Diffuse Lung Fibrosis Research Articles

MiR-29a-3p Regulates Autophagy by Targeting Akt3-Mediated mTOR in SiO2-Induced Lung Fibrosis.

Silicosis is a refractory pneumoconiosis of unknown etiology that is characterized by diffuse lung fibrosis, and microRNA (miRNA) dysregulation is connected to silicosis. Emerging evidence suggests that miRNAs modulate pulmonary fibrosis through autophagy; however, its underlying molecular mechanism remains unclear. In agreement with miRNA microarray analysis, the qRT-PCR results showed that miR-29a-3p was significantly decreased in the pulmonary fibrosis model both in vitro and in vivo. Increased autophagosome was observed via transmission electron microscopy in lung epithelial cell models and lung tissue of silicosis mice. The expression of autophagy-related proteins LC3α/β and Beclin1 were upregulated. The results from using 3-methyladenine, an autophagy inhibitor, or rapamycin, an autophagy inducer, together with TGF-β1, indicated that autophagy attenuates fibrosis by protecting lung epithelial cells. In TGF-β1-treated TC-1 cells, transfection with miR-29a-3p mimics activated protective autophagy and reduced alpha-smooth muscle actin and collagen I expression. miRNA TargetScan predicted, and dual-luciferase reporter experiments identified Akt3 as a direct target of miR-29a-3p. Furthermore, Akt3 expression was significantly elevated in the silicosis mouse model and TGF-β1-treated TC-1 cells. The mammalian target of rapamycin (mTOR) is a central regulator of the autophagy process. Silencing Akt3 inhibited the transduction of the mTOR signaling pathway and activated autophagy in TGF-β1-treated TC-1 cells. These results show that miR-29a-3p overexpression can partially reverse the fibrotic effects by activating autophagy of the pulmonary epithelial cells regulated by the Akt3/mTOR pathway. Therefore, targeting miR-29a-3p may provide a new therapeutic strategy for silica-induced pulmonary fibrosis.

A SEVERE CASE OF ORGANIZING PNEUMONIA FROM VAPING AND COCAINE USE

A SEVERE CASE OF ORGANIZING PNEUMONIA FROM VAPING AND COCAINE USE

Does pulmonary fibrosis increase lung cancer risk?

Abstract Background The concepts in lung fibrosis and increased lung cancer risk have arisen from clinical observations of the concurrent findings during the autopsy of lung cancer and pulmonary fibrosis. Scar carcinoma attributes the origin of carcinomas to abutting areas of scarring. The association between fibrosis and lung cancer risk immediately raises a query: whether lung fibrosis induces lung cancer? Aim The study was done to elucidate the incidence, risk factors, and clinical characteristics of lung cancer in diffuse lung fibrosis. Patients and methods A cohort study was done based on a prospective group of 50 patients with diffuse lung fibrosis to evaluate the incidence of lung cancer, as well as a retrospective group of 50 patients with lung cancer to search for background of pulmonary fibrosis between 2019 and 2020. Demographic, radiographic, and histologic characteristics were reviewed for both groups. Results Among 50 patients with interstitial lung disease, lung cancer developed in 2/50 (4%) during the follow-up, whereas in the retrospective group, 8/50 (16%) were diagnosed as having lung cancer with diffused lung fibrosis between 2019 and 2020. Lung cancer risk factors were male sex, smoking, and occupational dust exposure. Squamous carcinoma followed by adenocarcinoma was the commonest histologic form. Conclusion Evidence shows an association between interstitial lung diseases and lung cancer emergence. Epidemiological evidence differs owing to the various study designs and populations.

Video-assisted thoracoscopic diagnosis of trapped lung in malignant pleural effusions

PURPOSE. The aim of this study is to present the role of video-assisted thoracoscopy to assess the ability of the lung to expand in malignant pleural effusions. METHODS. The survey was conducted for a 3-year period in 13 patients with histologically diagnosed malignant pleural effusion and trapped lung. In each of the patients video-assisted thoracoscopy was performed. RESULTS. Two reasons for trapped lung were identified. In 10 of the patients it was due to multiple metastatic nodules. In 3 cases the cause was a diffuse fibrotic involvement of the lung resulting from the metastatic process.CONCLUSIONS. Our research confirmed two causes of trapped lung in malignant pleural effusions: multiple metastases on the lung surface and diffuse lung fibrosis, induced by the metastatic process, with the increased role of multiple metastases on the lung surface

Comorbidities in the management of patients with lung cancer.

Lung cancer represents a major public health issue worldwide. Unfortunately, more than half of them are diagnosed at an advanced stage. Moreover, even if diagnosed early, diagnosis procedures and treatment can be difficult due to the frequent comorbidities observed in these patients. Some of these comorbidities have a common major risk factor, i.e. smoking, whereas others are unrelated to smoking but frequently observed in the general population. These comorbidities must be carefully assessed before any diagnostic and/or therapeutic decisions are made regarding the lung cancer. For example, in a patient with severe emphysema or with diffuse lung fibrosis, transthoracic needle biopsy can be contraindicated, meaning that in some instances a precise diagnosis cannot be obtained; in a patient with chronic obstructive pulmonary disease, surgery may be impossible or should be preceded by intensive rehabilitation; patients with interstitial lung disease are at risk of radiation pneumonitis and should not receive drugs which can worsen the respiratory insufficiency. Patients who belong to what are called "special populations", e.g. elderly or HIV infected, should be treated specifically, especially regarding systemic treatment. Last but not least, psychosocial factors are of great importance and can vary from one country to another according to health insurance coverage.

What did you do for a living? The importance of a Comprehensive Geriatric Assessment

We present the case of an 80-year-old woman who had a 12-month history of progressive exertional dyspnoea, nonproductive cough, generalised weakness, and weight loss. Of note, she had worked until her fifties in many different jobs including 15 years of farming, managing paddy fields and vegetable farms, followed by five years in a wood factory. She was admitted to our hospital in September 2014 with a dense ischaemic stroke. Her medical history included hypertension and ischaemic heart disease. She had multiple admissions to different cardiology units in other hospitals with the symptoms described above. She was treated for congestive cardiac failure, after which, standard treatment of frusemide failed to improve her symptoms. On examination, she was alert, afebrile, tachypnoiec with a respiratory rate of 28 breaths/minute, blood pressure of 135/ 75 mmHg and oxygen saturation of 88% by pulse oximetry on room air. Pulmonary auscultation revealed course crepitations bibasally up to the level of midzones of both lung fields. She did not have the usual signs of heart failure such as raised jugular venous pressure and peripheral oedema. She had dysphasia and complete paralysis of her right side in keeping with her stroke. Her chest radiograph revealed bilateral diffuse lung fibrosis (Fig. 1a) and high resolution computed tomography (HRCT) (Fig. 1b–d) revealed dense fibrosis as well as traction bronchiolectasis at right upper lobe and both lower lobes, whereas the right middle lobe and left upper lobe showed reticulonodular opacities and ground-glass changes.

A comprehensive computational model of sound transmission through the porcine lung

A comprehensive computational simulation model of sound transmission through the porcine airways and lung is introduced and experimentally evaluated. This “subject-specific” model utilizes parenchymal and major airway geometry derived from x-ray CT images. The lung parenchyma is modeled as a poroviscoelastic material using Biot theory. A finite element (FE) mesh of the lung that includes airway detail is created, and COMSOL FE software is used to simulate the vibroacoustic response of the lung to sound input at the trachea. The FE model is validated by comparing simulation results with experimental measurements using scanning laser Doppler vibrometry on the surface of an excised and preserved lung. The FE model is also used to calculate and visualize vibroacoustic pressure and motion inside the lung and its airways caused by the acoustic input. The effect of diffuse lung fibrosis and a tumor on the lung acoustic response is simulated and visualized using the FE simulation. In the future, this type of visualization can be compared and matched with experimentally-obtained elastographic images in order to better quantify lung material properties. [Work supported by NIH Grant EB012142.]

Pirfenidone in idiopathic pulmonary fibrosis: the CAPACITY program

Idiopathic pulmonary fibrosis is the most lethal form of diffuse lung fibrosis, killing approximately half of those affected within 2–3 years of diagnosis. Until recently, no therapies had been shown to have an impact on disease progression. The Clinical Studies Assessing Pirfenidone (Esbriet®) in IPF: Research of Efficacy and Safety Outcomes (CAPACITY) program comprised two almost identical double-blind placebo-controlled studies assessing the effects of pirfenidone on change in forced vital capacity, the primary end point, over a 72-week period. One of these studies was positive, matching in magnitude the benefit seen in two previous positive Japanese studies. The other study did not meet its primary end point but positive trends were consistent in this and a number of secondary end point indices. Safety was acceptable, comprising mainly problems of tolerability rather than toxicity. It is likely that pirfenidone will be utilised in many countries as first-line therapy and will also be included in studies of combination therapy for this attritional disease.

Silicotuberculosis and silicosis as occupational diseases: Report of two cases

Silicosis, the most prevalent of the pneumoconioses, is caused by inhalation of crystalline silica particles. Silica-exposed workers are at increased risk for tuberculosis and other mycobacterium-related diseases. The risk of a patient with silicosis developing tuberculosis is higher (2.8 to 39 fold higher, depending on the severity of silicosis) than that found in healthy controls. The first patient was a 52-year-old male who was admitted in 2002 for the second time with dyspnoea, wheezing and fatigue over the last 11 years. He had worked in an iron smelting factory and was exposed to silica dust for 20 years. First hospitalization chest radiography showed bilateral pleural adhesions, diffuse lung fibrosis with signs of a specific lung process. Second hospitalization chest radiography showed bilateral massive irregular, non-homogenous calcified changes in the upper and middle parts of lungs. The patient died due to respiratory failure and chronic pulmonary heart in 2007. The main causes of his death were silicotuberculosis and chronic obstructive pulmonary disease. The second patient was a 50-year-old male who was admitted in 2005 for the second time with chest tightness, dyspnoea, wheezing and fatigue over the last 10 years. He had worked in an iron smelting factory and was exposed to silica dust for 30 years. First hospitalization chest radiography showed diffuse lung fibrosis and small nodular opacities. The patient was diagnosed with silicosis, small opacities sized level p/q, and profusion level 2/3. Second hospitalization chest radiography and CT showed diffuse lung fibrosis and small nodular opacities predominantly in the upper lobes. The patient was recognized as having an occupational disease, and received early retirement due to disability. In low-income countries, new cases of silicosis and associated lung cancer, chronic obstructive pulmonary disease and tuberculosis are likely to be seen for decades because necessary reduction of silica use will take time to be achieved.

Extra-Articular Manifestations of Seronegative and Seropositive Rheumatoid Arthritis

Although considered a "joint disease," rheumatoid arthritis is associated with the involvement of extra-articular manifestations. The aim of the study is the investigation and comparison of frequency and type of extra-articular manifestations in a well defined community based cohort of patients with seropositive and seronegative rheumatoid arthritis. Using the ACR (1987) criteria for rheumatoid arthritis, patients have been classified into the 2nd and 3rd functional class (ARA). The studied group consisted of 125 seronegative patients with titters lower than 1:64 as defined by Rose-Waaler test, whereas the control group consisted of 125 seropositive patients with titters of 1:64 or higher. All patients were between 25-60 years of age (Xb=49,96), with disease duration between 1-27 years (Xb=6,41). In order to present the findings of the study, the structure, prevalence, arithmetic mean (Xb), standard deviation (SB), variation quotient (QV%) and variation interval (Rmax-Rmin) have been used. Probability level has been expressed by p<0,01 and p<0,05. Correlation between the number of extra-articular manifestations and duration of the disease has been calculated by means of Pearson linear correlation. Higher presence of diffuse lung fibrosis, central and peripheral nervous system damages have been confirmed in the seropositive group, and osteoporosis in the seronegative; however, no statistical difference has been found. In extra-articular manifestations, "rheumatoid core" in the seropositive subset (chi2=4,80, p<0,05) presented significant statistical difference. Rheumatoid nodules were more frequent in seropositive subset (12%:16%), in both sexes; however, they were not of significant statistical difference. Neuropathy and lung diseases were also frequently present in seropositive group, but no statistical difference has been found regarding the statistical difference. Longer duration of the disease resulted in an increase of the number of extra-articular manifestations. Calculated linear correlation by Pearson, resulted as positive and high correlation in total (r=0,36, p<0,01), and for groups [(r=0,52, p<0,01) seronegative, (r=0,25, p<0,01) seropositive], nevertheless no significant statistical difference was found regarding the sero-status. In conclusion, extra-articular manifestations are more frequent in the seropositive patients. The longer the duration of the disease the larger the number of extra-articular manifestations. Differences with regard to sero-status and sex, with some exceptions, are not observed.

Oxidant–Antioxidant Imbalance as a Potential Contributor to the Progression of Human Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia. IPF is a disease with poor prognosis and an aggressive nature, and poses major challenges to clinicians. Thus, a large part of research in the area has focused on the pathogenesis on IPF. Characteristic features in IPF include fibrotic lesions devoid of inflammatory cell infiltrates. There are experimental models of lung fibrosis (e.g., bleomycin-induced fibrosis), but they typically contain a prominent inflammatory pattern in the lung, which leads to relatively diffuse lung fibrosis. Nonetheless, experimental models have provided important information about the progression and pathways contributing to the lung fibrosis, including activation of transforming growth factor beta (TGF-beta). Both patient material and experimental models of lung fibrosis have displayed marked elevation of several markers of oxidant burden and signs for disturbed antioxidant/oxidant balance. Several studies also suggest that reactive oxygen species can cause activation of growth-regulatory cytokines, including TGF-beta. In addition, there are indications that endogenous and exogenous antioxidants/redox modulators can influence fibrogenesis, protect the lung against fibrosis, and prevent its progression. Factors that restore the antioxidant capacity and prevent sustained activation of growth-regulatory cytokines may have a therapeutic role in IPF.

Improvement of hamster-lung fibrosis model by repeated intratracheal administration of bleomycin.

Suitable conditions of bleomycin (BLM)-treatment to effectively induce pulmonary fibrosis without high mortality were investigated in Syrian golden hamsters. Male 6-week-old hamsters were divided into 5 groups, each consisting of 5 animals. Groups 1-4 were intratracheally instilled with 2.5U/kg of BLM on day O and then repeatedly given BLM as follows: group 1, 2.5U/kg intratracheally on day 14; group 2, 1.0U/kg intratracheally on day 14; group 3, 1.0U/kg intratracheally each on days 7 and 14; group 4, 20U/kg intraperitoneally each on days 10and 14. Group 5 served as a vehicle control. The survival rate was 4/5 (80%) in groups l and 3, and 5/5 (100%) in other groups. One animal each in groups I and 3 was found dead on day 22, of which lungs histopathologically showed evident fibrosis accompanied with congestion, edema, inflammatory cell infiltration, and hemorrhage. The lung weight at the termination of the experiment on day 28 was the highest in group 1, and significantly higher in groups 1 (p<0.01) and 2 (p<0.05) than in group 5, well correlating with the histopathological severity of lungfibrosis. The lung weight of group 3 was also higher as compared to the group 5 value although this was not statistically significant and the lung weight of group 4 was almost comparable to that of group 5, again being in line with the histopathology of the lung. The results in the present study thus suggest that the repeated intratracheal instillation with 2.5U/kg BLM at intervals of 2 weeks may offer a favorable condition to induce diffuse lung fibrosis in hamsters.

Effects of inflammation and fibrosis on pulmonary function in diffuse lung fibrosis.

To investigate the relation between lung function and inflammation and fibrosis in patients with diffuse lung fibrosis, a study was made of untreated patients without appreciable airway obstruction (14 patients with cryptogenic fibrosing alveolitis and seven with pneumoconiosis). Quantitative assessment of inflammatory infiltration and fibrosis was carried out on open lung biopsy specimens and compared with lung volumes, carbon monoxide transfer factor (TLCO), TLCO corrected for alveolar volume (TLCO/VA), and arterial blood gases at rest and during exercise. The degree of fibrosis and the degree of cellular infiltration were positively correlated. Lung volumes and TLCO were correlated with the grades of fibrosis and cellular infiltration of alveoli; arterial blood gases during exercise tended to correlate with both fibrosis and infiltration (p less than 0.06). In contrast, morphological data were not correlated with gas exchange at rest or with TLCO/VA. It is concluded that, in untreated patients with diffuse lung fibrosis, lung volumes, TLCO, and arterial blood gases during exercise reflect the lung lesions, and that the pulmonary function tests used cannot discriminate between fibrosis and infiltration of the lung by inflammatory cells.

Thoracoabdominal mechanics in dyspnea.

80 severely ill patients with various lung diseases were studied in order to relate the feeling of breathlessness at rest with the severity of lung mechanical impairment. Moderate to severe dyspnea (grade 2 to grade 3) at rest was present only in 46 of 80 patients (57%) with severe lung disease. The prevalence of breathlessness at rest among the various lung diseases was as follows: 80% in acute bronchial asthma, 70% acute interstitial pneumonia, 50% in diffuse lung fibrosis and 30% in chronic obstructive lung disease. None of the 10 X 9 measured or calculated parameters (IVC, FEV1, FEV1/IVC X 100, TGV, RV, RV/TLC X 100, TLC, MMEF, CC/TLC X 100, SGaw I-E, FV curve indices, quasi-static transpulmonary pressure, dynamic compliance, gastric pressure and RR) seemed to characterize the patients presenting with severe dyspnea. High breathing frequency, low SCdyn and a near negative abdominal pressure consistently identified a small group of subjects with severe dyspnea at rest, regardless of the underlying lung disease.