Forms Of Diffuse Lung Disease Research Articles

Synthesis and structure-activity relationship studies of fusidic acid derivatives as anti-inflammatory agents for acute lung injury

Acute lung injury (ALI) are severe forms of diffuse lung disease that impose a substantial health burden all over the world. In the United States, approximately 190,000 cases per year of ALI each year, with an associated 74,500 deaths per year. Anti-inflammatory therapy has become a reasonable approach for the treatment of patients with ALI. In this study, fusidic acid derivatives were used to design new anti-inflammatory compounds with high pharmacological activity and low toxicity. A total of 30 new fusidic acid derivatives were discovered, synthesized, and screened for their anti-inflammatory activity against lipopolysaccharide (LPS)-treated RAW264.7 cells. Of them, b2 was found to be the most active, with a higher efficiency compared with fusidic acid and celecoxib in 10 μM. In vitro, we further measured b2 inhibited inflammatory factor NO (IC50 = 5.382 ± 0.655 μM), IL-6 (IC50 = 7.767 ± 0.871 μM), and TNF-α (IC50 = 7.089 ± 0.775 μM) and b2 inhibited inflammatory cytokines COX-2 and iNOS, ROS production, NF-κB/MAPK and Bax/Bcl-2 signaling pathway pathway. In vivo,b2 attenuated ALI pathological changes and inhibited inflammatory cytokines COX-2 and iNOS in lung tissue and NF-κB/MAPK and Bax/Bcl-2 signaling pathway. In conclusion, b2 may be a promising anti-inflammatory lead compound.

Update on Diffuse Lung Disease in Children.

Diffuse lung diseases in children, also called children's interstitial lung disease, are a diverse group of rare disorders that cause disturbances of gas exchange in the lungs. Although individually rare, there are many different forms of diffuse lung disease in children, and collectively these disorders are associated with significant morbidity and mortality, as well as health-care resource utilization. Over the past several years, there have been many significant advances in the field, including genetic discoveries and the development of clinical practice guidelines. This review summarizes recent advances in the understanding, diagnosis, and treatment of diffuse lung diseases in children.

Granulomas and giant cells in hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is an immunologically mediated form of diffuse lung disease, with histopathologic features that include cellular bronchiolitis, interstitial pneumonia, poorly formed granulomas, isolated multinucleated giant cells (MNGCs), organizing pneumonia, and interstitial fibrosis. This study describes the clinical and histopathologic findings in a retrospective series of 40 consecutive patients diagnosed with HP at the Mayo Clinic in Rochester, MN, between 1997 and 2011. Because the literature indicates that granulomas and MNGCs are located in the interstitium, particular attention was given to their distribution. Of the 40 patients, 33 underwent surgical lung biopsy and 7 underwent lung transplantation. Thirty-eight (95%) patients had interstitial pneumonia; 37 (93%), cellular bronchiolitis; 32 (80%), nonnecrotizing granulomas; 31 (78%), isolated MNGCs; 34 (85%) organizing pneumonia, and 31 (78%); interstitial fibrosis. In 27 cases, the granulomas were within airspaces; and in 26, they were interstitial. In 25 cases, MNGCs were within airspaces; and in 24, they were interstitial. In 3 (8%) cases, both granulomas and MNGCs were seen only within airspaces. Interstitial fibrosis was centrilobular in 22 cases, resembled usual interstitial pneumonia in 18 cases, and resembled nonspecific interstitial pneumonia in 11 cases. The "classic triad" of bronchiolitis, interstitial pneumonia, and granulomas was seen in 29 (73%) cases and was most frequent in biopsy than explant specimens (P = .004). This study confirms that granulomas and MNGCs are not confined to the pulmonary interstitium in HP.

Expression of Cytotoxic T-Lymphocyte Antigen 4 on CD4+ and CD8+ T Cells Is Increased in Acute Lung Injury

Acute lung injury (ALI) is a severe form of diffuse lung disease, which imposes a substantial health burden all over the world. The immune system plays a key role in the development of ALI. The aim of the study was to investigate the expression of cytotoxic T-lymphocyte antigen 4 (CTLA4) in ALI. Levels of CTLA4 were tested on CD4+ and CD8+ T cells in 62 ALI cases and 75 healthy controls by flow cytometry. Data revealed that prevalence of CTLA4 on CD4+ T cells was significantly increased in ALI patients (3.7%±2.1%) than in controls (0.7%±0.3%). Similarly, the proportion of CTLA4 on CD8+ T cells was also significantly elevated in cases (1.0%±0.4% versus 0.5%±0.1%, p<0.05). Further analysis showed that the frequency of CTLA4+CD4+ T cells was positively correlated with the score of Acute Physiology and Chronic Health Evaluation II (APACHE II) (p=0.0005). In addition, when investigating CTLA4 expression with ALI patient mortality, we observed that the level of CTLA4+CD4+ T cells in patients was higher at the time before death than at the time of recruitment (p=0.001). These data suggested that CTLA4 was involved in the pathogenesis and progression of ALI and could be used as a potential target for treating this disease.

Lung transplantation for childhood diffuse lung disease

Pediatric diffuse lung diseases comprise a heterogeneous group of rare lung disorders which may lead to end stage lung disease and referral for lung transplantation. Previous studies are limited by small numbers of patients with specific forms of diffuse lung disease. Children with all forms of diffuse lung disease who underwent lung transplantation at two pediatric centers were evaluated in terms of several pre- and post-transplant factors and compared to children with other end stage lung disorders. A retrospective chart review was performed on all patients transplanted between October 1, 2002 and June 15, 2007 at Texas Children's Hospital and St. Louis Children's Hospital. Multiple pre-transplant characteristics and post-transplant morbidities and mortality were compared between diffuse lung disease, cystic fibrosis, and pulmonary vascular disease groups. There were 31 diffuse lung disease (DLD), 57 cystic fibrosis (CF), and 16 pulmonary vascular disease (PVD) patients included in our analysis. Patients with DLD had significantly higher pre-transplant morbidity including lower percent predicted of forced expiratory volume in first second (P = 0.013) and more patients with pulmonary hypertension (P = 0.001) and hypercapnia (P = 0.031). Compared to CF patients, more DLD and PVD patients required invasive ventilation (P = 0.001) and care in the pediatric intensive care unit (P = 0.001). After transplant, there was a difference among the three groups with regards to number of acute allograft rejections but statistical limitations preclude knowing between which group the difference lies. A difference in time to bronchiolitis obliterans was found between the PVD and CF groups but not when compared to the DLD patients. The three groups had similar time to post-transplant lymphoproliferative disease, rate of infections, and survival. Lung transplantation is as successful for patients with end stage diffuse lung disease as compared to other lung transplant candidates.

Pulmonary Autotaxin Expression Contributes to the Pathogenesis of Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic form of diffuse lung disease occurring mainly in older adults. Increased lysophosphatidic acid (LPA) concentrations have been reported in the alveolar space of both idiopathic pulmonary fibrosis patients and a corresponding animal model, whereas the genetic deletion or pharmacological inhibition of LPA receptor 1 attenuated the development of the modeled disease, suggesting a direct involvement of LPA in disease pathogenesis. In this report, increased concentrations of autotaxin (ATX; ENPP2), the enzyme largely responsible for extracellular LPA production, were detected in both murine and human fibrotic lungs. The genetic deletion of ATX from bronchial epithelial cells or macrophages attenuated disease severity, establishing ATX as a novel player in IPF pathogenesis. Furthermore, the pharmacological inhibition of ATX attenuated the development of the modeled disease, suggesting that ATX is a possible therapeutic target in IPF.

Acute Lung Injury Review

The first report of acute respiratory distress syndrome (ARDS) was published in 1967, and even now acute lung injury (ALI) and ARDS are severe forms of diffuse lung disease that impose a substantial health burden all over the world. Recent estimates indicate approximately 190,000 cases per year of ALI in the United States each year, with an associated 74,500 deaths per year. Common causes of ALI/ARDS are sepsis, pneumonia, trauma, aspiration pneumonia, pancreatitis, and so on. Several pathologic stages of ALI/ARDS have been described: acute inflammation with neutrophil infiltration, fibroproliferative phase with hyaline membranes, with varying degrees of interstitial fibrosis, and resolution phase. There has been intense investigation into the pathophysiologic events relevant to each stage of ALI/ARDS, and much has been learned in the alveolar epithelial, endobronchial homeostasis, and alveolar cell immune responses, especially neutrophils and alveolar macrophages in an animal model. However, these effective results in the animal models are not equally adoptive to those in randomized, controlled trials. The clinical course of ALI/ARDS is variable with the likely pathophysiologic complexity of human ALI/ARDS. In 1994, the definition was recommended by the American-European Consensus Conference Committee, which facilitated easy nomination of patients with ALI/ARDS for a randomized, clinical trial. Here, we review the recent randomized, clinical trials of ALI/ARDS.

Surgical pathology of granulomatous interstitial pneumonia.

Agranulomatous interstitial pneumonia is a form of diffuse lung disease in which granulomas are a component of the histologic findings. The differential diagnosis is quite broad, but most cases represent examples of either sarcoidosis, diffuse granulomatous infections, or hypersensitivity pneumonitis. "Hot tub lung" is a recently described form of granulomatous interstitial pneumonia that appears to have some features of diffuse infections and some features of hypersensitivity pneumonitis. The pathologist's approach to these conditions can be facilitated by giving careful attention to the anatomic distribution of the granulomas, the qualitative features of the granulomas, and the histologic changes in the lung tissue around and away from the granulomas. These features, along with the results of cultures and special stains for micro-organisms and clinical and radiologic correlation allow for a diagnosis in the vast majority of cases.

Surgical pathology of granulomatous interstitial pneumonia

Agranulomatous interstitial pneumonia is a form of diffuse lung disease in which granulomas are a component of the histologic findings. The differential diagnosis is quite broad, but most cases represent examples of either sarcoidosis, diffuse granulomatous infections, or hypersensitivity pneumonitis. “Hot tub lung” is a recently described form of granulomatous interstitial pneumonia that appears to have some features of diffuse infections and some features of hypersensitivity pneumonitis. The pathologist's approach to these conditions can be facilitated by giving careful attention to the anatomic distribution of the granulomas, the qualitative features of the granulomas, and the histologic changes in the lung tissue around and away from the granulomas. These features, along with the results of cultures and special stains for micro-organisms and clinical and radiologic correlation allow for a diagnosis in the vast majority of cases. Ann Diagn Pathol 7: 127-138, 2003.

The Genetic Predisposition to Interstitial Lung Disease: Functional Relevance

The approach to the genetic predisposition to diffuse lung disease (previously known as interstitial lung disease) poses a number of unique problems. The diffuse lung diseases comprise a large number of distinct clinical diseases. Of these, the idiopathic interstitial pneumonias are of particular importance because they include idiopathic pulmonary fibrosis (IPF), the most lethal form of diffuse lung disease, together with a number of diffuse lung disorders that have been (and continue to be) misdiagnosed as IPF.

The ICU Chest Film:

We have discussed several diseases that diffusely affect the pulmonary parenchyma. The diagnostic problem is to separate cardiac pulmonary edema from noncardiac pulmonary edema, diffuse interstitial fibrosis, and lymphangitic spread of carcinoma. Frequently, this may not be possible by radiographic means alone, and additional historic and physiologic information must be obtained. It is also important to know that cardiac pulmonary edema may present in a focal or regional distribution in patients with chronic obstructive pulmonary disease. Several additional radiographic tests may be used to evaluate abnormal pulmonary parenchymal densities seen on the portable chest radiograph, when the differential diagnosis includes increased extravascular water, pneumonia, and pulmonary fibrosis. The easiest of these tests to perform is the gravitational shift test.