RESUMO
Currently, the global lifespan has increased, resulting in a higher proportion of the population over 65 years. Changes that occur in the lung during aging increase the risk of developing acute and chronic lung diseases, such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung cancer. During normal tissue homeostasis, cell proliferation and apoptosis create a dynamic balance that constitutes the physiological cell turnover. In basal conditions, the lungs have a low rate of cell turnover compared to other organs. During aging, changes in the rate of cell turnover in the lung are observed. In this work, we review the literature that evaluates the role of molecules involved in cell proliferation and apoptosis in lung aging and in the development of age-related lung diseases. The list of molecules that regulate cell proliferation, apoptosis, or both processes in lung aging includes TNC, FOXM1, DNA-PKcs, MicroRNAs, BCL-W, BCL-XL, TCF21, p16, NOX4, NRF2, MDM4, RPIA, DHEA, and MMP28. However, despite the studies carried out to date, the complete signaling pathways that regulate cell turnover in lung aging are still unknown. More research is needed to understand the changes that lead to the development of age-related lung diseases.
Assuntos
Envelhecimento , Apoptose , Proliferação de Células , Pulmão , Humanos , Envelhecimento/fisiologia , Pulmão/metabolismo , Pulmão/patologia , Animais , Transdução de Sinais , Pneumopatias/patologia , Pneumopatias/metabolismoRESUMO
BACKGROUND: Persistent respiratory symptoms and lung abnormalities post-COVID-19 are public health problems. This study evaluated biomarkers to stratify high-risk patients to the development or persistence of post-COVID-19 interstitial lung disease. METHODS: One hundred eighteen patients discharged with residual lung abnormalities compatible with interstitial lung disease (COVID-ILD patients) after a severe COVID-19 were followed for 1 year (post-COVID-ILD patients). Physical examination, pulmonary function tests, and chest high-resolution computed tomography (HRCT) were performed. Soluble forms (s) of PD-L1, PD-L2, TIM-3, and GAL-9 were evaluated in serum and cell culture supernatant, as well as T-cells subsets and the transmembrane expression of PD-L1 and PD-L2 on the cell surface. RESULTS: Eighty percent of the post-COVID-ILD patients normalized their lung function at 1-year follow-up, 8% presented COVID-independent ILD, and 12% still showed functional and HRCT alterations. PD-L2 levels were heterogeneous during acute COVID-19 (aCOVID); patients who increased (at least 30%) their sPD-L2 levels at 1 year post-COVID-19 and exhibited altered CD4/CD8 ratio showed persistence of chest tomographic and functional alterations. By contrast, patients who decreased sPD-L2 displayed a complete lung recovery. sPD-L1, sTIM-3, and sGAL-9 increased significantly during aCOVID and decreased in all patients after 1-year follow-up. CONCLUSION: Increased sPD-L2 and an altered CD4/CD8 ratio after 12 months of aCOVID are associated with the persistence of lung lesions, suggesting that they may contribute to lung damage post-COVID-19.
Assuntos
Relação CD4-CD8 , COVID-19 , Pulmão , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/sangue , COVID-19/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Pulmão/imunologia , Pulmão/patologia , Pulmão/diagnóstico por imagem , SARS-CoV-2/imunologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/sangue , Biomarcadores/sangue , Antígeno B7-H1/sangue , Testes de Função Respiratória , Tomografia Computadorizada por Raios X , Seguimentos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , AdultoRESUMO
Tuberculosis (TB) is an infectious, chronic, and progressive disease occurring globally. Human TB is caused mainly by Mycobacterium tuberculosis (M. tuberculosis), while the main causative agent of bovine TB is Mycobacterium bovis (M. bovis). The latter is one of the most important cattle pathogens and is considered the main cause of zoonotic TB worldwide. The mechanisms responsible for tissue damage (necrosis) during post-primary TB remain elusive. Recently, IL-17A was reported to be important for protection against M. tuberculosis infection, but it is also related to the production of an intense inflammatory response associated with necrosis. We used two M. bovis isolates with different levels of virulence and high IL-17A production to study this important cytokine's contrasting functions in a BALB/c mouse model of pulmonary TB. In the first part of the study, the gene expression kinetics and cellular sources of IL-17A were determined by real time PCR and immunohistochemistry respectively. Non-infected lungs showed low production of IL-17A, particularly by the bronchial epithelium, while lungs infected with the low-virulence 534 strain showed high IL-17A expression on Day 3 post-infection, followed by a decrease in expression in the early stage of the infection and another increase during late infection, on Day 60, when very low bacillary burdens were found. In contrast, infection with the highly virulent strain 04-303 induced a peak of IL-17A expression on Day 14 of infection, 1 week before extensive pulmonary necrosis was seen, being lymphocytes and macrophages the most important sources. In the second part of the study, the contribution of IL-17A to immune protection and pulmonary necrosis was evaluated by suppressing IL-17A via the administration of specific blocking antibodies. Infection with M. bovis strain 534 and treatment with IL-17A neutralizing antibodies did not affect mouse survival but produced a significant increase in bacillary load and a non-significant decrease in inflammatory infiltrate and granuloma area. In contrast, mice infected with the highly virulent 04-303 strain and treated with IL-17A blocking antibodies showed a significant decrease in survival, an increase in bacillary loads on Day 24 post-infection, and significantly more and earlier necrosis. Our results suggest that high expression of IL-17A is more related to protection than necrosis in a mouse model of pulmonary TB induced by M. bovis strains.
Assuntos
Interleucina-17 , Camundongos Endogâmicos BALB C , Mycobacterium bovis , Tuberculose Pulmonar , Interleucina-17/metabolismo , Interleucina-17/imunologia , Animais , Mycobacterium bovis/patogenicidade , Mycobacterium bovis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Camundongos , Virulência , Pulmão/microbiologia , Pulmão/patologia , Pulmão/imunologia , Feminino , BovinosRESUMO
IκB kinase (IKK)α controls noncanonical NF-κB signaling required for lymphoid organ development. We showed previously that lymph node formation is ablated in IkkαLyve-1 mice constitutively lacking IKKα in lymphatic endothelial cells (LECs). We now reveal that loss of IKKα in LECs leads to the formation of BALT in the lung. Tertiary lymphoid structures appear only in the lungs of IkkαLyve-1 mice and are not present in any other tissues, and these highly organized BALT structures form after birth and in the absence of inflammation. Additionally, we show that IkkαLyve-1 mice challenged with influenza A virus (IAV) exhibit markedly improved survival and reduced weight loss compared with littermate controls. Importantly, we determine that the improved morbidity and mortality of IkkαLyve-1 mice is independent of viral load and rate of clearance because both mice control and clear IAV infection similarly. Instead, we show that IFN-γ levels are decreased, and infiltration of CD8 T cells and monocytes into IkkαLyve-1 lungs is reduced. We conclude that ablating IKKα in LECs promotes BALT formation and reduces the susceptibility of IkkαLyve-1 mice to IAV infection through a decrease in proinflammatory stimuli.
Assuntos
Homeostase , Quinase I-kappa B , Vírus da Influenza A , Pulmão , Infecções por Orthomyxoviridae , Animais , Quinase I-kappa B/metabolismo , Quinase I-kappa B/genética , Camundongos , Pulmão/imunologia , Pulmão/virologia , Pulmão/patologia , Infecções por Orthomyxoviridae/imunologia , Vírus da Influenza A/imunologia , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Linfócitos T CD8-Positivos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Interferon gama/metabolismoRESUMO
Since human angiotensin-converting enzyme 2 (ACE2) serves as a primary receptor for SARS-CoV-2, characterizing ACE2 regions that allow SARS-CoV-2 to enter human cells is essential for designing peptide-based antiviral blockers and elucidating the pathogenesis of the virus. We identified and synthesized a 25-mer mimetic peptide (encompassing positions 22-46 of the ACE2 alpha-helix α1) implicated in the S1 receptor-binding domain (RBD)-ACE2 interface. The mimetic (wild-type, WT) ACE2 peptide significantly inhibited SARS-CoV-2 infection of human pulmonary Calu-3 cells in vitro. In silico protein modeling predicted that residues F28, K31, F32, F40, and Y41 of the ACE2 alpha-helix α1 are critical for the original, Delta, and Omicron strains of SARS-CoV-2 to establish the Spike RBD-ACE2 interface. Substituting these residues with alanine (A) or aspartic acid (D) abrogated the antiviral protective effect of the peptides, indicating that these positions are critical for viral entry into pulmonary cells. WT ACE2 peptide, but not the A or D mutated peptides, exhibited significant interaction with the SARS-CoV-2 S1 RBD, as shown through molecular dynamics simulations. Through identifying the critical amino acid residues of the ACE2 alpha-helix α1, which is necessary for the Spike RBD-ACE2 interface and mobilized during the in vitro viral infection of cells, we demonstrated that the WT ACE2 peptide protects susceptible K18-hACE2 mice against in vivo SARS-CoV-2 infection and is effective for the treatment of COVID-19.
Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Peptídeos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Humanos , Animais , SARS-CoV-2/efeitos dos fármacos , COVID-19/virologia , Camundongos , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Peptídeos/farmacologia , Peptídeos/química , Peptídeos/uso terapêutico , Tratamento Farmacológico da COVID-19 , Antivirais/farmacologia , Antivirais/química , Linhagem Celular , Pneumonia/tratamento farmacológico , Pneumonia/virologia , Pneumonia/prevenção & controle , Pulmão/virologia , Pulmão/patologia , FemininoRESUMO
Asthma is a chronic immunological disease related to oxidative stress and chronic inflammation; both processes promote airway remodeling with collagen deposition and matrix thickening, causing pulmonary damage and lost function. This study investigates the immunomodulation of C-phycocyanin (CPC), a natural blue pigment purified from cyanobacteria, as a potential alternative treatment to prevent the remodeling process against asthma. We conducted experiments using ovalbumin (OVA) to induce asthma in Sprague Dawley rats. Animals were divided into five groups: (1) sham + vehicle, (2) sham + CPC, (3) asthma + vehicle, (4) asthma + CPC, and (5) asthma + methylprednisolone (MP). Our findings reveal that asthma promotes hypoxemia, leukocytosis, and pulmonary myeloperoxidase (MPO) activity by increasing lipid peroxidation, reactive oxygen and nitrogen species, inflammation associated with Th2 response, and airway remodeling in the lungs. CPC and MP treatment partially prevented these physiological processes with similar action on the biomarkers evaluated. In conclusion, CPC treatment enhanced the antioxidant defense system, thereby preventing oxidative stress and reducing airway inflammation by regulating pro-inflammatory and anti-inflammatory cytokines, consequently avoiding asthma-induced airway remodeling.
Assuntos
Remodelação das Vias Aéreas , Asma , Modelos Animais de Doenças , Ovalbumina , Estresse Oxidativo , Ficocianina , Ratos Sprague-Dawley , Animais , Ficocianina/farmacologia , Ficocianina/uso terapêutico , Asma/tratamento farmacológico , Asma/metabolismo , Asma/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Ovalbumina/efeitos adversos , Ratos , Remodelação das Vias Aéreas/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Masculino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Citocinas/metabolismoRESUMO
The combination of a polyphenol, quercetin, with dasatinib initiated clinical trials to evaluate the safety and efficacy of senolytics in idiopathic pulmonary fibrosis, a lung disease associated with the presence of senescent cells. Another approach to senotherapeutics consists of controlling inflammation related to cellular senescence or "inflammaging", which participates, among other processes, in establishing pulmonary fibrosis. We evaluate whether polyphenols such as caffeic acid, chlorogenic acid, epicatechin, gallic acid, quercetin, or resveratrol combined with different senotherapeutics such as metformin or rapamycin, and antifibrotic drugs such as nintedanib or pirfenidone, could present beneficial actions in an in vitro model of senescent MRC-5 lung fibroblasts. A senescent-associated secretory phenotype (SASP) was evaluated by the measurement of interleukin (IL)-6, IL-8, and IL-1ß. The senescent-associated ß-galactosidase (SA-ß-gal) activity and cellular proliferation were assessed. Fibrosis was evaluated using a Picrosirius red assay and the gene expression of fibrosis-related genes. Epithelial-mesenchymal transition (EMT) was assayed in the A549 cell line exposed to Transforming Growth Factor (TGF)-ß in vitro. The combination that demonstrated the best results was metformin and caffeic acid, by inhibiting IL-6 and IL-8 in senescent MRC-5 cells. Metformin and caffeic acid also restore cellular proliferation and reduce SA-ß-gal activity during senescence induction. The collagen production by senescent MRC-5 cells was inhibited by epicatechin alone or combined with drugs. Epicatechin and nintedanib were able to control EMT in A549 cells. In conclusion, caffeic acid and epicatechin can potentially increase the effectiveness of senotherapeutic drugs in controlling lung diseases whose pathophysiological component is the presence of senescent cells and fibrosis.
Assuntos
Senescência Celular , Fibroblastos , Pulmão , Polifenóis , Humanos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Senescência Celular/efeitos dos fármacos , Polifenóis/farmacologia , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Células A549 , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Metformina/farmacologia , Ácidos Cafeicos/farmacologia , Indóis/farmacologia , Senoterapia/farmacologia , Linhagem Celular , Fenótipo Secretor Associado à Senescência/efeitos dos fármacos , Sirolimo/farmacologia , Interleucina-8/metabolismo , Interleucina-8/genética , Fator de Crescimento Transformador beta/metabolismo , PiridonasRESUMO
SUMMARY: Prior research on post-COVID-19 or long COVID primarily focused on the presence of SARS-CoV-2 mostly in symptomatic patients. This study aimed to investigate the persistence of SARS-CoV-2 after 1 year of asymptomatic or mild COVID-19. SARS-CoV-2 infected and control K18-hACE2 transgenic mice (n=25) were studied. Moderate and severe symptomatic subjects were sacrificed after eight days, while mild or asymptomatic mice were kept in BSL-III for twelve months. Analyses included general condition, histochemistry, immunohistochemistry, transmission electron microscopy, and qRT-PCR. Lungs from the twelve-month group showed thickening of alveolar walls, with some lungs exhibiting the recruitment of inflammatory cells, the presence of SARS- CoV-2 mRNA, immunopositivity for the SARS-CoV-2 spike protein, and TEM showed viruses (60-125 nm) within vesicles, indicating continued replication. Certain lung samples showed persistent SARS-CoV-2 presence in Club cells, endothelial cells, and macrophages. The eight-day group exhibited viral interstitial pneumonitis, SARS-CoV-2 immunopositivity, and mRNA. The eight-day hearts displayed viral mRNA, while the twelve-month hearts tested negative. Some asymptomatic twelve-month subjects presented reduced surfactant, basal membrane thickening, fibrosis, and mild autonomic nerve degeneration. In this study conducted on mice, findings indicate the potential for chronic persistence of SARS-CoV-2 in the lungs one year post initial mild or asymptomatic infection, which could suggest the possibility of recurrent episodes in similar human conditions. The observed thickening of alveolar walls and potential fibrotic areas in these mice may imply an increased risk of post-COVID fibrosis in humans. Furthermore, the presence of SARS-CoV-2-positive inflammatory cells in some asymptomatic murine cases could herald a progression toward ongoing inflammation and chronic lung disease in humans. Therefore, the necessity for further studies in human subjects and vigilant monitoring of high-risk human populations is underscored.
Investigaciones anteriores sobre COVID-19 o COVID prolongado se centraron principalmente en la presencia de SARS-CoV-2 principalmente en pacientes sintomáticos. Este estudio tuvo como objetivo investigar la persistencia del SARS-CoV-2 después de 1 año de COVID-19 asintomático o leve. Se estudiaron ratones transgénicos K18-hACE2 infectados con SARS-CoV-2 y de control (n=25). Los animales con síntomas moderados y graves se sacrificaron después de ocho días, mientras que los ratones con síntomas leves o asintomáticos se mantuvieron en BSL-III durante doce meses. Los análisis incluyeron estado general, histoquímica, inmunohistoquímica, microscopía electrónica de transmisión y qRT- PCR. Los pulmones del grupo de doce meses mostraron engrosamiento de las paredes alveolares, y algunos pulmones exhibieron reclutamiento de células inflamatorias, presencia de ARNm del SARS-CoV-2, inmunopositividad para la proteína de la espícula del SARS-CoV-2 y TEM mostró virus (60 -125 nm) dentro de las vesículas, lo que indica una replicación continua. Ciertas muestras de pulmón mostraron una presencia persistente de SARS- CoV-2 en exocrinocitos bronquiolares, células endoteliales y macrófagos. El grupo de ocho días presentó neumonitis intersticial viral, inmunopositividad al SARS-CoV-2 y ARNm. Los corazones de ocho días mostraron ARNm viral, mientras que los corazones de doce meses dieron negativo. Algunos animales asintomáticos de doce meses presentaron disminución del surfactante, engrosamiento de la membrana basal, fibrosis y degeneración leve del nervio autónomo. En este estudio realizado en ratones, los hallazgos indican la posibilidad de persistencia crónica del SARS-CoV-2 en los pulmones un año después de la infección inicial leve o asintomática, lo que podría sugerir la posibilidad de episodios recurrentes en condiciones humanas similares. El engrosamiento observado de las paredes alveolares y las posibles áreas fibróticas en estos ratones puede implicar un mayor riesgo de fibrosis post-COVID en humanos. Además, la presencia de células inflamatorias positivas para SARS- CoV-2 en algunos casos murinos asintomáticos podría presagiar una progresión hacia una inflamación continua y una enfermedad pulmonar crónica en humanos. Por lo tanto, se subraya la necesidad de realizar más estudios en seres humanos y realizar un seguimiento atento de las poblaciones humanas de alto riesgo.
Assuntos
Animais , Camundongos , Infecções Assintomáticas , COVID-19/patologia , Pulmão/patologia , Fibrose Pulmonar/patologia , RNA Mensageiro , RNA Viral/análise , Imuno-Histoquímica , Camundongos Transgênicos , Redução de Peso , Microscopia Eletrônica de Transmissão , Reação em Cadeia da Polimerase em Tempo Real , SARS-CoV-2/isolamento & purificação , COVID-19/virologia , Síndrome de COVID-19 Pós-Aguda/patologia , Pulmão/ultraestrutura , Pulmão/virologiaRESUMO
Acute lung injury caused by severe malaria (SM) is triggered by a dysregulated immune response towards the infection with Plasmodium parasites. Postmortem analysis of human lungs shows diffuse alveolar damage (DAD), the presence of CD8 lymphocytes, neutrophils, and increased expression of Intercellular Adhesion Molecule 1 (ICAM-1). P. berghei ANKA (PbA) infection in C57BL/6 mice reproduces many SM features, including acute lung injury characterized by DAD, CD8+ T lymphocytes and neutrophils in the lung parenchyma, and tissular expression of proinflammatory cytokines and adhesion molecules, such as IFNγ, TNFα, ICAM, and VCAM. Since this is related to a dysregulated immune response, immunomodulatory agents are proposed to reduce the complications of SM. The monocyte locomotion inhibitory factor (MLIF) is an immunomodulatory pentapeptide isolated from axenic cultures of Entamoeba hystolitica. Thus, we evaluated if the MLIF intraperitoneal (i.p.) treatment prevented SM-induced acute lung injury. The peptide prevented SM without a parasiticidal effect, indicating that its protective effect was related to modifications in the immune response. Furthermore, peripheral CD8+ leukocytes and neutrophil proportions were higher in infected treated mice. However, the treatment prevented DAD, CD8+ cell infiltration into the pulmonary tissue and downregulated IFNγ. Moreover, VCAM-1 expression was abrogated. These results indicate that the MLIF treatment downregulated adhesion molecule expression, impeding cell migration and proinflammatory cytokine tissular production, preventing acute lung injury induced by SM. Our findings represent a potential novel strategy to avoid this complication in various events where a dysregulated immune response triggers lung injury.
Assuntos
Lesão Pulmonar Aguda , Modelos Animais de Doenças , Malária , Plasmodium berghei , Animais , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/etiologia , Camundongos , Malária/imunologia , Plasmodium berghei/imunologia , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Pulmão/imunologia , Pulmão/patologia , Humanos , Feminino , OligopeptídeosRESUMO
The Brazilian Amazon is home to a rich fauna of scorpion species of medical importance, some of them still poorly characterized regarding their biological actions and range of clinical symptoms after envenoming. The Amazonian scorpion species Tityus strandi and Tityus dinizi constitute some of the scorpions in this group, with few studies in the literature regarding their systemic repercussions. In the present study, we characterized the clinical, inflammatory, and histopathological manifestations of T. strandi and T. dinizi envenoming in a murine model using Balb/c mice. The results show a robust clinical response based on clinical score, hyperglycemia, leukocytosis, increased cytokines, and histopathological changes in the kidneys and lungs. Tityus strandi envenomed mice presented more prominent clinical manifestations when compared to Tityus dinizi, pointing to the relevance of this species in the medical scenario, with both species inducing hyperglycemia, leukocytosis, increased cytokine production in the peritoneal lavage, increased inflammatory infiltrate in the lungs, and acute tubular necrosis after T. strandi envenoming. The results presented in this research can help to understand the systemic manifestations of scorpion accidents in humans caused by the target species of the study and point out therapeutic strategies in cases of scorpionism in remote regions of the Amazon.