Isolated IgG4 related disease of the trachea.

IgG4 related disease (IgG4-RD) is a multisystem inflammatory disease and can affect several organs including salivary glands, orbits, lungs, pancreas, kidneys and lymph nodes. Up to 40 % of patients have allergic manifestations including asthma, chronic rhinosinusitis, eczema and asthma. Commonly pulmonary manifestations include pulmonary nodules ranging from <1 to 5 cm in diameter, interstitial opacities and mediastinal lymphadenopathy. Rarely, IgG4-RD presents as isolated tracheal disease. Symptoms include dyspnea and stridor due to airway narrowing. Diagnosis of IgG4-RD including tracheal IgG4-RD requires a biopsy. The histologic specimen is characterized by lymphoplasmacytic infiltrate with high density of IgG4 positive plasma cells, and storiform fibrosis (a cartwheel appearance of fibroblasts and inflammatory cells). Up to 30 % of patients with IgG4-RD have normal serum IgG4 levels. The mainstay of therapy is glucocorticoids for those with systemic disease. Rituximab is an alternative for those who cannot tolerate glucocorticoids or those with disease recurrence. Patients with tracheal disease often require balloon dilation. Recurrence is common in patients and up to two thirds of patients have residual disease despite treatment. These patients often require surgical resection of affected area for symptomatic relief.

Epidemiology and Clinical Outcomes of Fusobacterium Infections: A Six-Year Retrospective Study.

Background and Objectives: Anaerobic bacteria like Fusobacterium can lead to severe and life-threatening infections. The inherent complexities in the isolation of these bacteria may result in diagnostic and therapeutic delays, thereby escalating both morbidity and mortality rates. We aimed to examine data from patients with infections due to Fusobacterium to gain insights into the epidemiology and clinical outcomes of patients with these infections. Methods and Results: We conducted a retrospective analysis of clinical data from a cohort of patients with cultures positive for Fusobacterium species at a tertiary care medical center in the United States. Between 2009 and 2015, we identified 96 patients with cultures positive for Fusobacterium. Patients could be categorized into three groups based on the site of primary infection. Patients with head and neck infections constituted 37% (n 36). Patients with infections of other soft tissue sites accounted for 38.5% (n 37). Patients with anaerobic bacteremia due to Fusobacterium formed 24% (n 23) of the cohort. Surgical intervention coupled with antibiotic therapy emerged as cornerstones of management for patients with head and neck or other soft tissue infections, who generally exhibited more favorable outcomes. Patients with bacteremia were older, more likely to have malignancy, and had a high mortality rate. When speciation was available, Fusobacterium necrophorum was the most frequently isolated species. Conclusions: Our retrospective analysis of epidemiology and clinical outcomes of Fusobacterium infections revealed three distinct cohorts. Patients with head, neck, or soft tissue infections had better outcomes than those with bacteremia. Our findings highlight the importance of employing management strategies based on infection site and underlying comorbidities in patients with Fusobacterium infections. Further research is needed to investigate the optimal therapeutic strategies and identify prognostic indicators to improve clinical outcomes for these complex infections.

A Unique Case of Prostate Carcinoma Presenting as Retroperitoneal Lymphadenopathy With Normal Levels of Prostate-Specific Antigen and a Prostate of Normal Size: A Case Report.

Despite the significant advancements in prostate-specific antigen (PSA) screening and the diverse array of available treatments, prostate cancer (PCa) still significantly contributes to cancer-related illness. The most prevalent sites for metastases are bones, distant lymph nodes, and abdominal organs. Nevertheless, metastasis to the renal and retroperitoneal regions originating from prostate cancer constitutes an exceptionally uncommon clinical occurrence. Metastatic PCa commonly presents with elevated serum PSA levels, a hallmark of its diagnostic profile. However, there are instances where patients exhibit atypical metastatic patterns or maintain normal PSA levels. In the case under consideration, the patient exhibited a periureteral tumor with an indeterminate primary origin, subsequently confirmed to be metastatic prostate cancer. This case underscores the importance of recognizing the varied and sometimes elusive presentations of metastatic PCa. Despite its rarity, the occurrence of renal and retroperitoneal metastasis emphasizes the need for vigilance and a comprehensive understanding of the diverse manifestations of advanced PCa for timely and accurate diagnosis, which is paramount in optimizing patient care and outcomes.

5-Fluorouracil Neurotoxicity in the Absence of Dihydropyrimidine Dehydrogenase Deficiency Case Report.

5 fluorouracil (5-FU)-related neurotoxicity is a rare and severe complication of 5-FU administration. Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with an increased risk of serious adverse reactions due to its role in 5-FU metabolism. We report a case of acute reversible neurotoxicity with global areas of diffusion restriction in a patient with colorectal adenocarcinoma being treated with leucovorin calcium, 5-fluorouracil, and oxaliplatin (FOLFOX) without DPD deficiency following uridine triacetate administration.

Pre-Existing Psychiatric Illness Is Associated With an Increased Risk of Delirium in Patients With Acute Respiratory Distress Syndrome.

BACKGROUND: Patients with acute respiratory distress syndrome (ARDS) are highly susceptible to developing delirium for a multitude of reasons. Previous studies have linked pre-existing depression with an increased risk of postoperative delirium in patients undergoing cardiac and non-cardiac surgery. However, the evidence regarding the association between pre-existing psychiatric illnesses and delirium in ARDS patients is unknown. In this study, we aim to determine the relationship between pre-existing psychiatric illness and the risk of development of delirium amongst ARDS patients. STUDY DESIGN AND METHODS: We performed a retrospective study of a mixed group of patients admitted to the intensive care unit (ICU) between January 2016 and December 2019 with a diagnosis of ARDS per the Berlin definition. The study group was divided into 2 cohorts: subjects with delirium and subjects without delirium. Comparison between the 2 groups was conducted to examine the impact of pre-existing psychiatric illnesses including major depressive disorder (MDD), generalized anxiety disorder (GAD), bipolar disorder, schizophrenia, or post-traumatic stress disorder. Multivariable logistic regression analysis was performed adjusting for benzodiazepine use, sedatives, analgesics, sequential organ failure assessment score, and corticosteroid use to determine the association between pre-existing psychiatric disorders and delirium. RESULTS: 286 patients with ARDS were identified; 124 (43%) of whom were diagnosed with ICU delirium. In patients diagnosed with ICU delirium, 49.2% were found to have preexisting psychiatric illnesses, compared to 34.0% without any preexisting psychiatric illness (OR = 1.94, P = 0.01). In a subgroup analysis of individual psychiatric illnesses, GAD and MDD were associated with the development of delirium (OR = 1.88, P = 0.04 and OR = 1.76, P = 0.05 respectively). INTERPRETATION: ARDS patients with preexisting psychiatric illnesses, particularly GAD and MDD are associated with an increased risk of developing ICU delirium. Clinicians should be aware of the effect of psychiatric co-morbidities on developing delirium in critically ill patients.

Pulmonary hypertension in eosinophilic versus noneosinophilic COPD.

BACKGROUND: The eosinophilic COPD phenotype is associated with greater airway remodelling, exacerbation risk and steroid responsiveness. However, little is known about the prevalence and characteristics of pulmonary hypertension (PH) in this patient population. METHODS: We retrospectively evaluated a cohort of COPD patients with right heart catheterisation (RHC) data at a university hospital between January 2011 and May 2019 and compared the pulmonary vascular profile and prevalence of PH between eosinophilic and noneosinophilic patients using a definition of eosinophilic COPD as at least three blood eosinophil values ≥300 cells·µL-1. We used multivariable logistic regression analyses to examine the association between eosinophilic COPD and various PH categories adjusting for age, sex, body mass index, forced expiratory volume in 1 s (%), smoking status and use of supplemental oxygen. RESULTS: Among 106 COPD patients with RHC data and at least three blood eosinophil values, 25% met the definition of eosinophilic COPD. Fewer patients among the eosinophilic group required long-term oxygen therapy (69% versus 93%, p=0.001) and total lung capacity was significantly lower in the eosinophilic group (p=0.006). This group had higher mean pulmonary arterial pressure (mPAP) (median (interquartile range) 30 (27-41) mmHg versus 25 (22-30) mmHg, p=0.001) and pulmonary vascular resistance (PVR) (4 (2.8-5.1) Wood units versus 2.9 (2.1-4.1) Wood units, p=0.018). On multivariable logistic regression analyses, eosinophilic phenotype was associated with PH (adjusted (a)OR 6.5, 95% CI 1.4-30.7; p=0.018) and pre-capillary PH (aOR 3.2, 95% CI 1.1-9; p=0.027), but not severe PH (aOR 2.1, 95% CI 0.6-7.2; p=0.219). CONCLUSION: Eosinophilic COPD was associated with higher mPAP and PVR and increased likelihood of PH. More studies are needed to further explore this finding.

Bidirectional interaction of airway epithelial remodeling and inflammation in asthma.

Asthma is a chronic disease of the airways that has long been viewed predominately as an inflammatory condition. Accordingly, current therapeutic interventions focus primarily on resolving inflammation. However, the mainstay of asthma therapy neither fully improves lung function nor prevents disease exacerbations, suggesting involvement of other factors. An emerging concept now holds that airway remodeling, another major pathological feature of asthma, is as important as inflammation in asthma pathogenesis. Structural changes associated with asthma include disrupted epithelial integrity, subepithelial fibrosis, goblet cell hyperplasia/metaplasia, smooth muscle hypertrophy/hyperplasia, and enhanced vascularity. These alterations are hypothesized to contribute to airway hyperresponsiveness, airway obstruction, airflow limitation, and progressive decline of lung function in asthmatic individuals. Consequently, targeting inflammation alone does not suffice to provide optimal clinical benefits. Here we review asthmatic airway remodeling, focusing on airway epithelium, which is critical to maintaining a healthy respiratory system, and is the primary defense against inhaled irritants. In asthma, airway epithelium is both a mediator and target of inflammation, manifesting remodeling and resulting obstruction among its downstream effects. We also highlight the potential benefits of therapeutically targeting airway structural alterations. Since pathological tissue remodeling is likewise observed in other injury- and inflammation-prone tissues and organs, our discussion may have implications beyond asthma and lung disease.

Pulmonary Embolism in Acute Asthma Exacerbation: Clinical Characteristics, Prediction Model and Hospital Outcomes.

PURPOSE: Little is known about the characteristics and impact of acute pulmonary embolism (PE) during episodes of asthma exacerbation. We aimed to characterize patients diagnosed with acute PE in the setting of asthma exacerbation, develop a prediction model to help identify future patients and assess the impact of acute PE on hospital outcomes. METHODS: We included 758 patients who were treated for asthma exacerbation and underwent a computed tomographic pulmonary angiography (CTA) during the same encounter at a university-based hospital between June 2011 and October 2018. We compared clinical characteristics of patients with and without acute PE and developed a machine learning prediction model to classify the PE status based on the clinical variables. We used multivariable regression analysis to evaluate the impact of acute PE on hospital outcomes. RESULTS: Twenty percent of the asthma exacerbation patients who underwent CTA had an acute PE. Factors associated with acute PE included previous history of PE, high CHA2DS2-VASc score, hyperlipidemia, history of deep vein thrombosis, malignancy, chronic systemic corticosteroids use, high body mass index and atrial fibrillation. Using these factors, we developed a random forest machine learning prediction model which had an 88% accuracy in classifying the acute PE status of the patients (area under the receiver operating characteristic curve = 0.899; 95% confidence interval: 0.885-0.913). Acute PE in asthma exacerbation was associated with longer hospital stay and intensive care unit stay. CONCLUSION: It is important to consider acute PE, a potentially life-threatening event, in the setting of asthma exacerbation especially when other risk factors are present.

Cigarette smoke downregulates Nur77 to exacerbate inflammation in chronic obstructive pulmonary disease (COPD).

Cigarette smoke (CS) contains multiple gaseous and particulate materials that can cause lung inflammation, and smoking is the major cause of chronic obstructive pulmonary disease (COPD). We sought to determine the mechanisms of how CS triggers lung inflammation. Nur77, a nuclear hormone receptor belonging to the immediate-early response gene family, controls inflammatory responses, mainly by suppressing the NF-κB signaling pathway. Because it is unknown if Nur77's anti-inflammatory role modulates COPD, we assessed if and how Nur77 expression and activity are altered in CS-induced airway inflammation. In lung tissues and bronchial epithelial cells from COPD patients, we found Nur77 was downregulated. In a murine model of CS-induced airway inflammation, CS promoted lung inflammation and also reduced Nur77 activity in wild type (WT) mice, whereas lungs of Nur77-deficient mice showed exaggerated CS-induced inflammatory responses. Our findings in in vitro studies of human airway epithelial cells complemented those in vivo data in mice, together showing that CS induced threonine-phosphorylation of Nur77, which is known to interfere with its anti-inflammatory functions. In summary, our findings point to Nur77 as an important regulator of CS-induced inflammatory responses and support the potential benefits of Nur77 activation for COPD treatment.

Glucocorticoid Receptor α Mediates Roflumilast's Ability to Restore Dexamethasone Sensitivity in COPD.

Background: Glucocorticoids are commonly prescribed to treat inflammation of the respiratory system; however, they are mostly ineffective for controlling chronic obstructive pulmonary disease (COPD)-associated inflammation. This study aimed to elucidate the molecular mechanisms responsible for such glucocorticoid inefficacy in COPD, which may be instrumental to providing better patient outcomes. Roflumilast is a selective phosphodiesterase-4 (PDE4) inhibitor with anti-inflammatory properties in severe COPD patients who have a history of exacerbations. Roflumilast has a suggested ability to mitigate glucocorticoid resistance, but the mechanism is unknown. Methods: To understand the mechanism that mediates roflumilast-induced restoration of glucocorticoid sensitivity in COPD, we tested the role of glucocorticoid receptor α (GRα). Roflumilast's effects on GRα expression and transcriptional activity were assessed in bronchial epithelial cells from COPD patients. Results: We found that both GRα expression and activity are downregulated in bronchial epithelial cells from COPD patients and that roflumilast stimulates both GRα mRNA synthesis and GRα's transcriptional activity in COPD bronchial epithelial cells. We also demonstrate that roflumilast enhances dexamethasone's ability to suppress pro-inflammatory mediator production, in a GRα-dependent manner. Discussion: Our findings highlight the significance of roflumilast-induced GRα upregulation for COPD therapeutic strategies by revealing that roflumilast restores glucocorticoid sensitivity by sustaining GRα expression.

A 34-Year-Old Man With Bilateral Paraspinal Masses and Shortness of Breath.

CASE PRESENTATION: A 34-year-old man with history of ß-thalassemia major and splenectomy presented with a 1-month history of progressively worsening dyspnea, orthopnea, localized chest discomfort, and lower extremity edema. He denied fevers, chills, nasal congestion, and night sweats. He denied tobacco, alcohol, and illicit substance abuse. Family history was remarkable for lung cancer in his mother.

Circulating angiotensin peptides levels in Acute Respiratory Distress Syndrome correlate with clinical outcomes: A pilot study.

RATIONALE: We propose renin angiotensin system (RAS) peptides are critical in wound reparative processes such as in acute respiratory distress syndrome (ARDS). Their role in predicting clinical outcomes in ARDS has been unexplored; thus, we used a targeted metabolomics approach to investigate them as potential predictors of outcomes. METHODS: Thirty-nine ARDS patients were enrolled within 24 hours of ARDS diagnosis. Plasma RAS peptide levels were quantified at study entry and 24, 48 and 72 hours using a liquid chromatography-mass spectrometry based metabolomics assay. RAS peptide concentrations were compared between survivors and non-survivors, and were correlated with clinical and pulmonary measures. MEASUREMENTS AND MAIN RESULTS: Angiotensin I (Ang-I or A(1-10)) levels were significantly higher in non-survivors at study entry and 72 hours. ARDS survival was associated with lower A(1-10) concentration (OR 0.36, 95% CI 0.18-0.72, p = 0.004) but higher A(1-9) concentration (OR 2.24, 95% CI 1.15-4.39, p = 0.018), a biologically active metabolite of A(1-10) and an agonist of angiotensin II receptor type 2. Survivors had significantly higher median A(1-9)/A(1-10) and A(1-7)/A(1-10) ratios than the non-survivors (p = 0.001). Increased A(1-9)/A(1-10) ratio suggests that angiotensin converting enzyme II (ACE2) activity is higher in patients who survived their ARDS insult while an increase in A(1-7)/A(1-10) ratio suggests that ACE activity is also higher in survivors. CONCLUSION: A(1-10) accumulation and reduced A(1-9) concentration in the non-survivor group suggest that ACE2 activities may be reduced in patients succumbing to ARDS. Plasma levels of both A(1-10) and A(1-9) and their ratio may serve as useful biomarkers for prognosis in ARDS patients.

Key Functions and Therapeutic Prospects of Nur77 in Inflammation Related Lung Diseases

The transcription factor Nur77 belongs to the NR4A subfamily of nuclear hormone receptors. It features an atypical ligand-binding site that precludes canonical ligand binding, leading to the designation orphan nuclear receptor. However, recent studies show that small molecules can interact with the receptor and modulate its activity by inducing a conformational change in the Nur77 ligand-binding site. Nur77 expression and activation are rapidly induced by various physiological and pathologic stimuli. Once expressed, Nur77 initiates transcriptional activity and modulates expression of its target genes. Both in vitro and in vivo evidence shows that Nur77 dampens the immune response to proinflammatory stimuli, such as tumor necrosis factor-α, Toll-like receptor ligands, and oxidized lipids, primarily by suppressing NF-κB signaling. Although studies focusing on Nur77's role in lung pathophysiology are currently incomplete, available data support its involvement in the pathogenesis of lung diseases, including asthma, acute lung injury, and pulmonary fibrosis, and thus suggest a therapeutic potential for Nur77 activation in these diseases. This review addresses the mechanisms that control Nur77 as well as its known roles in inflammation-related lung diseases. Evidence regarding the therapeutic potential of Nur77-targeting molecules will also be presented. Although current knowledge is limited, additional research followed by clinical studies may firmly identify Nur77 as a pharmacologic target for inflammation-related lung diseases.

An unusual case of chylothorax.

Pleural effusions occur in up to 70% of cases of malignant pleural mesothelioma (MPM). However, MPM rarely presents as a chylous effusion making it a diagnostic challenge. There are only six reported cases to date. Most cases of chylothoraces due to malignancy are due to lymphoma or bronchogenic carcinoma. We report an interesting case of MPM in a 75-year-old man who presented with recurrent chylothorax. He reported a four-month history of dyspnea and chest discomfort. Chest x-ray revealed a pleural effusion. Pleural fluid analysis was consistent with a chylothorax. Pleural fluid cytology was negative for malignancy. Computed tomography of the chest showed pleural calcifications, mediastinal adenopathy and left lung infiltrate. A fine needle aspirate of the lymph node and transbronchial biopsy specimen (TBBX) of the left lung infiltrate showed extensive reactive appearing mesothelial cells but none that appeared malignant. A video assisted thoracoscopic surgery was suggested but the patient declined. He returned 3 months later with recurrent pleural effusion and worsening airspace disease. Thoracentesis revealed a chylothorax again. Repeat analysis of TBBX and lymph node specimens showed extensive reactive appearing mesothelial cells. Due to concern for MPM, ancillary testing was obtained - loss of BRCA1 associated protein (BAP-1) and CDKN2A/p16 gene deletion. BAP1 staining was lost in the mesothelial cells supporting MPM. This case highlights a rare cause of MPM presenting as a chylous effusion. In a patient with an unknown etiology of chylothorax, MPM must remain in the differential.

Identification and Molecular Characterization of Peroxisome Proliferator-Activated Receptor δ as a Novel Target for Covalent Modification by 15-Deoxy-Δ12,14-prostaglandin J2.

PPARδ belongs to the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors. Upon activation by an agonist, PPARδ controls a variety of physiological processes via regulation of its target genes. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a cyclopentenone prostaglandin that features an electrophilic, α,ß-unsaturated ketone (an enone) in the cyclopentenone ring. Many of 15d-PGJ2's biological effects result from covalent interaction between C9 and the thiol group of a catalytic cysteine (Cys) in target proteins. In this study, we investigated whether 15d-PGJ2 activates PPARδ by forming a covalent adduct. Our data show that 15d-PGJ2 activates PPARδ's transcriptional activity through formation of a covalent adduct between its endocyclic enone at C9 and Cys249 in the receptor's ligand-binding domain. As expected, no adduct formation was seen following a Cys-to-Ser mutation at residue 249 (C249S) of PPARδ or with a PGD2/PGJ2 analogue that lacks the electrophilic C9. Furthermore, the PPARδ C249S mutation weakened induction of the receptor's DNA binding activity by 15d-PGJ2, which highlights the biological significance of our findings. Calculated chemical properties as well as data from molecular orbital calculations, reactive molecular dynamics simulations, and intrinsic reaction coordinate modeling also supported the selectivity of 15d-PGJ2's C9 toward PPARδ's Cys thiol. In summary, our results provide the molecular, chemical, and structural basis of 15d-PGJ2-mediated PPARδ activation, designating 15d-PGJ2 as the first covalent PPARδ ligand to be identified.

Role of GPx3 in PPARγ-induced protection against COPD-associated oxidative stress.

Cigarette smoke, a source of numerous oxidants, produces oxidative stress and exaggerated inflammatory responses that lead to irreversible lung tissue damage. It is the single, most significant risk factor for chronic obstructive pulmonary disease (COPD). Although an intrinsic defense system that includes both enzymatic and non-enzymatic modulators exists to protect lung tissues against oxidative stress, impairment of these protective mechanisms has been demonstrated in smokers and COPD patients. The antioxidant enzyme GSH peroxidase (GPx) is an important part of this intrinsic defense system. Although cigarette smoke has been shown to downregulate its expression and activity, the underlying mechanism is not known. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear hormone receptor with antioxidant effects. PPARγ activation has demonstrated protective effects against cigarette smoke-induced oxidative stress and inflammation. Molecular mechanisms for PPARγ's antioxidant function likewise remain to be elucidated. This study explored the link between PPARγ and GPx3 and found a positive association in cigarette smoke extract (CSE)-exposed human bronchial epithelial cells. Moreover, we provide evidence that identifies GPx3 as a PPARγ transcriptional target. Attenuation of antioxidant effects in the absence of GPx3 highlights the antioxidant's prominent role in mediating PPARγ's function. We also demonstrate that ligand-mediated PPARγ activation blocks CSE-induced reactive oxygen species and hydrogen peroxide production via upregulation of GPx3. In summary, our findings describing the molecular mechanisms involving GPx3 and PPARγ in CSE-induced oxidative stress and inflammation may provide valuable information for the development of more effective therapeutics for COPD.

Airway Epithelial Cell Peroxisome Proliferator-Activated Receptor γ Regulates Inflammation and Mucin Expression in Allergic Airway Disease.

Airway epithelial cells (AECs) orchestrate inflammatory responses to airborne irritants that enter the respiratory system. A viscous mucus layer produced by goblet cells in the airway epithelium also contributes to a physiological defense mechanism through the physical and chemical barriers it provides. Dysregulation or impairment in these functions has been implicated as a cause of the chronic inflammation and tissue remodeling that constitute major pathological features of asthma. In particular, mucus hypersecretion leading to airway obstruction and impaired pulmonary function is associated with morbidity and mortality in asthma patients. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor involved in a variety of cellular processes. Accumulating evidence indicates that PPARγ agonists antagonize exaggerated inflammatory responses, yet PPARγ's precise role in airway remodeling/mucus hypersecretion has yet to be defined. In this study, we created an AEC-specific PPARγ (AEC-PPARγ) deletion to investigate PPARγ's functions in a murine model of allergic airway disease. AEC-PPARγ deficiency exaggerated airway hyperresponsiveness, inflammation, cytokine expression, and tissue remodeling. We also found that PPARγ directly bound to a PPAR response element found in MUC5AC and repressed gene expression. Likewise, PPARγ regulated mucin and inflammatory factors in primary human bronchial epithelial cells. In light of the current standard therapies' limited and inadequate direct effect on airway mucus hypersecretion, our study showing AEC-PPARγ's role as a transcriptional repressor of MUC5AC highlights this receptor's potential as a pharmacological target for asthma.

Emerging pharmaceutical therapies for COPD.

COPD, for which cigarette smoking is the major risk factor, remains a worldwide burden. Current therapies provide only limited short-term benefit and fail to halt progression. A variety of potential therapeutic targets are currently being investigated, including COPD-related proinflammatory mediators and signaling pathways. Other investigational compounds target specific aspects or complications of COPD such as mucus hypersecretion and pulmonary hypertension. Although many candidate therapies have shown no significant effects, other emerging therapies have improved lung function, pulmonary hypertension, glucocorticoid sensitivity, and/or the frequency of exacerbations. Among these are compounds that inhibit the CXCR2 receptor, mitogen-activated protein kinase/Src kinase, myristoylated alanine-rich C kinase substrate, selectins, and the endothelin receptor. Activation of certain transcription factors may also be relevant, as a large retrospective cohort study of COPD patients with diabetes found that the peroxisome proliferator-activated receptor γ (PPARγ) agonists rosiglitazone and pioglitazone were associated with reduced COPD exacerbation rate. Notably, several therapies have shown efficacy only in identifiable subgroups of COPD patients, suggesting that subgroup identification may become more important in future treatment strategies. This review summarizes the status of emerging therapeutic pharmaceuticals for COPD and highlights those that appear most promising.

PPAR Agonists for the Prevention and Treatment of Lung Cancer.

Lung cancer is the most common and most fatal of all malignancies worldwide. Furthermore, with more than half of all lung cancer patients presenting with distant metastases at the time of initial diagnosis, the overall prognosis for the disease is poor. There is thus a desperate need for new prevention and treatment strategies. Recently, a family of nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs), has attracted significant attention for its role in various malignancies including lung cancer. Three PPARs, PPARα, PPARß/δ, and PPARγ, display distinct biological activities and varied influences on lung cancer biology. PPARα activation generally inhibits tumorigenesis through its antiangiogenic and anti-inflammatory effects. Activated PPARγ is also antitumorigenic and antimetastatic, regulating several functions of cancer cells and controlling the tumor microenvironment. Unlike PPARα and PPARγ, whether PPARß/δ activation is anti- or protumorigenic or even inconsequential currently remains an open question that requires additional investigation. This review of current literature emphasizes the multifaceted effects of PPAR agonists in lung cancer and discusses how they may be applied as novel therapeutic strategies for the disease.

PPARγ in Bacterial Infections: A Friend or Foe?

Peroxisome proliferator-activated receptor γ (PPARγ) is now recognized as an important modulator of leukocyte inflammatory responses and function. Its immunoregulatory function has been studied in a variety of contexts, including bacterial infections of the lungs and central nervous system, sepsis, and conditions such as chronic granulomatous disease. Although it is generally believed that PPARγ activation is beneficial for the host during bacterial infections via its anti-inflammatory and antibacterial properties, PPARγ agonists have also been shown to dampen the host immune response and in some cases exacerbate infection by promoting leukocyte apoptosis and interfering with leukocyte migration and infiltration. In this review we discuss the role of PPARγ and its activation during bacterial infections, with focus on the potential of PPARγ agonists and perhaps antagonists as novel therapeutic modalities. We conclude that adjustment in the dosage and timing of PPARγ agonist administration, based on the competence of host antimicrobial defenses and the extent of inflammatory response and tissue injury, is critical for achieving the essential balance between pro- and anti-inflammatory effects on the immune system.