RESUMO
Chronic mucosal inflammation is the hallmark of important and common airway diseases, such as allergic rhinitis (AR) and asthma. Lipoxin A4 (LXA4) is an endogenous pro-resolving mediator for mucosal inflammation that decreases allergic and asthmatic responses. Lipoxin B4 (LXB4) is a structurally distinct member of the lipoxin family that signals in a manner distinct from LXA4. LXB4 is generated by mucosal tissues, but its actions in allergic inflammation are unknown. Here, we used murine models of AR and asthma to investigate LXB4's activity in mucosal inflammation. In the upper airway, LXB4 significantly decreased nasal mucosal leukocytes and degranulation of mast cells (MCs) and eosinophils. In the lower airway, LXB4 significantly decreased airway inflammation, mucus metaplasia, and hyper-responsiveness. Inhibition of MC degranulation in vivo by LXB4 was more potent than dexamethasone, and these agents displayed unique profiles for cytokine regulation; however, their overall anti-inflammatory actions were comparable. LXB4 decreased eotaxin-dependent eosinophil chemotaxis, IgE-mediated MC degranulation, and expression of type 2 cytokine receptors. Together, these findings indicate that LXB4 carries cell type selective and mucosal protective actions that broaden the lipoxin family's therapeutic potential for upper and lower airway catabasis.
Assuntos
Lipoxinas/metabolismo , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Animais , Degranulação Celular/imunologia , Quimiotaxia de Leucócito/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Leucócitos/imunologia , Leucócitos/metabolismo , Leucócitos/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos , Muco/metabolismo , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Hipersensibilidade Respiratória/patologiaRESUMO
Acute lung injury (ALI) is a severe illness with excess mortality and no specific therapy. Protective actions were recently uncovered for docosahexaenoic acid-derived mediators, including D-series resolvins. Here, we used a murine self-limited model of hydrochloric acid-induced ALI to determine the effects of aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) on mucosal injury. RvD1 and its receptor ALX/FPR2 were identified in murine lung after ALI. AT-RvD1 (~0.5-5 µg kg(-1)) decreased peak inflammation, including bronchoalveolar lavage fluid (BALF) neutrophils by ~75%. Animals treated with AT-RvD1 had improved epithelial and endothelial barrier integrity and decreased airway resistance concomitant with increased BALF epinephrine levels. AT-RvD1 inhibited neutrophil-platelet heterotypic interactions by downregulating both P-selectin and its ligand CD24. AT-RvD1 also significantly decreased levels of BALF pro-inflammatory cytokines, including interleukin (IL)-1ß, IL-6, Kupffer cells, and tumor necrosis factor-α, and decreased nuclear factor-κB-phosphorylated p65 nuclear translocation. Taken together, these findings indicate that AT-RvD1 displays potent mucosal protection and promotes catabasis after ALI.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Ácidos Docosa-Hexaenoicos/metabolismo , Inflamação/metabolismo , Mucosa Respiratória/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Resistência das Vias Respiratórias , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , Plaquetas/metabolismo , Barreira Alveolocapilar/fisiopatologia , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/biossíntese , Epinefrina/metabolismo , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Leucócitos/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Neutrófilos/imunologia , Edema Pulmonar/imunologia , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Receptores de Formil Peptídeo/metabolismo , Mucosa Respiratória/patologia , Fator de Transcrição RelA/metabolismoRESUMO
Uncontrolled inflammation of the lung contributes to the major medical and economic burden on healthcare, and the need for therapeutics to dampen pathological inflammation is largely unmet. Recently, a new genus of anti-inflammatory/ pro-resolving lipid mediators has been identified: Lipoxins, resolvins, protectins and maresins. These compounds are enzymatically derived from the polyunsaturated fatty acids (PUFAs) arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) that have long been known to have beneficial health properties. These mediators have potent anti-inflammatory effects IN VITRO and IN VIVO in murine models of lung inflammation. Therefore, this group of compounds carries considerable therapeutic potential for the treatment of many inflammatory lung diseases including asthma, cystic fibrosis and acute lung injury.
Assuntos
Anti-Inflamatórios/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Pneumonia/tratamento farmacológico , Pneumonia/fisiopatologia , Pró-Fármacos/uso terapêutico , HumanosRESUMO
OBJECTIVE: CD4 and CD8 T-cell subsets accumulate in distinct microdomains within the inflamed rheumatoid synovium. The molecular basis for their differential distribution remains unclear. Since chemokines and adhesion molecules play an important role in the positioning of leucocytes at sites of inflammation, we tested the hypothesis that the differential expression and function of chemokine and/or adhesion molecules explains why CD4(+) T cells accumulate within perivascular cuffs, whereas CD8(+) T cells distribute diffusely within the tissue. METHODS: Expression of an extensive panel of chemokine receptors and adhesion molecules on matched CD4(+) and CD8(+) T cells from peripheral blood (PB) and synovial fluid (SF) was analysed by multicolour flow cytometry. Migration assays and flow-based adhesion assays were used to assess the functional consequences of any differences in the expression of chemokine and adhesion receptors. RESULTS: CD4(+) and CD8(+) T cells from PB and SF expressed unique yet consistent patterns of chemokine and adhesion receptors. SF CD8(+) T cells were much less promiscuous in their expression of chemokine receptors than SF CD4(+) T cells. The alpha(6)beta(1) integrin was highly expressed on PB CD4(+) T cells, but not on PB CD8(+) T cells. Laminin, the ligand for alpha(6)beta(1), retained CD4(+) T cells, but less so CD8(+) T cells, within inflamed synovial tissue. CONCLUSION: Infiltrating PB CD4(+) T cells, but not CD8(+) T cells, express functional levels of the alpha(6)beta(1) integrin. We propose that this leads to their retention within the rheumatoid synovium in perivascular cuffs, which are defined and delineated by the expression of laminin.
Assuntos
Artrite Reumatoide/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Integrina alfa6beta1/imunologia , Membrana Sinovial/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Integrina alfa6/metabolismo , Laminina/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Quimiocinas/metabolismo , Líquido Sinovial/imunologiaRESUMO
Acute inflammation in the lung is fundamentally important to host defence, but chronic or excessive inflammation leads to several common respiratory diseases, including asthma and acute respiratory distress syndrome. The resolution of inflammation is an active process. In health, events at the onset of acute inflammation establish biosynthetic circuits for specific chemical mediators that later serve as agonists to orchestrate a return to tissue homeostasis. In addition to an overabundance of pro-inflammatory stimuli, pathological inflammation can also result from defects in resolution signalling. The understanding of anti-inflammatory, pro-resolution molecules and their counter-regulatory signalling pathways is providing new insights into the molecular pathophysiology of lung disease and opportunities for the design of therapeutic strategies. In the present review, the growing family of lipid mediators of resolution is examined, including lipoxins, resolvins, protectins, cyclopentenones and presqualene diphosphate. Roles are uncovered for these compounds, or their structural analogues, in regulating airway inflammation.
Assuntos
Mediadores da Inflamação/imunologia , Inflamação/imunologia , Pneumopatias/imunologia , Animais , Apoptose , Antígenos CD59/biossíntese , Antígenos CD59/imunologia , Ciclopentanos/imunologia , Ácidos Docosa-Hexaenoicos/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Lipoxinas/biossíntese , Lipoxinas/imunologia , Pneumopatias/tratamento farmacológico , Pneumopatias/metabolismo , Pneumopatias/patologia , Fosfatos de Poli-Isoprenil/biossíntese , Fosfatos de Poli-Isoprenil/imunologiaRESUMO
The most surprising feature of the inflammatory response in rheumatoid arthritis is not that it occurs but that it does not resolve. The persistence of the chronic inflammatory response in conjunction with ongoing joint destruction is an all too familiar finding in many patients with rheumatoid arthritis. Despite the use of effective anti-inflammatory agents and disease modifying drugs, a significant proportion of patients with rheumatoid arthritis continue to have resistant disease. Complete clinical remission is unusual for more than six months and a formal cure of the disease remains elusive. In this report we focus on how attempts to address the question of why rheumatoid arthritis persists have led to a different interpretation of the pathogenesis of rheumatoid disease; one in which alterations in stromal cells such as fibroblasts play an important role in the switch from resolving to persistent disease.