deposition of collagen were measured by HE and Sirius stains staining. The contents of hydroxyproline and collagen were measured by using commercial kits. The survival rate of mice was calculated by Kaplan-Meier methods. The inflammatory cytokines in bronchoalveolar lavage fluid were measured by ELISA and the expressions of inflammation-related molecules were detected by Western blotting assay. Targeting of IL-17A could prevent the development of lung inflammation, decrease collagen deposition and the contents of hydroxyproline, and protect against the development of pulmonary fibrosis, which together led to an increase in the animal survival. Moreover, blocking IL-17A decreased the expression ofpro-fibrotic cytokines such as IL-17A, TGF-beta1 and IL-13; increased the expression of anti-fibrotic or anti-inflammatory factors such as IFN-gamma, COX-2, 5-LOX, 15-LOX. Indeed, IL-17A antagonism suppressed the activation of pro-inflammatory p65NF-kappaB but enhanced the activation of pro-resolving p50NF-kappaB. In conclusion, that blockade of IL-17A prevents the development of pulmonary fibrosis from acute lung injury, is because blocking IL-17A may prevent acute inflammation converting to chronic inflammation.
Acute Lung Injury ; chemically induced ; complications ; Animals ; Bleomycin ; Collagen ; metabolism ; Hydroxyproline ; metabolism ; Interleukin-13 ; metabolism ; Interleukin-17 ; antagonists & inhibitors ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; NF-kappa B p50 Subunit ; metabolism ; Pneumonia ; etiology ; metabolism ; Pulmonary Fibrosis ; etiology ; metabolism ; prevention & control ; Random Allocation ; Transcription Factor RelA ; metabolism ; Transforming Growth Factor beta1 ; metabolism ; Up-Regulation