RESUMEN
Background: Systemic immune-inflammation index (SII) is a novel comprehensive inflammatory marker. Inflammation is associated with impaired lung function. We aimed to explore the possible relationship between SII and lung function to examine the potential of SII in predicting lung function decline. Methods: A cross-sectional survey was conducted using the data of the NHANES from 2007 to 2012. Multiple linear regression models were used to analyze the linear relationship between SII and pulmonary functions. Sensitivity analyses, subgroup analyses, and interaction tests were used to examine the robustness of this relationship across populations. Fitted smooth curves and threshold effect analysis were used to describe the nonlinear relationships. Results: A total of 10,125 patients were included in this study. After adjusting for all covariates, multiple linear regression model analysis showed that high Log2-SII level was significantly associated with decreased FVC(ß, -23.4061; 95% CI, -42.2805- -4.5317), FEV1(ß, -46.7730; 95% CI, -63.3371- -30.2089), FEV1%(ß, -0.7923; 95% CI, -1.1635- -0.4211), FEV1/FVC(ß, -0.6366; 95% CI, -0.8328- -0.4404) and PEF(ß, -121.4468; 95% CI,-164.1939- -78.6998). The negative correlation between Log2-SII and pulmonary function indexes remained stable in trend test and stratified analysis. Inverted U-shaped relationships between Log2-SII and FVC, FEV1, FEV1%, and PEF were observed, while a negative linear correlation existed between FEV1/FVC and Log2-SII. The cutoff values of the nonlinear relationship between Log2-SII and FVC, FEV1, FEV1%, PEF were 8.3736, 8.0688, 8.3745, and 8.5255, respectively. When SII exceeded the critical value, the lung function decreased significantly. Conclusion: This study found a close correlation between SII and pulmonary function indicators. This study investigated the SII threshold when lung functions began to decline in the overall population. SII may become a promising serological indicator for predicting lung function decline. However, prospective studies were needed further to establish the causal relationship between these two factors.
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Mediadores de Inflamación , Inflamación , Pulmón , Encuestas Nutricionales , Valor Predictivo de las Pruebas , Humanos , Masculino , Estudios Transversales , Femenino , Persona de Mediana Edad , Pulmón/fisiopatología , Pulmón/inmunología , Volumen Espiratorio Forzado , Estados Unidos/epidemiología , Adulto , Capacidad Vital , Inflamación/fisiopatología , Inflamación/inmunología , Inflamación/diagnóstico , Inflamación/sangre , Mediadores de Inflamación/sangre , Anciano , Biomarcadores/sangre , Factores de Riesgo , Modelos LinealesRESUMEN
Alcohol use is an independent risk factor for the development of bacterial pneumonia due, in part, to impaired mucus-facilitated clearance, macrophage phagocytosis, and recruitment of neutrophils. Alcohol consumption is also known to reduce peripheral natural killer (NK) cell numbers and compromise NK cell cytolytic activity, especially NK cells with a mature phenotype. However, the role of innate lymphocytes, such as NK cells during host defense against alcohol-associated bacterial pneumonia is essentially unknown. We have previously shown that indole supplementation mitigates increases in pulmonary bacterial burden and improves pulmonary NK cell recruitment in alcohol-fed mice, which were dependent on aryl hydrocarbon receptor (AhR) signaling. Employing a binge-on-chronic alcohol-feeding model we sought to define the role and interaction of indole and NK cells during pulmonary host defense against alcohol-associated pneumonia. We demonstrate that alcohol dysregulates NK cell effector function and pulmonary recruitment via alterations in two key signaling pathways. We found that alcohol increases transforming growth factor beta (TGF-ß) signaling while suppressing AhR signaling. We further demonstrated that NK cells isolated from alcohol-fed mice have a reduced ability to kill Klebsiella pneumoniae. NK cell migratory capacity to chemokines was also significantly altered by alcohol, as NK cells isolated from alcohol-fed mice exhibited preferential migration in response to CXCR3 chemokines but exhibited reduced migration in response to CCR2, CXCR4, and CX3CR1 chemokines. Together this data suggests that alcohol disrupts NK cell-specific TGF-ß and AhR signaling pathways leading to decreased pulmonary recruitment and cytolytic activity thereby increasing susceptibility to alcohol-associated bacterial pneumonia.
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Células Asesinas Naturales , Ratones Endogámicos C57BL , Neumonía Bacteriana , Receptores de Hidrocarburo de Aril , Transducción de Señal , Animales , Células Asesinas Naturales/inmunología , Neumonía Bacteriana/inmunología , Neumonía Bacteriana/microbiología , Ratones , Receptores de Hidrocarburo de Aril/metabolismo , Pulmón/inmunología , Pulmón/microbiología , Factor de Crecimiento Transformador beta/metabolismo , Etanol , Receptores CCR2/metabolismo , Receptores CCR2/genética , Modelos Animales de Enfermedad , Indoles/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Masculino , Klebsiella pneumoniae , Receptores CXCR3/metabolismoRESUMEN
Exposure to storage mite (SM) and house dust mite (HDM) allergens is a risk factor for sensitization and asthma development; however, the related immune responses and their pathology have not been fully investigated. The HDMs Dermatophagoides farinae and Dermatophagoides pteronyssinus and SM Tyrophagus putrescentiae are potent allergens that induce asthma. Most SM-related studies have focused on the allergic reactions of individuals by measuring their immunoglobulin (Ig)E expression. Considering the limited research on this topic, the present study aims to investigate the differences in the immune responses induced by HDMs and SMs and histologically analyze lung tissues in a mouse asthma model to understand the differential effects of HDM and SM. The results revealed that all mite species induced airway inflammation. Mice challenged with T. putrescentiae had the highest airway resistance and total cell, eosinophil, and neutrophil counts in the bronchoalveolar lavage fluid (BALF). The SM-sensitized groups showed more severe lesions and mucus hypersecretions than the HDM-sensitized groups. Although the degree of HDM and SM exposure was the same, the damage to the respiratory lung tissue was more severe in SM-exposed mice, which resulted in excessive mucin secretion and increased fibrosis. Furthermore, these findings suggest that SM sensitization induces a more significant hypersensitivity response in mucosal immunity than HDM sensitization in asthma models.
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Asma , Pulmón , Pyroglyphidae , Animales , Ratones , Pyroglyphidae/inmunología , Pulmón/inmunología , Pulmón/patología , Asma/inmunología , Asma/patología , Femenino , Neumonía/inmunología , Neumonía/patología , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Acaridae/inmunología , Alérgenos/inmunología , Eosinófilos/inmunología , Eosinófilos/patologíaRESUMEN
Background: Respiratory failure can be a severe complication after polytrauma. Extensive systemic inflammation due to surgical interventions, as well as exacerbated post-traumatic immune responses influence the occurrence and progression of respiratory failure. This study investigated the effect of different surgical treatment modalities as well as combined inhibition of the complement component C5 and the toll-like receptor molecule CD14 (C5/CD14 inhibition) on the pulmonary microRNA (miRNA) signature after polytrauma, using a translational porcine polytrauma model. Methods: After induction of general anesthesia, animals were subjected to polytrauma, consisting of blunt chest trauma, bilateral femur fractures, hemorrhagic shock, and liver laceration. One sham group (n=6) and three treatment groups were defined; Early Total Care (ETC, n=8), Damage Control Orthopedics (DCO, n=8), and ETC + C5/CD14 inhibition (n=4). Animals were medically and operatively stabilized, and treated in an ICU setting for 72 h. Lung tissue was sampled, miRNAs were isolated, transcribed, and pooled for qPCR array analyses, followed by validation in the individual animal population. Lastly, mRNA target prediction was performed followed by functional enrichment analyses. Results: The miRNA arrays identified six significantly deregulated miRNAs in lung tissue. In the DCO group, miR-129, miR-192, miR-194, miR-382, and miR-503 were significantly upregulated compared to the ETC group. The miRNA expression profiles in the ETC + C5/CD14 inhibition group approximated those of the DCO group. Bioinformatic analysis revealed mRNA targets and signaling pathways related to alveolar edema, pulmonary fibrosis, inflammation response, and leukocytes recruitment. Collectively, the DCO group, as well as the ETC + C5/CD14 inhibition group, revealed more anti-inflammatory and regenerative miRNA expression profiles. Conclusion: This study showed that reduced surgical invasiveness and combining ETC with C5/CD14 inhibition can contribute to the reduction of pulmonary complications.
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Complemento C5 , Receptores de Lipopolisacáridos , MicroARNs , Traumatismo Múltiple , Animales , MicroARNs/genética , Receptores de Lipopolisacáridos/metabolismo , Receptores de Lipopolisacáridos/genética , Traumatismo Múltiple/inmunología , Traumatismo Múltiple/genética , Porcinos , Complemento C5/genética , Complemento C5/antagonistas & inhibidores , Complemento C5/metabolismo , Pulmón/metabolismo , Pulmón/inmunología , Pulmón/patología , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/genéticaRESUMEN
Bleomycin (BLM) induces lung injury, leading to inflammation and pulmonary fibrosis. Regulatory T cells (Tregs) maintain self-tolerance and control host immune responses. However, little is known about their involvement in the pathology of pulmonary fibrosis. Here we show that a unique Treg subset expressing trefoil factor family 1 (Tff1) emerges in the BLM-injured lung. These Tff1-expressing Tregs (Tff1-Tregs) were induced by IL-33. Moreover, although Tff1 ablation in Tregs did not change the pathological condition, selective ablation of Tff1-Tregs using an intersectional genetic method promoted pro-inflammatory features of macrophages in the injured lung and exacerbated the fibrosis. Taken together, our study revealed the presence of a unique Treg subset expressing Tff1 in BLM-injured lungs and their critical role in the injured lung to ameliorate fibrosis.
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Bleomicina , Pulmón , Fibrosis Pulmonar , Linfocitos T Reguladores , Factor Trefoil-1 , Bleomicina/efectos adversos , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Ratones , Pulmón/patología , Pulmón/metabolismo , Pulmón/inmunología , Factor Trefoil-1/genética , Factor Trefoil-1/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Ratones Noqueados , Masculino , Interleucina-33/metabolismo , Interleucina-33/genéticaRESUMEN
Objective: In this study, the impact of inhibiting the PI3K/AKT/NF-κB pathway on lung oxidative damage induced by Echinococcus granulosus cyst fluid was investigated. Methods: Twenty-four mice were randomly assigned to four groups. Three months after inoculation with hydatid cyst segments, mice in group A were treated with intraperitoneal and intratracheal saline injections; mice in group B were administered a caudal vein injection of a PI3K inhibitor, followed by cyst fluid sensitization; mice in group C received an AKT inhibitor via caudal vein, followed by cyst fluid sensitization; and mice in group D were subjected to cyst fluid sensitization without any inhibitor treatment. Cellular changes in lung tissues across all groups were evaluated, including pathological section analysis. Analysis of pulmonary tissue and serum from these mice included the assessment of PI3K/AKT/NF-κB pathway proteins, inflammatory factors, and related mRNA levels. Results: Mice in groups B and C exhibited a higher proportion of M2-type macrophages and significantly lower levels of PI3K/AKT/NF-κB pathway proteins, inflammatory factors (interleukin-6 [IL-6]/tumor necrosis factor-α [TNF-α]), and oxidative markers in lung tissues compared to mice in group D (P < 0.05). Conclusion: Our results in this study indicate that activation of the PI3K/AKT/NF-κB pathway contributed to an increase in the M1 macrophage phenotype, leading to enhanced secretion of peroxidases and inflammatory factors. This mechanism plays a crucial role in the oxidative and inflammatory lung damage associated with allergic reactions to E. granulosus cyst fluid.
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Echinococcus granulosus , FN-kappa B , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Animales , Echinococcus granulosus/inmunología , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Lesión Pulmonar/inmunología , Lesión Pulmonar/etiología , Lesión Pulmonar/parasitología , Macrófagos/inmunología , Pulmón/inmunología , Pulmón/patología , Pulmón/parasitología , Equinococosis/inmunología , Modelos Animales de Enfermedad , Femenino , Citocinas/metabolismo , Estrés OxidativoRESUMEN
OBJECTIVE: Environmental factors such as noise and music can significantly impact physiological responses, including inflammation. This study explored how environmental factors like noise and music affect lipopolysaccharide (LPS)-induced inflammation, with a focus on systemic and organ-specific responses. MATERIALS AND METHODS: 24 Wistar rats were divided into four groups (n = 6 per group): Control group, LPS group, noise-exposed group, and music-exposed group. All rats, except for the Control group, received 10 mg/kg LPS intraperitoneally. The rats in the noise-exposed group were exposed to 95 dB noise, and the music-exposed group listened to Mozart's K. 448 music (65-75 dB) for 1 h daily over 7 days. An enzyme-linked immunosorbent assay was utilized to detect the levels of inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), in serum and tissues (lung, liver, and kidney). Western blot examined the phosphorylation levels of nuclear factor-κB (NF-κB) p65 in organ tissues. RESULTS: Compared with the Control group, LPS-induced sepsis rats displayed a significant increase in the levels of TNF-α and IL-1ß in serum, lung, liver, and kidney tissues, as well as a remarkable elevation in the p-NF-κB p65 protein expression in lung, liver, and kidney tissues. Noise exposure further amplified these inflammatory markers, while music exposure reduced them in LPS-induced sepsis rats. CONCLUSION: Noise exposure exacerbates inflammation by activating the NF-κB pathway, leading to the up-regulation of inflammatory markers during sepsis. On the contrary, music exposure inhibits NF-κB signaling, indicating a potential therapeutic effect in reducing inflammation.
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Lipopolisacáridos , Música , Ruido , Ratas Wistar , Sepsis , Animales , Lipopolisacáridos/toxicidad , Sepsis/inmunología , Sepsis/complicaciones , Ruido/efectos adversos , Masculino , Interleucina-1beta/sangre , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Inflamación , Hígado/metabolismo , Ratas , Riñón/metabolismo , FN-kappa B/metabolismo , Citocinas/sangre , Citocinas/metabolismoRESUMEN
Circular RNA (circRNA) is a type of single-stranded RNA that forms a covalently closed continuous loop, unlike linear RNA. The expression of circRNAs in mammals is often conserved across species and shows tissue and cell specificity. Some circRNA serve as gene regulators. However, the biological function of most circRNAs is unclear. CircRNA does not have 5' or 3' ends. The unique structure of circRNAs provides them with a much longer half-life and more resistance to RNase R than linear RNAs. Inflammatory lung responses occur in the pathogenesis and recovery of many lung diseases. Macrophages form the first line of host defense/innate immune responses and initiate/mediate lung inflammation. For example, in bacterial pneumonia, upon pro-inflammatory activation, they release early response cytokines/chemokines that recruit neutrophils, macrophages, and lymphocytes to sites of infection and clear pathogens. The functional effects and mechanisms by which circRNAs exert physiological or pathological roles in macrophage activation and lung inflammation remain poorly understood. In this article, we will review the current understanding and progress of circRNA biogenesis, regulation, secretion, and degradation. Furthermore, we will review the current reports on the role of circRNAs in macrophage activation and polarization, as well as in the process of inflammatory lung responses.
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Pulmón , Activación de Macrófagos , ARN Circular , ARN Circular/genética , ARN Circular/metabolismo , Humanos , Activación de Macrófagos/genética , Animales , Pulmón/patología , Pulmón/metabolismo , Pulmón/inmunología , Macrófagos/metabolismo , Macrófagos/inmunología , Neumonía/genética , Neumonía/inmunología , Neumonía/metabolismo , Neumonía/patología , Inflamación/genética , Inflamación/patologíaRESUMEN
Asthma is a chronic lung disease with persistent airway inflammation, bronchial hyper-reactivity, mucus overproduction, and airway remodeling. Antagonizing T2 responses by triggering the immune system with microbial components such as Toll-like receptors (TLRs) has been suggested as a therapeutic concept for allergic asthma. The aim of this study was to evaluate the effect of a TLR2/6 agonist, FSL-1 (Pam2CGDPKHPKSF), administered by intranasal instillation after an allergic airway reaction was established in the ovalbumin (OVA) mouse model and to analyze the role of natural killer (NK) cells in this effect. We showed that FSL-1 decreased established OVA-induced airway hyper-responsiveness and eosinophilic inflammation but did not reduce the T2 or T17 response. FSL-1 increased the recruitment and activation of NK cells in the lung parenchyma and modified the repartition of NK cell subsets in lung compartments. Finally, the transfer or depletion of NK cells did not modify airway hyper-responsiveness and eosinophilia after OVA and/or FSL-1 treatment. Thus, the administration of FSL-1 reduces airway hyper-responsiveness and bronchoalveolar lavage eosinophilia. However, despite modifications of their functions following OVA sensitization, NK cells play no role in OVA-induced asthma and its inhibition by FSL-1. Therefore, the significance of NK cell functions and localization in the airways remains to be unraveled in asthma.
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Asma , Células Asesinas Naturales , Pulmón , Ovalbúmina , Receptor Toll-Like 2 , Receptor Toll-Like 6 , Animales , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Receptor Toll-Like 2/agonistas , Receptor Toll-Like 2/metabolismo , Ratones , Pulmón/patología , Pulmón/inmunología , Pulmón/efectos de los fármacos , Asma/tratamiento farmacológico , Asma/inmunología , Asma/patología , Receptor Toll-Like 6/agonistas , Ratones Endogámicos BALB C , Femenino , Modelos Animales de Enfermedad , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/inmunología , Hiperreactividad Bronquial/tratamiento farmacológico , Hiperreactividad Bronquial/inmunología , Líquido del Lavado Bronquioalveolar , Diglicéridos , OligopéptidosRESUMEN
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a deadly pulmonary disease with impaired immunological response that causes significant tissue damage and organ failure. Postmortem examination of the lung is a useful tool for understanding the immunopathogenesis of this virus. Lung autopsy samples from seven dead SARS-CoV-2 patients were obtained and evaluated using hematoxylin and eosin stain to analyze the histopathological changes in those samples, on the other hand, Immunohistochemical (IHC) staining was used for detection of CD21, CD1a, CR1 (CD35), CD68, Myeloperoxidase (MPO), CD15, CD56, CD3, CD20, CD4, and CD8 cells markers. Histopathological examination revealed diffuse alveolar damage with extensive parenchymal architecture distortion, intravascular fibrin clot, deposition of collagen fibers, vascular congestions and blood vessels containing thrombi, pneumocyte type II with inflammatory cell infiltration. The IHC staining for the innate immune cells such as antigen-presenting cells (APCs) including dendritic cells, Macrophages, and neutrophils showed a strong positive staining, while CD56 Natural killer (NK) cells showed negative staining. On the other hand, the specific immune cells including; CD20 B cells, CD3 T cells, and CD4 helper T cells, showed positive staining while CD8 Cytotoxic T cells showed negative staining. The lung autopsy samples from patients with COVID-19 confirmed the presence of APCs through the positive staining of CD21, CD1a, CD35, CD68, MPO, and CD15 expressed the virus recognition, proinflammatory cytokine production, and adaptive immune cells activation through CD3, CD4, and CD20 positive staining and the role of APCs in the severity of pulmonary infection and pathogenesis of SARS-CoV-2 infection however the absence of the CD56 NK and CD8 cytotoxic T explains the worse infection status for the patients.
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Células Presentadoras de Antígenos , Autopsia , COVID-19 , Pulmón , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/patología , Pulmón/patología , Pulmón/inmunología , Pulmón/virología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , SARS-CoV-2/inmunología , Masculino , Persona de Mediana Edad , Femenino , Anciano , Inmunohistoquímica , Adulto , Antígenos CD/metabolismoRESUMEN
Bacille Calmette-Guérin (BCG) remains the only licensed vaccine against tuberculosis (TB). While BCG protects against TB in children, its protection against pulmonary TB in adults is suboptimal, and the development of a better TB vaccine is a global health priority. Previously, we reported two recombinant BCG strains effective against murine TB with low virulence and lung pathology in immunocompromised mice and guinea pigs. We have recently combined these two recombinant BCG strains into one novel vaccine candidate (BCGΔBCG1419c::ESAT6-PE25SS) and evaluated its immunogenicity, efficacy and safety profile in mice. This new vaccine candidate is non-inferior to BCG in protection against TB, presents reduced pro-inflammatory immune responses and displays an enhanced safety profile.
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Vacuna BCG , Huésped Inmunocomprometido , Vacunas Sintéticas , Animales , Vacuna BCG/inmunología , Vacuna BCG/efectos adversos , Vacuna BCG/genética , Ratones , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/efectos adversos , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Femenino , Tuberculosis/prevención & control , Tuberculosis/inmunología , Mycobacterium bovis/inmunología , Mycobacterium bovis/genética , Mycobacterium bovis/patogenicidad , Modelos Animales de Enfermedad , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidad , Ratones Endogámicos C57BL , Pulmón/microbiología , Pulmón/patología , Pulmón/inmunología , Tuberculosis Pulmonar/prevención & control , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Eficacia de las VacunasRESUMEN
BACKGROUND: Schistosomiasis is a parasitic infection that can cause pulmonary hypertension (PH). Th2 CD4 T cells are necessary for experimental Schistosoma-PH. However, if T cells migrate to the lung to initiate, the localized inflammation that drives vascular remodeling and PH is unknown. METHODS: Mice were sensitized to Schistosoma mansoni eggs intraperitoneally and then challenged using tail vein injection. FTY720 was administered, which blocks lymphocyte egress from lymph nodes. T cells were quantified using flow cytometry, PH severity via heart catheterization, and cytokine concentration through ELISA. RESULTS: FTY720 decreased T cells in the peripheral blood, and increased T cells in the mediastinal lymph nodes. However, FTY720 treatment resulted in no change in PH or type 2 inflammation severity in mice sensitized and challenged with S. mansoni eggs, and the number of memory and effector CD4 T cells in the lung parenchyma was also unchanged. Notably, intraperitoneal Schistosoma egg sensitization alone resulted in a significant increase in intravascular lymphocytes and T cells, including memory T cells, although there was no significant change in parenchymal cell density, IL-4 or IL-13 expression, or PH. CONCLUSION: Blocking T cell migration did not suppress PH following Schistosoma egg challenge. Memory CD4 T cells, located in the lung intravascular space following egg sensitization, appear sufficient to cause type 2 inflammation and PH.
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Hipertensión Pulmonar , Pulmón , Schistosoma mansoni , Animales , Ratones , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/parasitología , Hipertensión Pulmonar/inmunología , Pulmón/parasitología , Pulmón/inmunología , Pulmón/patología , Schistosoma mansoni/inmunología , Clorhidrato de Fingolimod/farmacología , Femenino , Linfocitos T CD4-Positivos/inmunología , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/complicaciones , Esquistosomiasis mansoni/patología , Modelos Animales de Enfermedad , Interleucina-4/metabolismo , Citocinas/metabolismo , Ratones Endogámicos C57BL , Linfocitos T/inmunología , Linfocitos T/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Esquistosomiasis/complicaciones , Esquistosomiasis/inmunología , Esquistosomiasis/parasitologíaRESUMEN
While antiretroviral therapy (ART) has revolutionized the management of human immunodeficiency virus (HIV) and has enabled people living with HIV (PLWH) to achieve near-normal life expectancies, an HIV cure remains elusive due to the presence of HIV reservoirs. Furthermore, compared with individuals in the general population, PLWH support a higher burden of multimorbidity, including pulmonary diseases of both an infectious and non-infection nature, which may be a consequence of the formation of HIV reservoirs. Their gut, lymph nodes, brain, testes and lungs constitute important anatomic sites for the reservoirs. While CD4+ T cells, and particularly memory CD4+ T cells, are the best characterized cellular HIV reservoirs, tissue resident macrophages (TRM) and alveolar macrophages (AM) also harbor HIV infection. AM are the most abundant cells in bronchoalveolar (BAL) fluid in healthy conditions, and act as sentinels in the alveolar space by patrolling and clearing debris, microbes and surfactant recycling. Long-lived tissue-resident AM of embryonic origin have the capacity of self-renewal without replenishment from peripheral monocytes. As in other tissues, close cell-cell contacts in lungs also provide a milieu conducive for cell-to-cell spread of HIV infection and establishment of reservoirs. As lungs are in constant exposure to antigens from the external environment, this situation contributes to pro-inflammatory phenotype rendering pulmonary immune cells exhausted and senescent-an environment facilitating HIV persistence. Factors such as tobacco and e-cigarette smoking, lung microbiome dysbiosis and respiratory coinfections further drive antigenic stimulation and HIV replication. HIV replication, in turn, contributes to ongoing inflammation and clonal expansion. Herein, the potential role of AM in HIV persistence is discussed. Furthermore, their contribution towards pulmonary inflammation and immune dysregulation, which may in turn render PLWH susceptible to chronic lung disease, despite ART, is explored. Finally, strategies to eliminate HIV-infected AM are discussed.
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Infecciones por VIH , Enfermedades Pulmonares , Macrófagos Alveolares , Humanos , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/complicaciones , Macrófagos Alveolares/virología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/fisiología , Enfermedades Pulmonares/virología , Enfermedades Pulmonares/inmunología , Pulmón/virología , Pulmón/inmunología , VIH-1/fisiología , Reservorios de Enfermedades/virología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virologíaRESUMEN
While antiretroviral therapy (ART) has revolutionized the management of human immunodeficiency virus (HIV) and has enabled people living with HIV (PLWH) to achieve near-normal life expectancies, an HIV cure remains elusive due to the presence of HIV reservoirs. Furthermore, compared with individuals in the general population, PLWH support a higher burden of multimorbidity, including pulmonary diseases of both an infectious and non-infection nature, which may be a consequence of the formation of HIV reservoirs. Their gut, lymph nodes, brain, testes and lungs constitute important anatomic sites for the reservoirs. While CD4+ T-cells, and particularly memory CD4+ T-cells, are the best characterized cellular HIV reservoirs, tissue resident macrophages (TRM) and alveolar macrophages (AM) also harbor HIV infection. AM are the most abundant cells in bronchoalveolar (BAL) fluid in healthy conditions, and act as sentinels in the alveolar space by patrolling and clearing debris, microbes and surfactant recycling. Long-lived tissue-resident AM of embryonic origin have the capacity of self-renewal without replenishment from peripheral monocytes. As in other tissues, close cell-cell contacts in lungs also provide a milieu conducive for cell-to-cell spread of HIV infection and establishment of reservoirs. As lungs are in constant exposure to antigens from the external environment, this situation contributes to pro-inflammatory phenotype rendering pulmonary immune cells exhausted and senescent-an environment facilitating HIV persistence. Factors such as tobacco and e-cigarette smoking, lung microbiome dysbiosis and respiratory co-infections further drive antigenic stimulation and HIV replication. HIV replication, in turn, contributes to ongoing inflammation and clonal expansion. Herein, the potential role of AM in HIV persistence is discussed. Furthermore, their contribution towards pulmonary inflammation and immune dysregulation, which may in turn render PLWH susceptible to chronic lung disease, despite ART, is explored. Finally, strategies to eliminate HIV-infected AM are discussed.
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Infecciones por VIH , Enfermedades Pulmonares , Macrófagos Alveolares , Humanos , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Macrófagos Alveolares/virología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/fisiología , Enfermedades Pulmonares/virología , Enfermedades Pulmonares/inmunología , VIH-1/fisiología , Pulmón/virología , Pulmón/inmunología , Reservorios de Enfermedades/virologíaRESUMEN
Major histocompatibility complex class I (MHC I) molecules present peptides to CD8+ T-cells for immunosurveillance of infection and cancer. Recent studies indicate lineage-specific heterogeneity in MHC I expression. While respiratory diseases rank among the leading causes of mortality, studies in mice have shown that lung epithelial cells (LECs) express the lowest levels of MHC I in the lung. This study aims to answer three questions: (i) Do human LECs express low levels of MHC I? (ii) Is LEC MHC I expression modulated in chronic respiratory diseases? (iii) Which factors regulate MHC I levels in human LECs? We analyzed human LECs from parenchymal explants using single-cell RNA sequencing and immunostaining. We confirmed low constitutive MHC I expression in human LECs, with significant upregulation in chronic respiratory diseases. We observed a sexual dimorphism, with males having higher MHC I levels under steady-state conditions, likely due to differential redox balance. Our study unveils the complex interplay between MHC I expression, sex, and respiratory disease. Since MHC I upregulation contributes to the development of immunopathologies in other models, we propose that it may have a similar impact on chronic lung disease.
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Células Epiteliales , Antígenos de Histocompatibilidad Clase I , Pulmón , Humanos , Femenino , Masculino , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Pulmón/metabolismo , Pulmón/citología , Pulmón/inmunología , Células Epiteliales/metabolismo , Caracteres Sexuales , Enfermedades Pulmonares/metabolismoRESUMEN
The emerging field of gut-lung axis research has revealed a complex interplay between the gut microbiota and respiratory health, particularly in asthma. This review comprehensively explored the intricate relationship between these two systems, focusing on their influence on immune responses, inflammation, and the pathogenesis of respiratory diseases. Recent studies have demonstrated that gut microbiota dysbiosis can contribute to asthma onset and exacerbation, prompting investigations into therapeutic strategies to correct this imbalance. Probiotics and prebiotics, known for their ability to modulate gut microbial compositions, were discussed as potential interventions to restore immune homeostasis. The impact of antibiotics and metabolites, including short-chain fatty acids produced by the gut microbiota, on immune regulation was examined. Fecal microbiota transplantation has shown promise in various diseases, but its role in respiratory disorders is not established. Innovative approaches, including mucus transplants, inhaled probiotics, and microencapsulation strategies, have been proposed as novel therapeutic avenues. Despite challenges, including the sophisticated adaptability of microbial communities and the need for mechanistic clarity, the potential for microbiota-based interventions is considerable. Collaboration between researchers, clinicians, and other experts is essential to unravel the complexities of the gut-lung axis, paving a way for innovative strategies that could transform the management of respiratory diseases.
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Asma , Disbiosis , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Prebióticos , Probióticos , Humanos , Probióticos/uso terapéutico , Asma/microbiología , Asma/inmunología , Asma/terapia , Animales , Pulmón/microbiología , Pulmón/inmunología , Pulmón/metabolismo , Enfermedades Pulmonares/microbiología , Enfermedades Pulmonares/terapia , Enfermedades Pulmonares/inmunologíaRESUMEN
Staphylococcus aureus (SA) is a common Gram-positive bacterium that activates inflammatory cells, expressing various cytokines and inducing an inflammatory response. Recent research revealed aconitate decarboxylase 1 (ACOD1) as a regulator of the immune response through various metabolic pathways, playing a dual role in the inflammatory response. However, the mechanism by which ACOD1 participates in the regulation of SA-induced inflammatory responses in macrophages remains unknown. Therefore, this study aims to investigate the function and underlying regulatory mechanisms of ACOD1 in SA-induced inflammatory response. This study reveals that SA induced a macrophage inflammatory response and upregulated ACOD1 expression. ACOD1 knockdown significantly inhibited SA-induced macrophage inflammatory response, attenuated SA-induced nuclear envelope wrinkling, and plasma membrane rupture, and suppressed the TLR4/NF-κB signaling pathway. Furthermore, ACOD1 knockdown reduced the inflammatory response and alleviated lung tissue injury and cellular damage, leading to decreased bacterial loads in the lungs of SA-infected mice. Collectively, these findings demonstrate that SA induces an inflammatory response in macrophages and increases ACOD1 expression. ACOD1 enhances SA-induced inflammatory responses via the TLR4/NF-κB signaling pathway. Our findings highlight the significant role of ACOD1 in mediating the inflammatory response in SA-infected macrophages and elucidate its molecular mechanism in regulating the SA-induced inflammatory response.
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Carboxiliasas , Macrófagos , Transducción de Señal , Infecciones Estafilocócicas , Staphylococcus aureus , Animales , Humanos , Ratones , Carboxiliasas/metabolismo , Carboxiliasas/genética , Inflamación/inmunología , Inflamación/metabolismo , Pulmón/inmunología , Pulmón/patología , Pulmón/microbiología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Células RAW 264.7 , Transducción de Señal/inmunología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genéticaRESUMEN
Bronchopulmonary dysplasia (BPD) is the most common sequela of prematurity and is characterized by alveolar simplification and lung angiogenesis failure. The aim of this study was to explore the immune signatures of BPD. Differentially expressed gene analysis and immune infiltration analysis were conducted to identify key immune cell types and related genes by using the mRNA-seq dataset GSE25286. The expression patterns of key genes were validated in the scRNA-seq dataset GSE209664 and in experiments. The cell-cell crosstalk of key immune cells was explored with CellChat. We found that differentially expressed genes between BPD mice and controls were mostly enriched in leukocyte migration and M1 macrophages were highly enriched in BPD lungs. Hub genes (Cybb, Papss2, F7 and Fpr2) were validated at the single-cell level, among which the downregulation of Cybb was most closely related to macrophage infiltration. The reduced mRNA and protein levels of Cybb were further validated in animal experiments. Colocalization analysis of Cybb and macrophage markers demonstrated a significant decrease of Cybb in M1 macrophages. Cell-cell crosstalk found that alveolar epithelial cells interacted actively with macrophages through MIF-(CD74 + CD44) signalling. In conclusion, M1 macrophages played important roles in promoting BPD-like lung injury, which was correlated with a specific reduction of Cybb in macrophages and the potential activation of MIF signalling.
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Displasia Broncopulmonar , Biología Computacional , Regulación hacia Abajo , Hiperoxia , Macrófagos , Displasia Broncopulmonar/patología , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/genética , Animales , Biología Computacional/métodos , Hiperoxia/metabolismo , Ratones , Macrófagos/metabolismo , Macrófagos/inmunología , Humanos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Pulmón/patología , Pulmón/metabolismo , Pulmón/inmunología , Perfilación de la Expresión GénicaRESUMEN
Innate lymphoid cells (ILCs) are a heterogeneous population that play diverse roles in airway inflammation after exposure to allergens and infections. However, how ILCs respond after exposure to environmental toxins is not well understood. Here we show a novel method for studying the heterogeneity of rare lung ILC populations by magnetic enrichment for lung ILCs followed by particle-templated instant partition sequencing (PIP-seq). Using this method, we were able to identify novel group 1 and group 2 ILC subsets that exist after exposure to both fungal allergen and burn pit-related constituents (BPC) that include dioxin, aromatic hydrocarbon, and particulate matter. Toxin exposure in combination with fungal allergen induced activation of specific ILC1/NK and ILC2 populations as well as promoted neutrophilic lung inflammation. Oxidative stress pathways and downregulation of specific ribosomal protein genes (Rpl41 and Rps19) implicated in anti-inflammatory responses were present after BPC exposure. Increased IFNγ expression and other pro-neutrophilic mediator transcripts were increased in BPC-stimulated lung innate lymphoid cells. Further, the addition of BPC induced Hspa8 (encodes HSC70) and aryl hydrocarbon transcription factor activity across multiple lung ILC subsets. Overall, using an airway disease model that develops after occupational and environmental exposures, we demonstrate an effective method to better understand heterogenous ILC subset activation.
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Inmunidad Innata , Pulmón , Linfocitos , Animales , Inmunidad Innata/efectos de los fármacos , Pulmón/inmunología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones , Linfocitos/inmunología , Linfocitos/metabolismo , Linfocitos/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Ratones Endogámicos C57BL , Material Particulado/efectos adversos , Material Particulado/toxicidad , Alérgenos/inmunología , Neumonía/inmunología , Neumonía/genéticaRESUMEN
SARS-CoV-2 infection induces the generation of virus-specific CD4+ and CD8+ effector and memory T cells. However, the contribution of T cells in controlling SARS-CoV-2 during infection is not well understood. Following infection of C57BL/6 mice, SARS-CoV-2-specific CD4+ and CD8+ T cells are recruited to the respiratory tract, and a vast proportion secrete the cytotoxic molecule granzyme B. Using depleting antibodies, we found that T cells within the lungs play a minimal role in viral control, and viral clearance occurs in the absence of both CD4+ and CD8+ T cells through 28 days postinfection. In the nasal compartment, depletion of both CD4+ and CD8+ T cells, but not individually, results in persistent, culturable virus replicating in the nasal epithelial layer through 28 days postinfection. Viral sequencing analysis revealed adapted mutations across the SARS-CoV-2 genome, including a large deletion in ORF6. Overall, our findings highlight the importance of T cells in controlling virus replication within the respiratory tract during SARS-CoV-2 infection.