Stress-induced eosinophil activation contributes to postoperative morbidity and mortality after lung resection.

Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death.

Therapeutic targeting of full-length interleukin-33 protein levels with cell-permeable decoy peptides attenuates fibrosis in the bleomycin model in vivo.

Interleukin (IL)-33 has been shown to centrally regulate, among other processes, inflammation and fibrosis. Both intracellular full-length (FLIL33) precursor and extracellular mature cytokine (MIL33) forms exert such regulation, albeit differentially. Drug development efforts to target the IL-33 pathway have focused mostly on MIL33 and its specific cell-surface receptor, ST2, with limited attempts to negotiate the pathophysiological contributions from FLIL33.

CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization.

Introduction: The CC chemokine ligand 18 (CCL18) is a chemokine highly expressed in chronic inflammation in humans. Recent observations of elevated CCL18 plasma levels in patients with acute cardiovascular syndromes prompted an investigation into the role of CCL18 in the pathogenesis of human and mouse atherosclerosis.

Methods And Results: CCL18 was profoundly upregulated in ruptured human atherosclerotic plaque, particularly within macrophages.

Wild-type S100A3 and S100A13 restore calcium homeostasis and mitigate mitochondrial dysregulation in pulmonary fibrosis patient-derived cells.

Patients with digenic S100A3 and S100A13 mutations exhibited an atypical and progressive interstitial pulmonary fibrosis, with impaired intracellular calcium homeostasis and mitochondrial dysfunction. Here we provide direct evidence of a causative effect of the mutation on receptor mediated calcium signaling and calcium store responses in control cells transfected with mutant S100A3 and mutant S100A13. We demonstrate that the mutations lead to increased mitochondrial mass and hyperpolarization, both of which were reversed by transfecting patient-derived cells with the wild type S100A3 and S100A13, or extracellular treatment with the recombinant proteins.

Cytokine profiling in plasma distinguishes the histological inflammatory subtype of head and neck squamous cell carcinoma and a novel regulatory role of osteopontin.

Head and neck squamous cell carcinoma (HNSCC) can be classified according to the histological inflammatory subtype (HIS) into inflamed (HIS-INF) or immune excluded (HIS-IE). HIS-IE was previously associated with higher levels of soluble Semaphorin 4D (HsS4D) in plasma, and higher transcriptional levels of osteopontin (OPN) in the tumor tissue, compared to HIS-INF. The goal of the current study is to investigate whether the HIS inflammatory subtype can be distinguished by a differential cytokine panel in peripheral blood.

Altered sialidase expression in human myeloid cells undergoing apoptosis and differentiation.

To gain insight into sialic acid biology and sialidase/neuraminidase (NEU) expression in mature human neutrophil (PMN)s, we studied NEU activity and expression in PMNs and the HL60 promyelocytic leukemic cell line, and changes that might occur in PMNs undergoing apoptosis and HL60 cells during their differentiation into PMN-like cells. Mature human PMNs contained NEU activity and expressed NEU2, but not NEU1, the NEU1 chaperone, protective protein/cathepsin A(PPCA), NEU3, and NEU4 proteins. In proapoptotic PMNs, NEU2 protein expression increased > 30.

Ischemia reperfusion injury facilitates lung allograft acceptance through IL-33-mediated activation of donor-derived IL-5 producing group 2 innate lymphoid cells.

Pathways regulating lung alloimmune responses differ from most other solid organs and remain poorly explored. Based on our recent work identifying the unique role of eosinophils in downregulating lung alloimmunity, we sought to define pathways contributing to eosinophil migration and homeostasis. Using a murine lung transplant model, we have uncovered that immunosuppression increases eosinophil infiltration into the allograft in an IL-5-dependent manner.

Mammalian Neuraminidases in Immune-Mediated Diseases: Mucins and Beyond.

Mammalian neuraminidases (NEUs), also known as sialidases, are enzymes that cleave off the terminal neuraminic, or sialic, acid resides from the carbohydrate moieties of glycolipids and glycoproteins. A rapidly growing body of literature indicates that in addition to their metabolic functions, NEUs also regulate the activity of their glycoprotein targets. The simple post-translational modification of NEU protein targets-removal of the highly electronegative sialic acid-affects protein folding, alters protein interactions with their ligands, and exposes or covers proteolytic sites.

Demystifying idiopathic interstitial pneumonia: time for more etiology-focused nomenclature in interstitial lung disease.

Introduction: A major focus of interstitial lung disease (ILD) has centered on disorders termed idiopathic interstitial pneumonias (IIPs) which include, among others, idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, and respiratory bronchiolitis-interstitial lung disease.

Areas Covered: We review the radiologic and histologic patterns for the nine disorders classified by multidisciplinary approach as IIP, and describe the remarkable amount of published epidemiologic, translational, and molecular studies demonstrating their associations with numerous yet definitive environmental exposures, occupational exposures, pulmonary diseases, systemic diseases, medication toxicities, and genetic variants.

Expert Opinion: In the 21st century, these disorders termed IIPs are rarely idiopathic, but rather are well-described radiologic and histologic patterns of lung injury that are associated with a wide array of diverse etiologies.

Regulator of Cell Cycle Protein (RGCC/RGC-32) Protects against Pulmonary Fibrosis.

Some previous studies in tissue fibrosis have suggested a profibrotic contribution from elevated expression of a protein termed either RGCC (regulator of cell cycle) or RGC-32 (response gene to complement 32 protein). Our analysis of public gene expression datasets, by contrast, revealed a consistent decrease in RGCC mRNA levels in association with pulmonary fibrosis. Consistent with this observation, we found that stimulating primary adult human lung fibroblasts with transforming growth factor (TGF)-β in cell cultures elevated collagen expression and simultaneously attenuated RGCC mRNA and protein levels.

Potent T cell-mediated anti-inflammatory role of the selective CB2 agonist lenabasum in multiple sclerosis.

Background: Lenabasum is a synthetic cannabinoid receptor type-2 (CB2) agonist able to exert potent anti-inflammatory effects, but its role on T cells remains unknown.

Objectives: The present study was undertaken to investigate anti-inflammatory mechanisms of lenabasum in T lymphocyte subsets and its in vivo therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE).

Methods: Mononuclear cells from 17 healthy subjects (HS) and 25 relapsing-remitting multiple sclerosis (RRMS) patients were activated in presence or absence of lenabasum and analysed by flow cytometry and qRT-PCR.

A Physiologically Based Pharmacokinetic and Drug-Drug Interaction Model for the CB2 Agonist Lenabasum.

Background And Objectives: Lenabasum is a synthetic agonist of the cannabinoid receptor type 2 (CB2) with anti-inflammatory and antifibrotic properties. Utilizing Simcyp, we developed a physiologically based pharmacokinetic (PBPK) model based on physicochemical properties, cell culture data, and cytochrome P450 (CYP) phenotyping, inhibition, and induction data.

Methods: Clinical data from healthy volunteers treated with 20 mg of lenabasum in a single ascending dose (SAD) study were used for model development.

A comprehensive assessment of environmental exposures and the medical history guides multidisciplinary discussion in interstitial lung disease.

Background: Multidisciplinary discussion (MDD) is widely recommended for patients with interstitial lung disease (ILD), but published primary data from MDD has been scarce, and factors influencing MDD other than chest computed tomography (CT) and lung histopathology interpretations have not been well-described.

Methods: Single institution MDD of 179 patients with ILD.

Results: MDD consensus clinical diagnoses included autoimmune-related ILD, chronic hypersensitivity pneumonitis, smoking-related ILD, idiopathic pulmonary fibrosis, medication-induced ILD, occupation-related ILD, unclassifiable ILD, and a few less common pulmonary disorders.

Therapeutic Effect of Neuraminidase-1-Selective Inhibition in Mouse Models of Bleomycin-Induced Pulmonary Inflammation and Fibrosis.

Pulmonary fibrosis remains a serious biomedical problem with no cure and an urgent need for better therapies. Neuraminidases (NEUs), including NEU1, have been recently implicated in the mechanism of pulmonary fibrosis by us and others. We now have tested the ability of a broad-spectrum neuraminidase inhibitor, 2,3-dehydro-2-deoxy--acetylneuraminic acid (DANA), to modulate the in vivo response to acute intratracheal bleomycin challenge as an experimental model of pulmonary fibrosis.

Full-length IL-33 regulates Smad3 phosphorylation and gene transcription in a distinctive AP2-dependent manner.

IL-33 has emerged as a central mediator of immune, inflammatory, and fibrotic responses. Many studies have focused on mature IL-33, but elevated expression of the precursor, full-length IL-33 (FLIL33), has also been implicated in a spectrum of diseases, including tissue fibrosis. We previously reported and now confirmed that overexpression of FLIL33 induced phosphorylation of the key profibrotic signaling mediator of TGF-β, Smad3, in primary human lung fibroblasts from healthy donors and idiopathic pulmonary fibrosis patients.

SIRT7 deficiency suppresses inflammation, induces EndoMT, and increases vascular permeability in primary pulmonary endothelial cells.

Acute lung injury (ALI), a common condition in critically ill patients, has limited treatments and high mortality. Aging is a risk factor for ALI. Sirtuins (SIRTs), central regulators of the aging process, decrease during normal aging and in aging-related diseases.

Combined Pulmonary Fibrosis and Emphysema: Pulmonary Function Testing and a Pathophysiology Perspective.

Combined pulmonary fibrosis and emphysema (CPFE) has been increasingly recognized over the past 10-15 years as a clinical entity characterized by rather severe imaging and gas exchange abnormalities, but often only mild impairment in spirometric and lung volume indices. In this review, we explore the gas exchange and mechanical pathophysiologic abnormalities of pulmonary emphysema, pulmonary fibrosis, and combined emphysema and fibrosis with the goal of understanding how individual pathophysiologic observations in emphysema and fibrosis alone may impact clinical observations on pulmonary function testing (PFT) patterns in patients with CPFE. Lung elastance and lung compliance in patients with CPFE are likely intermediate between those of patients with emphysema and fibrosis alone, suggesting a counter-balancing effect of each individual process.

An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes and .

Background: Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death.

Methods: 13 patients born to consanguineous parents from two unrelated families presenting with interstitial lung disease were clinically investigated.

Identification of the IL-33 protein segment that controls subcellular localization, extracellular secretion, and functional maturation.

Proteolytic activation of the IL-33 precursor, full-length interleukin-33 (FLIL33), at multiple sites within the sensor domain (aa 95-109) yields several functionally mature (MIL33) forms. Unlike nuclear FLIL33, intracellular MIL33 occurs in the cytoplasm, is secreted from source cells, and exerts biological effects by activating the ST2 receptor on target cells. Previous studies and our findings in this report indicated that IL-33 forms that are substantially longer than those produced by cleavage within the sensor domain are biologically indistinguishable from classical MIL33.

Interstitial Lung Disease and Pulmonary Fibrosis: A Practical Approach for General Medicine Physicians with Focus on the Medical History.

Interstitial lung disease (ILD) and pulmonary fibrosis comprise a wide array of inflammatory and fibrotic lung diseases which are often confusing to general medicine and pulmonary physicians alike. In addition to the myriad of clinical and radiologic nomenclature used in ILD, histopathologic descriptors may be particularly confusing, and are often extrapolated to radiologic imaging patterns which may further add to the confusion. We propose that rather than focusing on precise histologic findings, focus should be on identifying an accurate etiology of ILD through a comprehensive and detailed medical history.

Neuraminidase 1-mediated desialylation of the mucin 1 ectodomain releases a decoy receptor that protects against lung infection.

(Pa) expresses an adhesin, flagellin, that engages the mucin 1 (MUC1) ectodomain (ED) expressed on airway epithelia, increasing association of MUC1-ED with neuraminidase 1 (NEU1) and MUC1-ED desialylation. The MUC1-ED desialylation unmasks both cryptic binding sites for Pa and a protease recognition site, permitting its proteolytic release as a hyperadhesive decoy receptor for Pa. We found here that intranasal administration of Pa strain K (PAK) to BALB/c mice increases MUC1-ED shedding into the bronchoalveolar compartment.