The Evolution of Triamcinolone Acetonide Therapeutic Use in Retinal Diseases: From Off-Label Intravitreal Injection to Advanced Nano-Drug Delivery Systems.

Ophthalmic drug delivery to the posterior segment of the eye has been challenging due to the complex ocular anatomy. Intravitreal injection of drugs was introduced to deliver therapeutic doses in the posterior segment. Different posterior segment diseases including age-related macular degeneration, diabetic macular edema, retinal vein occlusions, uveitis, and cystoid macular edema, among others, have been historically treated with intravitreal corticosteroids injections, and more recently with intravitreal corticosteroids drug implants. Triamcinolone acetonide (TA) is the most frequently used intraocular synthetic corticosteroid. Using nanoparticle-based TA delivery systems has been proposed as an alternative to intravitreal injections in the treatment of posterior segment diseases. From these novel delivery systems, topical liposomes have been the most promising strategy. This review is oriented to exhibit triamcinolone acetonide drug evolution and its results in treating posterior segment diseases using diverse delivery platforms.

The HLA-DRB1*07 Allele Is Associated with Interstitial Lung Abnormalities (ILA) and Subpleural Location in a Mexican Mestizo Population.

Interstitial lung abnormalities (ILA) are defined as the presence of different patterns of increased lung density, including ground glass attenuation and reticular opacities on chest high-resolution computed tomography (HRCT). In this study, we included 90 subjects with ILA and 189 healthy controls (HC) from our Aging Lung Program. We found that subjects with ILA are older, have a significant smoking history, and have worse pulmonary function than HC (p < 0.05). When we evaluated the allele frequencies of the human leukocyte antigen (HLA) system, we found that HLA-DRB1*07 was associated with a higher risk for ILA (p < 0.05, OR = 1.95, 95% CI = 1.06-3.57). When we compared subjects with subpleural ILA vs. HC, the association with HLA-DRB1*07 became stronger than the whole ILA group (p < 0.05, OR = 2.29, 95% CI = 1.24-4.25). Furthermore, subjects with subpleural ILA and central ILA display differences in allele frequencies with HLA-DRB1*14 (3.33% vs. 13.33%, p < 0.05) and *15 (3.33% vs. 20%, p < 0.05). Our findings indicate that the HLA-DRB1*07 allele contributes to the risk of ILA, especially those of subpleural locations.

Differential Genomic Profile in TERT, DSP, and FAM13A Between COPD Patients With Emphysema, IPF, and CPFE Syndrome.

Background: Genetic association studies have identified single nucleotide polymorphisms (SNPs) associated with lasting lung diseases such as Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF), as well as the simultaneous presentation, known as Combined Pulmonary Fibrosis and Emphysema (CPFE) Syndrome. It is unknown if these diseases share genetic variants previously described in an independent way. This study aims to identify common or differential variants between COPD, IPF, and CPFE. Materials and methods: The association analysis was carried out through a case-control design in a Mexican mestizo population (n = 828); three patients' groups were included: COPD smokers (COPD-S, n = 178), IPF patients (n = 93), and CPFE patients (n = 16). Also, two comparison groups were analyzed: smokers without COPD (SWOC, n = 367) and healthy subjects belonging to the Mexican Pulmonary Aging Cohort (PAC, n = 174). Five SNPs in four genes previously associated to interstitial and obstructive diseases were selected: rs2609255 (FAM13A), rs2736100 (TERT), rs2076295 (DSP) rs5743890, and rs111521887 (TOLLIP). Genotyping was performed by qPCR using predesigned Taqman probes. Results: In comparing IPF vs. PAC, significant differences were found in the frequency of the rs260955 G allele associated with the IPF risk (OR = 1.68, p = 0.01). Also, the genotypes, GG of rs260955 (OR = 2.86, p = 0.01) and TT of rs2076295 (OR = 1.79, p = 0.03) were associated with an increased risk of IPF; after adjusting by covariables, only the rs260955 G allele remain significant (p = 0.01). For the CPFE vs. PAC comparison, an increased CPFE risk was identified since there is a difference in the rs2736100 C allele (OR = 4.02, p < 0.01; adjusted p < 0.01). For COPD-S, the rs2609255 TG genotype was associated with increased COPD risk after adjusting by covariables. Conclusion: The rs2736100 C allele is associated with decreased IPF risk and confers an increased risk for CPFE. Also, the rs2076295 TT genotype is associated with increased IPF risk, while the GG genotype is associated with CFPE susceptibility. The rs2609255 G allele and GG genotype are associated with IPF susceptibility, while the TG genotype is present in patients with emphysema.

Single Nucleotide Polymorphism in the IL17A Gene Is Associated with Interstitial Lung Disease Positive to Anti-Jo1 Antisynthetase Autoantibodies.

Antisynthetase syndrome (ASSD) is a rare multisystemic connective tissue disease affecting the skin, joints, muscles, and lungs, characterized by anti-aminoacyl transfer-RNA-synthetases (anti-tRNA) autoantibodies production, being anti-Jo1 the most frequent. We included one-hundred twenty-one ASSD patients and 340 healthy subjects (HS), and also, we divided the case group into anti-Jo1 and non-anti-Jo1. Two single nucleotide polymorphisms (SNPs) in the IL17A gene were evaluated. Anti-Jo1 was the most common anti-tRNA antibody in our cohort, and the most frequent tomographic pattern was non-specific interstitial pneumonia (NSIP). Anti-Jo1 ASSD patients had higher levels of creatine phosphokinase than the non-anti-Jo1 group. Significant differences in genotype frequencies with rs8193036/CC between anti-Jo1 vs. non-anti-Jo1 ASSD patients (p < 0.001), maintaining the association after Bonferroni correction (p = 0.002). Additionally, in the anti-Jo1 group vs. HS comparison, we found a statistically significant difference with the same SNP (p = 0.018, OR = 2.91, 95% CI = 1.15-7.35), maintaining the association after Bonferroni correction (p = 0.036). The rs8193036/CC genotype in IL17A is associated with ASSD patients with anti-Jo1. Also, anti-Jo1 and non-anti-Jo1 patients display differences in genotype frequencies.

Role of the Host Genetic Susceptibility to 2009 Pandemic Influenza A H1N1.

Influenza A virus (IAV) is the most common infectious agent in humans, and infects approximately 10-20% of the world's population, resulting in 3-5 million hospitalizations per year. A scientific literature search was performed using the PubMed database and the Medical Subject Headings (MeSH) "Influenza A H1N1" and "Genetic susceptibility". Due to the amount of information and evidence about genetic susceptibility generated from the studies carried out in the last influenza A H1N1 pandemic, studies published between January 2009 to May 2020 were considered; 119 papers were found. Several pathways are involved in the host defense against IAV infection (innate immune response, pro-inflammatory cytokines, chemokines, complement activation, and HLA molecules participating in viral antigen presentation). On the other hand, single nucleotide polymorphisms (SNPs) are a type of variation involving the change of a single base pair that can mean that encoded proteins do not carry out their functions properly, allowing higher viral replication and abnormal host response to infection, such as a cytokine storm. Some of the most studied SNPs associated with IAV infection genetic susceptibility are located in the FCGR2A, C1QBP, CD55, and RPAIN genes, affecting host immune responses through abnormal complement activation. Also, SNPs in IFITM3 (which participates in endosomes and lysosomes fusion) represent some of the most critical polymorphisms associated with IAV infection, suggesting an ineffective virus clearance. Regarding inflammatory response genes, single nucleotide variants in IL1B, TNF, LTA IL17A, IL8, IL6, IRAK2, PIK3CG, and HLA complex are associated with altered phenotype in pro-inflammatory molecules, participating in IAV infection and the severest form of the disease.

Multidrug-resistant tuberculosis patients expressing the HLA-DRB1*04 allele, and after treatment they show a low frequency of HLA-II+ monocytes and a chronic systemic inflammation.

Tuberculosis (TB) is an infectious disease caused by the bacilli Mycobacterium tuberculosis (Mtb); most TB patients are infected with strains of Mtb sensitive to first-line drugs (DS-TB), but in the last years has been increased the presence of multidrug-resistant TB (MDR-TB). HLA class II (HLA-II) is expressed on antigen-presenting cells and reported the association between HLA alleles and DS-TB in the Mexican population. We studied HLA-II + CD16+ monocytes frequency and its relation with a pro-inflammatory profile during DS-TB versus MDR-TB, both before as in response to anti-tuberculosis treatment. Peripheral blood was obtained from MDR-TB at the basal time (before use of therapy), 1, 3, and 8 months of anti-TB therapy (moTBt), whereas DS-TB at basal and 1 and 6 moTBt. Our data showed that contrary to DS-TB, MDR-TB patients have decreased the frequency of HLA-II + monocytes and increased the pro-inflammatory CD16+ monocytes from basal time until 8 moTBt. Similarly, only MDR-TB patients still have a high plasma level of IFN-γ and TNF pro-inflammatory cytokines for a long-time, and although MDR-TB patients showed an increased level of the soluble form of TIM3 and GAL9 at baseline, those molecules decreased as a response to anti-TB therapy. Finally, our data indicated that MDR-TB displayed DRB1*04 allele, suggesting an association between the infection by multidrug-resistance Mtb strain and the presence of the DRB1*04 allele in Mexican TB patients.

Genetic Susceptibility to Antisynthetase Syndrome Associated With Single-Nucleotide Variants in the IL1B Gene That Lead Variation in IL-1ß Serum Levels.

The antisynthetase syndrome (ASSD) is an autoimmune disorder characterized by myositis, arthritis, mechanic's hands, fever, Raynaud phenomenon, and interstitial lung disease (ILD). We aimed to evaluate single-nucleotide polymorphisms in the interleukin 1B (IL1B) gene and their association between ILD with antisynthetase autoantibodies, as well as IL-1ß serum levels. The most frequent antisynthetase autoantibody was anti-Jo1. The most frequent tomographic pattern was non-specific interstitial pneumonia, whereas in the anti-Jo1 subjects, it was organized pneumonia. Anti-Jo1 patients tend to have more significant arthritis, and Raynaud phenomenon have higher levels of creatinine phosphokinase. In the IL1B gene, the GG genotype and G allele of rs1143634 [odds ratio (OR) = 2.21 and OR = 2.60, respectively, p < 0.05] are associated with an increased risk, as well as with the dominant and recessive models (p < 0.05). This finding is maintained after logistic regression analysis adjusting for potential confounding variables (p < 0.05). Subjects with the rs16944/AG heterozygous genotype had higher serum levels of IL-1ß compared to homozygous (p < 0.05). In conclusion, rs1143634 is associated with a higher risk of ASSD. Also, the GA genotype is associated with higher levels of IL-1ß in ASSD patients.

Polymorphisms in Processing and Antigen Presentation-Related Genes and Their Association with Host Susceptibility to Influenza A/H1N1 2009 Pandemic in a Mexican Mestizo Population.

(1) Background: The influenza A/H1N1 pdm09 virus rapidly spread throughout the world. Despite the inflammatory and virus-degradation pathways described in the pathogenesis of influenza A virus (IAV) infection, little is known about the role of the single nucleotide polymorphisms (SNPs) in the genes involved in the processing and antigenic presentation-related mechanisms. (2) Methods: In this case-control study, we evaluated 17 SNPs in five genes (TAP1, TAP2, TAPBP, PSMB8, and PSMB9). One hundred and twenty-eight patients with influenza A/H1N1 infection (INF-P) and 111 healthy contacts (HC) were included; all of them are Mexican mestizo. (3) Results: In allele and genotype comparison, the rs241433/C allele (TAP2), as well as AG haplotype (rs3763365 and rs4148882), are associated with reduced risk for influenza A/H1N1 infection (p < 0.05). On the other hand, the rs2071888G allele (TAPBP) and GG haplotype (rs3763365 and rs9276810) are associated with a higher risk for influenza A/H1N1 infection. In addition, after adjustment for covariates, the association to a reduced risk for influenza A/H1N1 infection remains with rs241433/C allele (p < 0.0001, OR = 0.24, 95% CI = 0.13-0.43), and the association with TAPBP is also maintained with the G allele (p = 0.0095, OR = 1.89, 95% CI = 1.17-3.06) and GG genotype models (p < 0.05, OR = 2.18, 95% CI = 1.27-3.74). (4) Conclusion: The rs241433/C allele and AC genotype (TAP2) and the AG haplotype are associated with a reduced risk for influenza A/H1N1 infection. In addition, the rs2071888/G allele and GG genotype (TAPBP) and the GG haplotype are associated with a higher risk for developing influenza A/H1N1 infection in a Mexican mestizo population.

Haplotype in SERPINA1 (AAT) Is Associated with Reduced Risk for COPD in a Mexican Mestizo Population.

Protease inhibitor S (PiS) and protease inhibitor Z (PiZ) variants in the SERPINA1 gene are the main genetics factors associated with COPD; however, investigations about other polymorphisms are scanty. The aim of this study was to evaluate two missense single nucleotide polymorphisms (SNPs) (rs709932 and rs1303) in the SERPINA1 gene in Mexican mestizo patients with chronic obstructive pulmonary disease (COPD) related to tobacco smoking and biomass-burning exposure. 1700 subjects were genotyped and divided into four groups: COPD related to tobacco smoking (COPD-S, n = 297), COPD related to biomass-burning exposure (COPD-BB, n = 178), smokers without COPD (SWOC, n = 674), and biomass-burning exposed subjects (BBES, n = 551) by real-time PCR. Moreover, the patients' groups were divided according to their exacerbations' frequency. We carried out a haplotype analysis. We did not find differences in allele and genotype frequencies between groups in unadjusted and adjusted analyses, neither with these SNPs and lung function decline. Exacerbations' frequency is not associated with these SNPs. However, we found a haplotype with major alleles (CT) associated with reduced risk for COPD (p < 0.05). Our analysis reveals that SNPs different from PiS and PiZ (rs709932 and rs1303) in the SERPINA1 gene are not associated with COPD and lung function decline in a Mexican mestizo population. However, a haplotype shaped by both major alleles (CT haplotype) is associated with reduced risk for COPD.

Type 2 macrophages and Th2 CD4+ cells in interstitial lung diseases (ILDs): an overview.

Interstitial lung diseases (ILDs) are a heterogeneous group characterized mainly by damage to pulmonary parenchyma, through histopathological processes such as granulomatous pneumopathy, inflammation and fibrosis. Factors that generate susceptibility to ILDs include age, exposure to occupational and environmental compounds, genetic, family history, radiation and chemotherapy/immunomodulatory and cigarette smoke. IFN-γ, IL-1ß, and LPS are necessary to induce a classical activation of macrophages, whereas cytokines as IL-4 and IL-13 can induce an alternative activation in macrophages, through the JAK-STAT mediated signal transduction. M2 macrophages are identified based on the gene transcription or protein expression of a set of M2 markers. These markers include transmembrane glycoproteins, scavenger receptors, enzymes, growth factors, hormones, cytokines, and cytokine receptors with diverse and often yet unexplored functions. Fibrotic lung disorders may have a M2 polarization background. The Th2 pathway with an elevated CCL-18 (marker of M2) concentration in the bronchoalveolar lavage fluid (BALF) is linked to fibrosis in ILDs. Besides the role of M2 in tissue repair and ECM remodeling, activated fibroblasts summon and stimulate macrophages by producing MCP-1, M-CSF and other chemokines, as well as activated macrophages secrete cytokines that attract and stimulate proliferation, survival and migration of fibroblast mediated by platelet-derived growth factor (PDGF). (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 98-108).

Th17 profile in COPD exacerbations.

COPD is characterized by an ongoing inflammatory process of the airways that leads to obstruction or limitation of airflow. It is mainly associated with exposure to cigarette smoke. In addition, it is considered, at present, a serious public health problem, ranking fourth in mortality worldwide. Many cells participate in the pathophysiology of COPD, the most important are neutrophils, macrophages and CD4+ and CD8+ T cells. Neutrophil migration to the inflammation area could be mediated largely by cytokines related to CD4+ Th17 lymphocytes, because it has been shown that IL-17A, IL-17F and IL-22 act as inducers for CXCL8, CXCL1, CXCL5, G-CSF, and GM-CSF secretion by epithelial cells of the airways. The aims of these molecules are differentiation, proliferation and recruitment of neutrophils. Furthermore, it is believed that CD4+ lymphocytes Th17 may be involved in protection against pathogens for which Th1 and Th2 are not prepared to fight. In COPD exacerbations, there is an increased cellularity in the lung region and respiratory tract. Therefore, the increase in the number of neutrophils and macrophages in the airways and the increase in proinflammatory cytokines are directly related to the severity of exacerbations and that is the importance of the functions of Th17 profile in this entity.