Normal ex vivo mesenchymal stem cell function combined with abnormal immune profiles sets the stage for informative cell therapy trials in idiopathic pulmonary fibrosis patients.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive pulmonary disease characterized by aberrant tissue remodeling, formation of scar tissue within the lungs and continuous loss of lung function. The areas of fibrosis seen in lungs of IPF patients share many features with normal aging lung including cellular senescence. The contribution of the immune system to the etiology of IPF remains poorly understood. Evidence obtained from animal models and human studies suggests that innate and adaptive immune processes can orchestrate existing fibrotic responses. Currently, there is only modest effective pharmacotherapy for IPF. Mesenchymal stem cells (MSCs)-based therapies have emerged as a potential option treatment of IPF. This study characterizes the functionality of autologous MSCs for use as an IPF therapy and presents an attempt to determine whether the disease occurring in the lungs is associated with an alterated immune system. METHODS: Comprehensive characterization of autologous adipose-derived MSCs (aMSCs) from 5 IPF patient and 5 age- and gender-matched healthy controls (HC) was done using flow cytometry, PCR (ddPCR), multiplex Luminex xMAP technology, confocal microscopy self-renewal capacity and osteogenic differentiation. Additionally, multi-parameter quantitative flow cytometry of unmanipulated whole blood of 15 IPF patients and 87 (30 age- and gender-matched) HC was used to analyze 110 peripheral phenotypes to determine disease-associated changes in the immune system. RESULTS: There are no differences between autologous aMSCs from IPF patients and HC in their stem cell properties, self-renewal capacity, osteogenic differentiation, secretome content, cell cycle inhibitor marker levels and mitochondrial health. IPF patients had altered peripheral blood immunophenotype including reduced B cells subsets, increased T cell subsets and increased granulocytes demonstrating disease-associated alterations in the immune system. CONCLUSIONS: Our results indicate that there are no differences in aMSC properties from IPF patients and HC, suggesting that autologous aMSCs may be an acceptable option for IPF therapy. The altered immune system of IPF patients may be a valuable biomarker for disease burden and monitoring therapeutic response.

Antifibrotics Modify B-Cell-induced Fibroblast Migration and Activation in Patients with Idiopathic Pulmonary Fibrosis.

B-cell activation is increasingly linked to numerous fibrotic lung diseases, and it is well known that aggregates of lymphocytes form in the lung of many of these patients. Activation of B-cells by pattern recognition receptors (PRRs) drives the release of inflammatory cytokines, chemokines, and metalloproteases important in the pathophysiology of pulmonary fibrosis. However, the specific mechanisms of B-cell activation in patients with idiopathic pulmonary fibrosis (IPF) are poorly understood. Herein, we have demonstrated that B-cell activation by microbial antigens contributes to the inflammatory and profibrotic milieu seen in patients with IPF. B-cell stimulation by CpG and ß-glucan via PRRs resulted in activation of mTOR-dependent and independent pathways. Moreover, we showed that the B-cell-secreted inflammatory milieu is specific to the inducing antigen and causes differential fibroblast migration and activation. B-cell responses to infectious agents and subsequent B-cell-mediated fibroblast activation are modifiable by antifibrotics, but each seems to exert a specific and different effect. These results suggest that, upon PRR activation by microbial antigens, B-cells can contribute to the inflammatory and fibrotic changes seen in patients with IPF, and antifibrotics are able to at least partially reverse these responses.

Marked hypereosinophilia secondary to endometrioid ovarian cancer presenting with asthma symptoms, a case report.

BACKGROUND: Hypereosinophilia (HE) is defined by the presence of >1.5 × 109/L eosinophils in the peripheral blood. Paraneoplastic HE has been reported in a number of solid and hematologic malignancies including ovarian cancer. We present a case with paraneoplastic HE in the setting of underlying endometrioid ovarian carcinoma. CASE PRESENTATION: An 88-year-old woman presented with cough, dyspnea and 20-pound unintentional weight loss of one month duration. Evaluation revealed peripheral hypereosinophilia (HE) with absolute eosinophil count of 15.38 × 109/L (53.8%) and an elevated exhaled nitric oxide at 172 parts per billion (normal < 39 PPB). Given the HE and unintentional weight loss, computed tomography (CT) scan was obtained and showed a pelvic mass. The patient underwent bilateral salpingo-ophorectomy with pathology consistent with endometrioid ovarian carcinoma. The patient experienced complete resolution of her cough, dyspnea, and peripheral eosinophilia following surgical resection. CONCLUSION: This case highlights that solid malignancy should be considered in patients with marked HE.

Dendriform pulmonary ossification complicated by recurrent spontaneous pneumothorax: Two case reports and a review of the literature.

BACKGROUND: Dendriform pulmonary ossification (DPO) is a rare disease characterized by the presence of mature bone in the lung parenchyma with typical radiologic findings of diffuse and numerous calcified nodules. We present two cases of primary DPO complicated by recurrent spontaneous pneumothorax. CASE PRESENTATION: Case 1 is a 53-year-old male with recurrent pneumothorax unresponsive to chest tube drainage or subtotal pleurectomy via video assisted thoracoscopy (VATS) who was finally treated with talc pleurodesis. Chest computed tomography (CT) revealed bilateral partially calcified reticulonodular opacities with a basal predominance. VATS biopsy revealed patchy foci of fibrous organizing pneumonia with multifocal ossifications confirming DPO histopathology. Pneumothorax recurred on the same side eight months later managed with talc pleurodesis. Case 2 is a 45-year-old Caucasian male who presented for evaluation of three prior spontaneous left-sided pneumothoraces occurring over eight years, treated with chest tube drainage and eventual talc pleurodesis. Chest CT demonstrated multiple high attenuation peripheral branching opacities greatest in the left lower lobe with several nonspecific, non-calcified pulmonary nodules. VATS biopsy revealed cicatrical organizing pneumonia with associated extensive intraalveolar ossification consistent with DPO. CONCLUSIONS: We describe two cases of DPO complicated by recurrent pneumothorax and reviewed the world literature. Summarized findings included a propensity for middle-aged males with a generally indolent course though pneumothorax was often refractory to initial chest tube drainage requiring more definitive mechanical management. There was also a predominance of primary disease without associated causes other than several reports of obstructive lung disease (asthma).

An ex vivo technique for quantifying mouse lung injury using ultrasound surface wave elastography.

Idiopathic pulmonary fibrosis is a progressively fatal disease with limited treatments. The bleomycin mouse model is often used to simulate the disease process in laboratory studies. The aim of this study was to develop an ex vivo technique for assessing mice lung injury using lung ultrasound surface wave elastography (LUSWE) in the bleomycin mouse model. The surface wave speeds were measured at three frequencies of 100, 200, and 300 Hz for mice lungs from control, mild, and severe groups. The results showed significant differences in the lung surface wave speeds, pulse oximetry, and compliance between control mice and mice with severe pulmonary fibrosis. LUSWE is an evolving technique for evaluating lung stiffness and may be useful for assessing pulmonary fibrosis in the bleomycin mouse model.

Non-antimicrobial airway management of non-cystic fibrosis bronchiectasis.

Bronchiectasis are often encountered in clinical practice, and are characterized by abnormal airway dilatation and distortion associated with impaired mucociliary clearance and mucous plugging, which are frequently associated with recurrent infections. Numerous etiologies can underlie the development of bronchiectasis, but the most important distinction in research and clinical practice is between bronchiectasis due to cystic fibrosis (CF) and bronchiectasis due to all other reasons (non-CF bronchiectasis). The causes of non-CF bronchiectasis are varied and often unclear. Patients disease severity and phenotypes of non-CF bronchiectasis also varied, which can influence disease trajectory, frequency of exacerbations and mortality. This article reviews the published evidence and suggests interventions to enhance airways clearance in patients with non-CF bronchiectasis, which are key components of an individualized therapeutic program in order to achieve symptomatic relief and prevention of exacerbations and functional decline.

Phenytoin induced Steven-Johnson syndrome and bronchiolitis obliterans - case report and review of literature.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are both rare but serious idiosyncratic drug reactions characterized by diffuse muco-epidermoid injury and high mortality. Keratinocytes in both skin and mucous membranes (including eyes, mouth and genitalia) are injured resulting in a diffuse maculopapular rash, blistering lesions and epithelial detachment with minimal force (Nikolsky's sign). SJS is typically diagnosed when less than 10% of the skin surface is involved and the term TEN is used in cases with more than 30% involvement. Respiratory involvement in SJS-TEN is common with 30-50% of cases demonstrating respiratory epithelial sloughing with severe short and long term complications. Patients who survive SJS-TEN are often left with impaired respiratory function and bronchiolitis obliterans. Cases of bronchiolitis obliterans with SJS/TEN have been very rarely reported. We report a case of phenytoin induced SJS/TEN followed by severe bronchiolitis obliterans in an adult patient. The presentation, pathophysiology and management of SJS/TEN related bronchiolitis obliterans is also reviewed.