ABSTRACT
Coronavirus disease-19 (COVID-19) has resulted in much acute morbidity and mortality worldwide. There is now a growing recognition of the post-acute sequela of COVID-19, termed long COVID. However, the risk factors contributing to this condition remain unclear. Here, we address the growing controversy in the literature of whether hospitalization is a risk factor for long COVID. We found that hospitalization is associated with worse pulmonary restriction and reduction in diffusion capacity at 3 months post-infection. However, the impact on mental health, functional and quality of life is equally severe in those who have and have not been hospitalized during the acute infection. These findings suggest that hospitalization is a risk factor for pulmonary complications of long COVID but not the overall severity of long COVID.
Subject(s)
COVID-19 , COVID-19/complications , Disease Progression , Hospitalization , Humans , Quality of Life , SARS-CoV-2 , Post-Acute COVID-19 SyndromeABSTRACT
Acute lung injury (ALI) is an inflammatory disorder associated with recruitment and activation of neutrophils in lungs. Rac2, a member of the Rho GTPase subfamily, is an essential regulator of neutrophil degranulation, superoxide release, and chemotaxis. Here, we hypothesized that Rac2 is important in mediating lung injury. Using a model of IgG immune complex-mediated ALI, we showed that injury was attenuated in rac2(-/-) mice compared with wild-type (WT) mice undergoing ALI, with significant decreases in alveolar leukocyte numbers, vascular leakage, and the inflammatory mediators, myeloperoxidase (MPO) and matrix metalloproteinases (MMPs). Reduced injury in rac2(-/-) mice was not associated with diminished cytokine and chemokine production, since bronchoalveolar lavage (BAL) levels of IL-17, TNF, CCL3, CXCL1, and CXCL2 were similarly increased in WT and rac2(-/-) mice with ALI compared with sham-treated mice (no ALI). BAL levels of MMP-2 and MMP-9 were significantly decreased in the airways of rac2(-/-) mice with ALI. Immunohistochemical analysis revealed that MMP-2 and MMP-9 expression was evident in alveolar macrophages and interstitial neutrophils in WT ALI. In contrast, MMP-positive cells were less prominent in rac2(-/-) mice with ALI. Chimeric mice showed that Rac2-mediated lung injury was dependent on hematopoietic cells derived from bone marrow. We propose that lung injury in response to immune complex deposition is dependent on Rac2 in alveolar macrophages and neutrophils.
Subject(s)
Acute Lung Injury/complications , Acute Lung Injury/immunology , Antigen-Antibody Complex/immunology , Inflammation/complications , Inflammation/immunology , rac GTP-Binding Proteins/metabolism , Acute Lung Injury/enzymology , Animals , Bronchoalveolar Lavage Fluid/immunology , Cell Movement , Chemokines/biosynthesis , Epithelial Cells/pathology , Hematopoietic Stem Cells/pathology , Inflammation Mediators/metabolism , Lung/enzymology , Lung/immunology , Lung/pathology , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Neutrophils/pathology , Peroxidase/metabolism , Superoxides/metabolism , rac GTP-Binding Proteins/deficiency , RAC2 GTP-Binding ProteinABSTRACT
Syk kinase is best known as a critical component of immunoreceptor signaling in leukocytes. Activation of Syk following cross-linking of Fcgamma and Fcepsilon receptors on macrophages, mast cells, and other cells induces various inflammatory events. We hypothesized that Syk is involved in inflammatory responses induced by the lipopolysaccharide (LPS). We studied the role of Syk using its inhibition by antisense oligonucleotides, or small interfering RNA. Our data demonstrated that in vivo inhibition of Syk caused down-regulation of LPS-induced responses in rat alveolar macrophages. In in vitro experiments, inhibition of Syk in rat peritoneal macrophages, as well as in human myelomonocyte cell line THP-1 also caused a decrease in LPS-induced cytokine release. Our data support the hypothesis that, in macrophages, Syk is involved in LPS-induced intracellular signaling pathways leading to the release of pro-inflammatory mediators. Understanding the role of Syk in LPS-induced signaling may help in developing new therapeutic tools for inflammatory disorders.
Subject(s)
Cytokines/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Lipopolysaccharides/metabolism , Macrophages, Alveolar/metabolism , Macrophages, Peritoneal/metabolism , Protein-Tyrosine Kinases/metabolism , Animals , Blotting, Western , Cell Line , Cytokines/immunology , Enzyme-Linked Immunosorbent Assay , Humans , Inflammation Mediators/metabolism , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/immunology , Lipopolysaccharides/immunology , Liposomes , Macrophages, Alveolar/enzymology , Macrophages, Alveolar/immunology , Macrophages, Peritoneal/enzymology , Macrophages, Peritoneal/immunology , Male , Monocytes/immunology , Monocytes/metabolism , Nitric Oxide/metabolism , Oligonucleotides, Antisense/metabolism , Oligonucleotides, Antisense/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/immunology , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Syk Kinase , Transfection , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Decentralization or removal (ganglionectomy) of the superior cervical ganglia (SCG) reduces the responses of circulating neutrophils to chemotactic stimuli and attenuates the pulmonary neutrophilia that develops 8 h after antigen challenge of Nippostrongylus brasiliensis-sensitized rats. The denervation-induced modification in neutrophil function is reserved by removal of the submandibular glands. In contrast, the reduced TNF-α release from mast cells seen in both decentralized and sialadenectomized rats was abolished if both operations were performed in the same animal. Multiple mechanisms appear to exist by which the cervical sympathetic trunk-submandibular axis regulates immunological function.
ABSTRACT
This study examined the structure activity relationship of NH(3)-Phe-Glu-Gly-COO(-) (FEG), a potent inhibitor of intestinal anaphylaxis. The inhibition by FEG analogues of antigen-provoked contractions of isolated ileal segments obtained from ovalbumin-sensitized rats was determined and molecular modeling performed. A combination of aromaticity of the first residue, minimal extension of the carboxyl group on residue 2, and underivatized N and C termini were essential for biological activity. FEG, WEG, WDG and the d-enantiomeric forms of FEG (feG) and YEG (yeG) retained biological activity. By considering dipole moments, the structural and conformational features critical to biological activity were established as the glutamyl-carboxyl group/Phe side chain and carboxyl/amino termini interactions. Analysis of Ramachandran plots for position 1 sidechains indicate that mobility of the aromatic sidechain must be restricted to retain biological activity. The anti-anaphylactic effects of FEG, characterized by specific structural and conformational restrictions, indicate a selective interaction with a receptor for this peptide in the intestine.
Subject(s)
Oligopeptides/chemistry , Oligopeptides/metabolism , Submandibular Gland/metabolism , Animals , Aspartic Acid/chemistry , Ileum/drug effects , Ileum/metabolism , Intestinal Mucosa/metabolism , Male , Models, Molecular , Ovalbumin/pharmacology , Peptide Biosynthesis , Protein Conformation , Protein Structure, Tertiary , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Clarithromycin exhibits anti-inflammatory as well as antimicrobial activity, leading to decreased symptoms of asthma and chronic sinusitis. The mode of anti-inflammatory effects of clarithromycin on inflammatory cells is not well understood. We hypothesized that clarithromycin inhibits inflammatory cell mediator release and survival. METHODS: We investigated the effects of this drug on survival and mediator release from mast cells, eosinophils and neutrophils. RESULTS: Human eosinophil and neutrophil respiratory burst was inhibited by up to 54% after 1-2 h pretreatment with 100 microg/ml clarithromycin. Similar doses of erythromycin did not affect respiratory burst responses in these cells. Clarithromycin at doses of up to 100 microg/ml had no effect on granule-derived mediators released from mast cells and neutrophils. However, we found that clarithromycin (100 microg/ml) induced cell death in mast cells and eosinophils after 16-48 h incubation. CONCLUSION: Clarithromycin inhibited inflammatory cell mediator release and survival, which may enhance its ability to reduce the symptoms of chronic sinusitis and asthma.
Subject(s)
Anti-Bacterial Agents/pharmacology , Clarithromycin/pharmacology , Eosinophils/drug effects , Mast Cells/drug effects , Neutrophils/drug effects , Cell Culture Techniques , Cell Survival , Eosinophils/physiology , Humans , Inflammation , Mast Cells/physiology , Neutrophils/physiology , Respiratory BurstABSTRACT
BACKGROUND: Mast cells and eosinophils are important effector cells in asthma. Understanding their interactions is essential for studying asthma pathophysiology. Inflammatory mediators released from mast cells, such as arachidonic acid metabolites, TNF and IL-5, are important in eosinophil biology. However, little is known about the effects of mast cell-specific mediators, such as tryptase, on eosinophils. Our objective was to investigate the effects of mast cell tryptase on human peripheral blood eosinophils. METHODS: Peripheral blood eosinophils isolated from asthmatic individuals were activated using various concentrations of tryptase- and protease-activated receptor-2 (PAR-2)-activating peptides (PAR-2 AP). Eosinophil activation was evaluated by the release of granule mediators, superoxide release, estimation of eosinophil survival, changes in intracellular Ca2+ concentration and mitogen-activated protein kinase activation. RESULTS: Tryptase induced the release of eosinophil peroxidase and beta-hexosaminidase from peripheral blood eosinophils but had no effect on RANTES release. Eosinophils isolated from two thirds of our donors responded to tryptase, while the remainder appeared not to respond. Release of granule mediators was dependent on tryptase enzymatic activity. To identify the mechanism of eosinophil activation by tryptase, we studied the expression of PAR-2 by eosinophils and its function. Using RT-PCR, we amplified PAR-2 from eosinophils. However, flow cytometry failed to detect significant PAR-2 expression on the surface of eosinophils. The PAR-2 AP SLIGRL-NH2 did not induce eosinophil activation by any of the methods we employed. CONCLUSION: Our data indicate that mast cell tryptase may affect eosinophil activation status independently of PAR-2.