Vassallo, Robert

Context.— Pulmonary hypertension (PHT) is a complication of pulmonary Langerhans cell histiocytosis (PLCH); however, the pathogenesis remains largely unknown. Few studies have evaluated histopathologic changes in pulmonary arteries (PAs) of patients with PLCH; systematic quantification of arterial remodeling has yet to be undertaken. Objective.— To quantify the extent of arterial remodeling among patients with PLCH through morphometry and to correlate these results with pertinent clinical parameters. Design.— Patients with PLCH were identified from institutional files (1995–2015) along with age-, sex-, and smoking status–matched controls. Morphometric analysis of intimal and medial thickness of small to medium PAs was performed in patients with PLCH (within PLCH lesions [lesional] and away from PLCH lesions [nonlesional]) and controls. Paired measures were compared with Wilcoxon signed rank tests. Results.— Twenty-five patients with PLCH (14 men: median age, 46 years; interquartile range, 37–55 years) and 25 controls were included. The lesional arteries of patients with PLCH demonstrated thicker PA intima and media than controls (P < .001 and P < .001, respectively), as did PLCH nonlesional arteries compared to controls (P < .001 and P < .001, respectively). The PA intima and media were thicker within the PLCH lesions than nonlesional arteries (P = .02 and P = .002, respectively). Patients with PLCH-related PHT had a worse prognosis than those without PHT (P = .04; hazard ratio, 4.5 [1.1, 22.2]). Echocardiography parameters including right atrial size (P = .007), estimated right atrial pressure (P = .01), and right ventricular systolic pressure (P = .01) were inversely associated with survival. Conclusions.— Our findings suggest that factors other than direct vascular obstruction or inflammatory cell infiltration contribute, at least in part, to the vascular remodeling in PLCH.

ABSTRACT Myofibroblasts play key roles in wound healing and pathological fibrosis. Here, we used an RNAi screen to characterize myofibroblast regulatory genes, using a high-content imaging approach to quantify α-smooth muscle actin stress fibers in cultured human fibroblasts. Screen hits were validated on physiological compliance hydrogels, and selected hits tested in primary fibroblasts from patients with idiopathic pulmonary fibrosis. Our RNAi screen led to the identification of STAT3 as an essential mediator of myofibroblast activation and function. Strikingly, we found that STAT3 phosphorylation, while responsive to exogenous ligands on both soft and stiff matrices, is innately active on a stiff matrix in a ligand/receptor-independent, but ROCK- and JAK2-dependent fashion. These results demonstrate how a cytokine-inducible signal can become persistently activated by pathological matrix stiffening. Consistent with a pivotal role for this pathway in driving persistent fibrosis, a STAT3 inhibitor attenuated murine pulmonary fibrosis when administered in a therapeutic fashion after bleomycin injury. Our results identify novel genes essential for the myofibroblast phenotype, and point to STAT3 as an important target in pulmonary fibrosis and other fibrotic diseases.

Abstract Acute eosinophilic pneumonia (AEP) is an uncommon acute respiratory illness of varying severity that includes presentation as acute respiratory distress syndrome with fatal outcome. AEP may be idiopathic, but identifiable causes include smoking and other inhalational exposures, medications, and infections. The pathogenesis of AEP is poorly understood but likely varies depending on the underlying cause. Airway epithelial injury, endothelial injury, and release of IL-33 are early events that subsequently promote eosinophil recruitment to the lung; eosinophilic infiltration and degranulation appear to mediate subsequent lung inflammation and associated clinical manifestations. Crucial for the diagnosis are the demonstration of pulmonary eosinophilia in the BAL fluid and the exclusion of other disease processes that can present with acute pulmonary infiltrates. Although peripheral blood eosinophilia at initial presentation may be a clue in suggesting the diagnosis of AEP, it may be absent or delayed, especially in smoking-related AEP. Optimal management of AEP depends on the recognition and elimination of the underlying cause when identifiable. The cessation of the exposure to the inciting agent (e.g., smoking), and glucocorticoids represent the mainstay of treating AEP of noninfectious origin. If AEP is recognized and treated in a timely manner, the prognosis is generally excellent, with prompt and complete clinical recovery, even in those patients manifesting acute respiratory failure.

PurposeTo investigate the use of magnetic resonance elastography (MRE) in the quantitative assessment of pulmonary fibrosis by comparing quantitative shear stiffness measurements of lung parenchyma in patients diagnosed with fibrotic interstitial lung disease (ILD) and healthy controls.Materials and MethodsA 1.5T spin‐echo, echo planar imaging MRE (SE‐EPI MRE) pulse sequence was utilized to assess absolute lung shear stiffness in 15 patients with diagnosed ILD and in 11 healthy controls. Data were collected at residual volume (RV) and total lung capacity (TLC). Spirometry data were obtained immediately prior to scanning. To test for statistical significance between RV and TLC shear stiffness estimates a two‐sample t‐test was performed. To assess variability within individual subject shear stiffness estimates, the intraclass correlation coefficient (ICC) and Krippendorff's alpha were calculated.ResultsPatients with ILD exhibited an average (±1 standard deviation) shear stiffness of 2.74 (±0.896) kPa at TLC and 1.32 (±0.300) kPa at RV. The corresponding values for healthy individuals were 1.33 (±0.195) kPa and 0.849 (±0.250) kPa, respectively. The difference in shear stiffness between RV and TLC was statistically significant (P < 0.001). At TLC, the ICC and alpha values were 0.909 and 0.887, respectively. At RV, the ICC and alpha values were 0.852 and 0.862, respectively.ConclusionIn subjects with known fibrotic interstitial lung disease, parenchymal shear stiffness is increased when compared to normal controls at both RV and TLC, with TLC demonstrating the most significant difference. MRE‐derived parenchymal shear stiffness is a promising new noninvasive imaging‐based biomarker of interstitial lung disease.Level of Evidence: 1Technical Efficacy: Stage 2J. MAGN. RESON. IMAGING 2017;46:365–374

AbstractBackgroundLangerhans cell histiocytosis (LCH) is a clonal neoplasm characterized by widely varied clinical presentations, including multisystem involvement and systemic inflammatory symptoms. The AKT pathway is relevant to survival and proliferation of dendritic cells, and is also often upregulated in hematopoietic malignancies. A clinical response in an adult patient with LCH participating in the first‐in‐human trial of afuresertib prompted this prospective trial.ProcedureThe population in the current study included treatment‐naïve (n = 7) and recurrent/refractory patients with LCH (n = 10), who received oral afuresertib (125 mg). The majority of patients were treated for > 24 weeks, with four patients receiving treatment for > 48 weeks.ResultsPharmacokinetic analysis showed similar exposures in previously reported patients with other hematologic malignancies. Primary drug‐related toxicities included Grade 1/2 nausea, diarrhea, dyspepsia, and vomiting. Grade 3 toxicities included fatigue, diarrhea, and pain (one of each). Another severe adverse event involved soft tissue necrosis. The overall response rate in evaluable subjects was 33% in treatment‐naïve patients and 28% in patients with recurrent/refractory disease, which did not meet the predefined Bayesian criteria for efficacy.ConclusionAfuresertib has clinical activity in some patients with newly diagnosed and advanced LCH.

Long‐term exposure to cigarette smoke (CS) triggers airway hyperreactivity and remodeling, effects that involve airway smooth muscle (ASM). We previously showed that CS destabilizes the networked morphology of mitochondria in human ASM by regulating the expression of mitochondrial fission and fusion proteins via multiple signaling mechanisms. Emerging data link regulation of mitochondrial morphology to cellular structure and function. We hypothesized that CS‐induced changes in ASM mitochondrial morphology detrimentally affect mitochondrial function, leading to CS effects on contractility and remodeling. Here, ASM cells were exposed to 1% cigarette smoke extract (CSE) for 48 h to alter mitochondrial fission/fusion, or by inhibiting the fission protein Drp1 or the fusion protein Mfn2. Mitochondrial function was assessed via changes in bioenergetics or altered rates of proliferation and apoptosis. Our results indicate that both exposure to CS and inhibition of mitochondrial fission/fusion proteins affect mitochondrial function (i.e., energy metabolism, proliferation, and apoptosis) in ASM cells. In vivo, the airways in mice chronically exposed to CS are thickened and fibrotic, and the expression of proteins involved in mitochondrial function is dramatically altered in the ASM of these mice. We conclude that CS‐induced changes in mitochondrial morphology (fission/fusion balance) correlate with mitochondrial function, and thus may control ASM proliferation, which plays a central role in airway health. J. Cell. Physiol. 232: 1053–1068, 2017. © 2016 Wiley Periodicals, Inc.

Abstract The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.

Abstract The diffuse cystic lung diseases have a broad differential diagnosis. A wide variety of pathophysiological processes spanning the spectrum from airway obstruction to lung remodeling can lead to multifocal cyst development in the lung. Although lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis are perhaps more frequently seen in the clinic, disorders such as Birt-Hogg-Dubé syndrome, lymphocytic interstitial pneumonia, follicular bronchiolitis, and light-chain deposition disease are increasingly being recognized. Obtaining an accurate diagnosis can be challenging, and management approaches are highly disease dependent. Unique imaging features, genetic tests, serum studies, and clinical features provide invaluable clues that help clinicians distinguish among the various etiologies, but biopsy is often required for definitive diagnosis. In part II of this review, we present an overview of the diffuse cystic lung diseases caused by lymphoproliferative disorders, genetic mutations, or aberrant lung development and provide an approach to aid in their diagnosis and management.