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Although our understanding of the genetics and pathology of congenital lung diseases such as surfactant protein deficiency, cystic fibrosis, and alpha-1 antitrypsin deficiency is extensive, treatment options are lacking. Because the lung is a barrier organ in direct communication with the external environment, targeted delivery of gene corrective technologies to the respiratory system via intratracheal or intranasal routes is an attractive option for therapy. CRISPR/Cas9 gene-editing technology is a promising approach to repairing or inactivating disease-causing mutations. Recent reports have provided proof of concept by using CRISPR/Cas9 to successfully repair or inactivate mutations in animal models of monogenic human diseases. Potential pulmonary applications of CRISPR/Cas9 gene editing include gene correction of monogenic diseases in pre- or postnatal lungs and ex vivo gene editing of patient-specific airway stem cells followed by autologous cell transplant. Strategies to enhance gene-editing efficiency and eliminate off-target effects by targeting pulmonary stem/progenitor cells and the assessment of short-term and long-term effects of gene editing are important considerations as the field advances. If methods continue to advance rapidly, CRISPR/Cas9-mediated gene editing may provide a novel opportunity to correct monogenic diseases of the respiratory system.

Major mutations of SERPINA1, the gene encoding alpha1-antitrypsin (A1AT), are known to cause severe emphysema. Our study aimed to investigate the role of major mutations modulating A1AT levels in several lung pathologies and control groups. Blood samples were collected from healthy non-smokers (N0 = 85), healthy smokers (N0 = 291), healthy ex-smokers (N0 = 127), smokers with chronic obstructive lung disease (COPD, N0 = 187), ex-smokers with COPD (N0 = 64), and patients with asthma (N0 = 194), interstitial lung disease (ILD) (N0 = 93), sarcoidosis (N0 = 30) and cystic fibrosis (N0 = 26). Clinical and respiratory parameters, A1AT levels, the extent of emphysema and comorbidities on low-dose CT scans were evaluated, and patients answered a smoking history and comorbidity questionnaire. A1AT single-nucleotide polymorphisms were determined for the S, Z, M2/M4, 0 and eQTL locations by SNP probes using real-time PCR. A1AT levels showed significant differences between cigarette smoke-induced and other lung diseases. Compared to controls, A1AT levels were found to be lower in sarcoidosis and increasingly higher in smokers and patients with COPD, ILD and CF, respectively. The presence and pattern of emphysema were found to influence A1AT levels: lower values were observed in COPD patients without emphysema, while higher values were observed in patients with central and panlobular emphysema. Antitrypsin levels increased with COPD GOLD stages and asthma GINA stages. Variable A1AT levels were also found in ILD subgroups. The distribution of variants at the S, Z, M2/M4 and 0 polymorphic sites and the eQTL location showed no significant differences between patient groups with impaired lung function, except for Z heterozygotes, which were prevalent in patients with severe asthma. The eQTL TT genotypes had higher A1AT levels and the occurrence of emphysema and/or bronchitis was increased. A1AT levels correlated with several clinical and respiratory parameters in pulmonary patients, while FEV1/FVC inversely correlated with levels of A1AT. Molar antielastase activity was increased in smokers and patients with lung diseases; however, in COPD, antielastase activity decreased. The most reduced antielastase activity could be found in CF. Certain genotypes were characterized by increased cardiovascular comorbidity scores and antitrypsin levels. Our data suggest that in addition to emphysema, A1AT may play an important role in the development of a wide variety of lung diseases and cardiovascular comorbidities. Further research is needed to clarify the role of A1AT and its regulation in lung pathologies.

Virus-induced respiratory tract infections are a major health burden in childhood, and available treatments are supportive rather than disease modifying. Rhinoviruses (RVs), the cause of approximately 80% of common colds, are detected in nearly half of all infants with bronchiolitis and the majority of children with an asthma exacerbation. Bronchiolitis in early life is a strong risk factor for the development of asthma. Here, we found that RV infection induced the expression of miRNA 122 (miR-122) in mouse lungs and in human airway epithelial cells. In vivo inhibition specifically in the lung reduced neutrophilic inflammation and CXCL2 expression, boosted innate IFN responses, and ameliorated airway hyperreactivity in the absence and in the presence of allergic lung inflammation. Inhibition of miR-122 in the lung increased the levels of suppressor of cytokine signaling 1 (SOCS1), which is an in vitro-validated target of miR-122. Importantly, gene silencing of SOCS1 in vivo completely reversed the protective effects of miR-122 inhibition on RV-induced lung disease. Higher miR-122 expression in nasopharyngeal aspirates was associated with a longer time on oxygen therapy and a higher rate of treatment failure in 87 infants hospitalized with moderately severe bronchiolitis. These results suggest that miR-122 promotes RV-induced lung disease via suppression of its target SOCS1 in vivo. Higher miR-122 expression was associated with worse clinical outcomes, highlighting the potential use of anti-miR-122 oligonucleotides, successfully trialed for treatment of hepatitis C, as potential therapeutics for RV-induced bronchiolitis and asthma exacerbations.

The potential effects of combinations of dilute whole diesel exhaust (DE) and ozone (O 3 ), each a common component of ambient airborne pollutant mixtures, on lung function were examined. Healthy young human volunteers were exposed for 2 hr to pollutants while exercising (~50 L/min) intermittently on two consecutive days. Day 1 exposures were either to filtered air, DE (300 μg/m 3 ), O 3 (0.300 ppm), or the combination of both pollutants. On Day 2 all exposures were to O 3 (0.300 ppm), and Day 3 served as a followup observation day. Lung function was assessed by spirometry just prior to, immediately after, and up to 4 hr post-exposure on each exposure day. Functional pulmonary responses to the pollutants were also characterized based on stratification by glutathione S-transferase mu 1 (GSTM1) genotype. On Day 1, exposure to air or DE did not change FEV1 or FVC in the subject population (n = 15). The co-exposure to O 3 and DE decreased FEV1 (17.6%) to a greater extent than O 3 alone (9.9%). To test for synergistic exposure effects, i.e., in a greater than additive fashion, FEV1 changes post individual O 3 and DE exposures were summed together and compared to the combined DE and O 3 exposure; the p value was 0.057. On Day 2, subjects who received DE exposure on Day 1 had a larger FEV1 decrement (14.7%) immediately after the O 3 exposure than the individuals' matched response following a Day 1 air exposure (10.9%). GSTM1 genotype did not affect the magnitude of lung function changes in a significant fashion. These data suggest that altered respiratory responses to the combination of O 3 and DE exposure can be observed showing a greater than additive manner. In addition, O 3 -induced lung function decrements are greater with a prior exposure to DE compared to a prior exposure to filtered air. Based on the joint occurrence of these pollutants in the ambient environment, the potential exists for interactions in more than an additive fashion affecting lung physiological processes.

PD-1/PD-L1 might have a causal role in operating lung cancer risk. However, such an association has not been investigated in the general population. We assessed whether PD-L1 has an independent effect on lung cancer risk using two-sample Mendelian randomization (MR) based on a proteomic genome-wide association study (3301 health participants) of European ancestry and the International Lung cancer Consortium (11,348 cases and 15,861 controls). Negative control analyses using chronic obstructive pulmonary disease (COPD)/asthma/interstitial lung disease (ILD)-related infection (~ 22,730 cases and ~ 112,908 controls) were also conducted to enhance the credibility of the selected instruments and MR-based estimates. This study found that genetically predicted PD-1/PD-L1 were not significantly associated with lung cancer after adjustment for multiplicity. However, suggestive evidence was observed for the total effect of higher PD-1 with decreased lung cancer risk and the direct effect (i.e., not mediated by PD-1 and smoking) of lower PD-L1 with decreased lung cancer risk. No association between genetically predicted PD-L1 and COPD/asthma/ILD related infection was noted. Taken together, our findings suggest that interventions decreasing PD-L1 might have a role in lowering lung cancer risk.

Pulmonary surfactants consist of phospholipids and the hydrophobic proteins surfactant protein B and surfactant protein C. These surfactants keep the alveoli in the lung open to the atmosphere. Mutations in the genes encoding these proteins cause a variety of pulmonary syndromes. The pulmonary diseases associated with some of these mutations exemplify the consequences of the accumulation of misfolded proteins in tissue. The hydrophobic surfactant proteins B and C are essential for lung function and pulmonary homeostasis after birth. These proteins enhance the spreading, adsorption, and stability of surfactant lipids required for the reduction of surface tension in the alveolus. Surfactant proteins B and C also participate in the regulation of intracellular and extracellular processes critical for the maintenance of respiratory structure and function. Mutations in the genes encoding surfactant protein B and surfactant protein C ( SFTPB and SFTPC, respectively) are associated with acute respiratory failure and interstitial lung diseases. In this article, we review the current knowledge regarding the structure . . .

Definition of the disease Ataxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome. Epidemiology The world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births. Clinical description A-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages. Neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities including immunoglobulin and antibody deficiencies and lymphopenia. People with A-T have an increased predisposition for cancers, particularly of lymphoid origin. Pulmonary disease and problems with feeding, swallowing and nutrition are common, and there also may be dermatological and endocrine manifestations. Etiology A-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress. Diagnosis The diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels). Because certain neurological features may arise later, a diagnosis of A-T should be carefully considered for any ataxic child with an otherwise elusive diagnosis. A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene. Differential diagnosis There are several other neurologic and rare disorders that physicians must consider when diagnosing A-T and that can be confused with A-T. Differentiation of these various disorders is often possible with clinical features and selected laboratory tests, including gene sequencing. Antenatal diagnosis Antenatal diagnosis can be performed if the pathological ATM mutations in that family have been identified in an affected child. In the absence of identifying mutations, antenatal diagnosis can be made by haplotype analysis if an unambiguous diagnosis of the affected child has been made through clinical and laboratory findings and/or ATM protein analysis. Genetic counseling Genetic counseling can help family members of a patient with A-T understand when genetic testing for A-T is feasible, and how the test results should be interpreted. Management and prognosis Treatment of the neurologic problems associated with A-T is symptomatic and supportive, as there are no treatments known to slow or stop the neurodegeneration. However, other manifestations of A-T, e.g. immunodeficiency, pulmonary disease, failure to thrive and diabetes can be treated effectively.

BackgroundPleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants.MethodsIndividuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis.ResultsIn the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB.ConclusionLung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.

Lung lipid metabolism participates both in infant and adult pulmonary disease. The lung is composed by multiple cell types with specialized functions and coordinately acting to meet specific physiologic requirements. The alveoli are the niche of the most active lipid metabolic cell in the lung, the type 2 cell (T2C). T2C synthesize surfactant lipids that are an absolute requirement for respiration, including dipalmitoylphosphatidylcholine. After its synthesis and secretion into the alveoli, surfactant is recycled by the T2C or degraded by the alveolar macrophages (AM). Surfactant biosynthesis and recycling is tightly regulated, and dysregulation of this pathway occurs in many pulmonary disease processes. Alveolar lipids can participate in the development of pulmonary disease from their extracellular location in the lumen of the alveoli, and from their intracellular location in T2C or AM. External insults like smoke and pollution can disturb surfactant homeostasis and result in either surfactant insufficiency or accumulation. But disruption of surfactant homeostasis is also observed in many chronic adult diseases, including chronic obstructive pulmonary disease (COPD), and others. Sustained damage to the T2C is one of the postulated causes of idiopathic pulmonary fibrosis (IPF), and surfactant homeostasis is disrupted during fibrotic conditions. Similarly, surfactant homeostasis is impacted during acute respiratory distress syndrome (ARDS) and infections. Bioactive lipids like eicosanoids and sphingolipids also participate in chronic lung disease and in respiratory infections. We review the most recent knowledge on alveolar lipids and their essential metabolic and signaling functions during homeostasis and during some of the most commonly observed pulmonary diseases.

Stephanie London and colleagues from the CHARGE Consortium report genome-wide association studies for pulmonary function. Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV 1 ) and its ratio to forced vital capacity (FEV 1 /FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV 1 /FVC ( HHIP , GPR126 , ADAM19 , AGER - PPT2 , FAM13A , PTCH1 , PID1 and HTR4 ) and one locus associated with FEV 1 ( INTS12-GSTCD-NPNT ) at or near genome-wide significance ( P < 5 × 10 −8 ) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.