RESUMO
RATIONALE AND OBJECTIVES: The minimal clinically important difference (MCID) and upper limit of normal (ULN) for MRI ventilation defect percent (VDP) were previously reported for hyperpolarized 3He gas MRI. Hyperpolarized 129Xe VDP is more sensitive to airway dysfunction than 3He, therefore the objective of this study was to determine the ULN and MCID for 129Xe MRI VDP in healthy and asthma participants. MATERIALS AND METHODS: We retrospectively evaluated healthy and asthma participants who underwent spirometry and 129XeMRI on a single visit; participants with asthma completed the asthma control questionnaire (ACQ-7). The MCID was estimated using distribution- (smallest detectable difference [SDD]) and anchor-based (ACQ-7) methods. Two observers measured VDP (semiautomated k-means-cluster segmentation algorithm) in 10 participants with asthma, five-times each in random order, to determine SDD. The ULN was estimated based on the 95% confidence interval of the relationships between VDP and age. RESULTS: Mean VDP was 1.6 ± 1.2% for healthy (n = 27) and 13.7 ± 12.9% for asthma participants (n = 55). ACQ-7 and VDP were correlated (r = .37, p = .006; VDP = 3.5·ACQ + 4.9). The anchor-based MCID was 1.75% while the mean SDD and distribution-based MCID was 2.25%. VDP was correlated with age for healthy participants (p = .56, p =.003; VDP = .04·Age-.01). The ULN for all healthy participants was 2.0%. By age tertiles, the ULN was 1.3% ages 18-39 years, 2.5% for 40-59 years and 3.8% for 60-79 years. CONCLUSION: The 129Xe MRI VDP MCID was estimated in participants with asthma; the ULN was estimated in healthy participants across a range of ages, both of which provide a way to interpret VDP measurements in clinical investigations.
Assuntos
Asma , Pulmão , Humanos , Lactente , Adolescente , Adulto Jovem , Adulto , Estudos Retrospectivos , Diferença Mínima Clinicamente Importante , Asma/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) often coexists with lower airway disease. With the overlap between upper and lower airway disease, optimal management of the upper airways is undertaken in conjunction with that of the lower airways. Biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of both upper and lower airway diseases. Knowledge gaps nevertheless exist in how best to approach patient care as a whole. There have been sixteen randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL- 5R, IL-33, and immunoglobulin (Ig)E. This white paper considers the perspectives of experts in various disciplines such as rhinology, allergy, and respirology across Canada, all of whom have unique and valuable insights to contribute on how to best approach patients with upper airway disease from a multidisciplinary perspective. METHODS: A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. A national multidisciplinary expert panel of 34 certified specialists was created, composed of 16 rhinologists, 7 allergists, and 11 respirologists who evaluated the 20 original statements on a scale of 1-9 and provided comments. All ratings were quantitively reviewed by mean, median, mode, range, standard deviation and inter-rater reliability. Consensus was defined by relative interrater reliability measures-kappa coefficient ([Formula: see text]) value > 0.61. RESULTS: After three rounds, a total of 22 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with upper airway disease. CONCLUSION: This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of upper airway disease from a multidisciplinary perspective, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years.
Assuntos
Produtos Biológicos , Pólipos Nasais , Rinite , Sinusite , Humanos , Produtos Biológicos/uso terapêutico , Canadá , Doença Crônica , Consenso , Técnica Delphi , Pólipos Nasais/metabolismo , Reprodutibilidade dos Testes , Rinite/tratamento farmacológico , Sinusite/tratamento farmacológicoRESUMO
BACKGROUND: We previously showed in patients with poorly controlled eosinophilic asthma that a single dose of benralizumab resulted in significantly improved Asthma Control Questionnaire (ACQ-6) score and 129Xe MRI ventilation defect percent (VDP) 28 days postinjection, and 129Xe MRI VDP and CT airway mucus occlusions were shown to independently predict this early ACQ-6 response to benralizumab. RESEARCH QUESTION: Do early VDP responses at 28 days persist, and do FEV1, fractional exhaled nitric oxide, and mucus plug score improve during a 2.5 year treatment period? STUDY DESIGN AND METHODS: Participants with poorly controlled eosinophilic asthma completed spirometry, ACQ-6, and MRI, 28 days, 1 year, and 2.5 years after initiation of treatment with benralizumab; chest CT was acquired at enrollment and 2.5 years later. RESULTS: Of 29 participants evaluated at 28 days post-benralizumab, 16 participants returned for follow-up while on therapy at 1 year, and 13 participants were evaluable while on therapy at 2.5 years post-benralizumab initiation. As compared with 28 days post-benralizumab, ACQ-6 score (2.0 ± 1.4) significantly improved after 1 year (0.5 ± 0.6, P = .02; 95% CI, 0.1-1.1) and 2.5 years (0.5 ± 0.5, P = .03; 95% CI, 0.1-1.1). The mean VDP change at 2.5 years (-4% ± 3%) was greater than the minimal clinically important difference, but not significantly different from VDP measured 28 days post-benralizumab. Mucus score (3 ± 4) was significantly improved at 2.5 years (1 ± 1, P = .03; 95% CI, 0.3-5.5). In six of eight participants with previous occlusions, mucus plugs vanished or substantially diminished 2.5 years later. VDP (P < .001) and mucus score (P < .001) measured at baseline, but not fractional exhaled nitric oxide or FEV1, independently predicted ACQ-6 score after 2.5 years. INTERPRETATION: In poorly controlled eosinophilic asthma, early MRI VDP responses at 28 days post-benralizumab persisted 2.5 years later, alongside significantly improved mucus scores and asthma control.
Assuntos
Obstrução das Vias Respiratórias , Antiasmáticos , Asma , Eosinofilia Pulmonar , Humanos , Óxido Nítrico , Asma/diagnóstico por imagem , Asma/tratamento farmacológico , Eosinofilia Pulmonar/tratamento farmacológico , Muco , Imageamento por Ressonância Magnética/métodos , Tomografia Computadorizada por Raios X , Antiasmáticos/uso terapêuticoRESUMO
BACKGROUND: Patients with eosinophilic asthma often report poor symptomatic control and quality of life. Anti-IL-5 therapy, including anti-IL-5Rα (benralizumab), rapidly depletes eosinophils in the blood and airways and also reduces asthma exacerbations and improves quality of life scores. In patients with severe asthma, eosinophilic inflammation-driven airway mucus occlusions have been measured using thoracic x-ray CT imaging. Pulmonary 129Xe MRI ventilation defect percentage (VDP) also sensitively measures asthma airway dysfunction caused by airway hyperresponsiveness, remodeling, and luminal mucus occlusions. Using 129Xe MRI and CT imaging together, it is feasible to measure both airway luminal occlusions and airway ventilation in relationship to anti-IL-5 therapy to ascertain the direct impact of therapy-induced eosinophil depletion on airway function. RESEARCH QUESTION: Does 129Xe MRI detect airway functional responses to eosinophil depletion after a single benralizumab dose and do airway mucus occlusions mediate this response? STUDY DESIGN AND METHODS: MRI, eosinophil count, spirometry, oscillometry, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ), and St. George's Respiratory Questionnaire were completed on day 0 and 28 days after a single 30-mg subcutaneous benralizumab dose. CT scan mucus plugs were scored on day 0, and MRI VDP was quantified on days 0 and 28. RESULTS: Twenty-nine participants (27 with baseline CT imaging) completed day 0 and day 28 visits. On day 28 after a single benralizumab dose, significantly improved blood eosinophil counts, VDP, ACQ 6 scores, AQLQ scores (all P < .001), and peripheral airway resistance (P = .04) were found in all participants. On day 28, significantly improved VDP and ACQ 6 scores also were found in the subgroup of nine participants with five or more mucus plugs, but not in the subgroup (n = 18) with fewer than five mucus plugs. Based on univariate relationships for change in ACQ 6 score, multivariate models were generated and showed that day 0 VDP (P < .001) and day 0 CT scan mucus score (P < .001) were significant variables for change in ACQ 6 score on day 28 after benralizumab injection. INTERPRETATION: 129Xe ventilation significantly improved in participants with uncontrolled asthma and in those with significant mucus plugging after a single dose of benralizumab. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03733535; URL: www. CLINICALTRIALS: gov.
Assuntos
Obstrução das Vias Respiratórias , Antiasmáticos , Asma , Eosinofilia Pulmonar , Manuseio das Vias Aéreas , Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados , Asma/tratamento farmacológico , Eosinófilos , Humanos , Imageamento por Ressonância Magnética/métodos , Muco , Eosinofilia Pulmonar/tratamento farmacológico , Qualidade de Vida , RespiraçãoRESUMO
Although abundant evidence exists that adverse events during pregnancy lead to chronic conditions, there is limited information on the impact of acute insults such as sepsis. This study tested the hypothesis that impaired fetal development leads to altered organ responses to a septic insult in both male and female adult offspring. Fetal growth restricted (FGR) rats were generated using a maternal protein-restricted diet. Male and female FGR and control diet rats were housed until 150-160 d of age when they were exposed either a saline (control) or a fecal slurry intraperitoneal (Sepsis) injection. After 6 h, livers and lungs were analyzed for inflammation and, additionally, the amounts and function of pulmonary surfactant were measured. The results showed increases in the steady-state mRNA levels of inflammatory cytokines in the liver in response to the septic insult in both males and females; these responses were not different between FGR and control diet groups. In the lungs, cytokines were not detectable in any of the experimental groups. A significant decrease in the relative amount of surfactant was observed in male FGR offspring, but this was not observed in control males or in female animals. Overall, it is concluded that FGR induced by maternal protein restriction does not impact liver and lung inflammatory response to sepsis in either male or female adult rats. An altered septic response in male FGR offspring with respect to surfactant may imply a contribution to lung dysfunction.
Assuntos
Dieta com Restrição de Proteínas/efeitos adversos , Sepse/fisiopatologia , Fenômenos Fisiológicos da Nutrição Animal , Animais , Dieta com Restrição de Proteínas/métodos , Modelos Animais de Doenças , Quebeque , Ratos , Ratos Wistar , Sepse/dietoterapiaRESUMO
BACKGROUND: Lung inflammation is associated with many respiratory conditions. Consequently, anti-inflammatory medications, like glucocorticoids, have become mainstay intrapulmonary therapeutics. However, their effectiveness for treating inflammation occurring in the alveolar regions of the lung is limited by suboptimal delivery. To improve the pulmonary distribution of glucocorticoids, such as budesonide to distal regions of the lung, exogenous surfactant has been proposed as an ideal delivery vehicle for such therapies. It was therefore hypothesized that fortifying an exogenous surfactant (BLES) with budesonide would enhance efficacy for treating pulmonary inflammation in vivo. METHODS: An intratracheal instillation of heat-killed bacteria was used to elicit an inflammatory response in the lungs of male and female rats. Thirty minutes after this initial instillation, either budesonide or BLES combined with budesonide was administered intratracheally. To evaluate the efficacy of surfactant delivery, various markers of inflammation were measured in the bronchoalveolar lavage and lung tissue. RESULTS: Although budesonide exhibited anti-inflammatory effects when administered alone, delivery with BLES enhanced those effects by lowering the lavage neutrophil counts and myeloperoxidase activity in lung tissue. Combining budesonide with BLES was also shown to reduce several other pro-inflammatory mediators. These results were shown across both sexes, with no observed sex differences. CONCLUSION: Based on these findings, it was concluded that exogenous surfactant can enhance the delivery and efficacy of budesonide in vivo.
Assuntos
Produtos Biológicos/administração & dosagem , Budesonida/administração & dosagem , Glucocorticoides/administração & dosagem , Pneumonia/tratamento farmacológico , Surfactantes Pulmonares/administração & dosagem , Animais , Modelos Animais de Doenças , Feminino , Masculino , Veículos Farmacêuticos , Pneumonia/etiologia , Ratos , Ratos WistarAssuntos
Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , COVID-19 , Canadá , Humanos , Retorno ao Trabalho , SARS-CoV-2RESUMO
The rising incidence of antibiotic-resistant lung infections has instigated a much-needed search for new therapeutic strategies. One proposed strategy is the use of exogenous surfactants to deliver antimicrobial peptides (AMPs), like CATH-2, to infected regions of the lung. CATH-2 can kill bacteria through a diverse range of antibacterial pathways and exogenous surfactant can improve pulmonary drug distribution. Unfortunately, mixing AMPs with commercially available exogenous surfactants has been shown to negatively impact their antimicrobial function. It was hypothesized that the phosphatidylglycerol component of surfactant was inhibiting AMP function and that an exogenous surfactant, with a reduced phosphatidylglycerol composition would increase peptide mediated killing at a distal site. To better understand how surfactant lipids interacted with CATH-2 and affected its function, isothermal titration calorimetry and solid-state nuclear magnetic resonance spectroscopy as well as bacterial killing curves against Pseudomonas aeruginosa were utilized. Additionally, the wet bridge transfer system was used to evaluate surfactant spreading and peptide transport. Phosphatidylglycerol was the only surfactant lipid to significantly inhibit CATH-2 function, showing a stronger electrostatic interaction with the peptide than other lipids. Although diluting the phosphatidylglycerol content in an existing surfactant, through the addition of other lipids, significantly improved peptide function and distal killing, it also reduced surfactant spreading. A synthetic phosphatidylglycerol-free surfactant however, was shown to further improve CATH-2 delivery and function at a remote site. Based on these in vitro experiments synthetic phosphatidylglycerol-free surfactants seem optimal for delivering AMPs to the lung.
Assuntos
Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Peptídeos Catiônicos Antimicrobianos/química , Galinhas/metabolismo , Surfactantes Pulmonares/química , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/química , Sistemas de Liberação de Medicamentos/métodos , Excipientes/química , Lipídeos/química , Pulmão/efeitos dos fármacos , Fosfatidilgliceróis/química , Pseudomonas aeruginosa/efeitos dos fármacosRESUMO
Limited information is available on how fetal growth retardation (FGR) affects the lung in the neonatal period in males and females. This led us to test the hypothesis that FGR alters lung mechanics and the surfactant system during the neonatal period. To test this hypothesis a model of FGR was utilized in which pregnant rat dams were fed a low protein diet during both the gestation and lactation period. We subsequently analyzed lung mechanics using a FlexiVent ventilator in male and female pups at postnatal day 7 and 21. Lung lavage material was obtained at postnatal day 1, 7 and 21, and was used for analysis of the surfactant system which included measurement of the pool size of surfactant and its subfraction as well as the surface tension reducing ability of the surfactant. The main result of the study was a significantly lower lung compliance and higher tissue elastance which was observed in FGR female offspring at day 21 compared to control offspring. In addition, female LP offspring exhibited lower surfactant pool sizes at postnatal day 1compared to controls. These changes were not observed in the male offspring. It is concluded that FGR has a different impact on pulmonary function and on surfactant in female, as compared to male, offspring.
Assuntos
Fenômenos Fisiológicos da Nutrição Animal/fisiologia , Dieta com Restrição de Proteínas/efeitos adversos , Retardo do Crescimento Fetal/fisiopatologia , Surfactantes Pulmonares/metabolismo , Mecânica Respiratória/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Retardo do Crescimento Fetal/etiologia , Lactação , Pulmão/crescimento & desenvolvimento , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Gravidez , Ratos Wistar , Fatores SexuaisRESUMO
Due to its branching structure, drug delivery to the peripheral areas of the lung is a major challenge. Consequently, most pulmonary therapies utilize large systemic dosing, with the potential for adverse side effects. One proposed strategy to overcome this challenge is to use exogenous surfactant, a material capable of distributing throughout the lung, as a pulmonary drug delivery vehicle. The objective was to develop and test an in vitro system to rapidly assess surfactant based therapies prior to animal studies. The Wet Bridge Transfer System consisted of two connected wells in which drugs were instilled into a delivery well and function was tested in a remote well which mimicked the remote areas of the lung where drug activity would be required. The system was used to assess surfactant as a carrier for antibiotics (Gentamicin, Ciprofloxacin, and Colistin) by measuring their ability to kill Pseudomonas aeruginosa bacteria in the remote well. Anti-inflammatory agents (Budesonide and a host defense peptide, CATH-2) with and without exogenous surfactant were examined using stimulated macrophages in the remote well and IL-6 concentration as an outcome. The results showed that being paired with surfactant, Gentamicin and Ciprofloxacin, but not Colistin, had significantly greater bacterial killing in the remote wells. Similarly, when combined with a surfactant, both Budesonide and CATH-2 significantly lowered IL-6 concentrations. We conclude that the wet-bridge system can be used to rapidly screen surfactant-based therapies prior to their assessment in vivo. Furthermore, exogenous surfactant was an effective delivery vehicle for several antimicrobial and anti-inflammatory therapeutics.
Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Pulmão/efeitos dos fármacos , Surfactantes Pulmonares/administração & dosagem , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Camundongos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Surfactantes Pulmonares/farmacocinética , Células RAW 264.7RESUMO
Cystic fibrosis (CF) is characterized by recurrent airway infections with antibiotic-resistant bacteria and chronic inflammation. Chicken cathelicin-2 (CATH-2) has been shown to exhibit antimicrobial activity against antibiotic-resistant bacteria and to reduce inflammation. In addition, exogenous pulmonary surfactant has been suggested to enhance pulmonary drug delivery. It was hypothesized that CATH-2 when combined with an exogenous surfactant delivery vehicle, bovine lipid extract surfactant (BLES), would exhibit antimicrobial activity against CF-derived bacteria and downregulate inflammation. Twelve strains of CF-pathogens were exposed to BLES+CATH-2 in vitro and killing curves were obtained to determine bactericidal activity. Secondly, heat-killed bacteria were administered in vivo to elicit a pro-inflammatory response with either a co-administration or delayed administration of BLES+CATH-2 to assess the antimicrobial-independent, anti-inflammatory properties of BLES+CATH-2. CATH-2 alone exhibited potent antimicrobial activity against all clinical strains of antibiotic-resistant bacteria, while BLES+CATH-2 demonstrated a reduction, but significant antimicrobial activity against bacterial isolates. Furthermore, BLES+CATH-2 reduced inflammation in vivo when either co-administered with killed bacteria or after delayed administration. The use of a host-defense peptide combined with an exogenous surfactant compound, BLES+CATH-2, is shown to exhibit antimicrobial activity against antibiotic-resistant CF bacterial isolates and reduce inflammation.
Assuntos
Achromobacter denitrificans/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos/farmacologia , Produtos Biológicos/farmacologia , Fibrose Cística/terapia , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Adulto , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Doença Crônica , Fibrose Cística/microbiologia , Farmacorresistência Bacteriana , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Surfactantes Pulmonares/farmacologia , Doenças Respiratórias/microbiologia , Tensoativos/farmacologiaRESUMO
The development of antibiotic resistance by Pseudomonas aeruginosa is a major concern in the treatment of bacterial pneumonia. In the search for novel anti-infective therapies, the chicken-derived peptide cathelicidin-2 (CATH-2) has emerged as a potential candidate, with strong broad-spectrum antimicrobial activity and the ability to limit inflammation by inhibiting Toll-like receptor 2 (TLR2) and TLR4 activation. However, as it is unknown how CATH-2 affects inflammation in vivo, we investigated how CATH-2-mediated killing of P. aeruginosa affects lung inflammation in a murine model. First, murine macrophages were used to determine whether CATH-2-mediated killing of P. aeruginosa reduced proinflammatory cytokine production in vitro Next, a murine lung model was used to analyze how CATH-2-mediated killing of P. aeruginosa affects neutrophil and macrophage recruitment as well as cytokine/chemokine production in the lung. Our results show that CATH-2 kills P. aeruginosa in an immunogenically silent manner both in vitro and in vivo Treatment with CATH-2-killed P. aeruginosa showed reduced neutrophil recruitment to the lung as well as inhibition of cytokine and chemokine production, compared to treatment with heat- or gentamicin-killed bacteria. Together, these results show the potential for CATH-2 as a dual-activity antibiotic in bacterial pneumonia, which can both kill P. aeruginosa and prevent excessive inflammation.
Assuntos
Peptídeos Catiônicos Antimicrobianos/imunologia , Inflamação/prevenção & controle , Pulmão/microbiologia , Pneumonia Bacteriana/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Peptídeos Catiônicos Antimicrobianos/farmacologia , Linhagem Celular , Quimiocinas/imunologia , Galinhas/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Imunidade Inata , Inflamação/imunologia , Pulmão/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Pneumonia Bacteriana/prevenção & controle , Infecções por Pseudomonas/veterináriaRESUMO
Alterations to the pulmonary surfactant system have been observed consistently in ventilation-induced lung injury (VILI) including composition changes and impairments in the surface tension reducing ability of the isolated extracellular surfactant. However, there is limited information about the effects of VILI on the intracellular form of surfactant, the lamellar body. It is hypothesized that VILI leads to alterations of lamellar body numbers and function. To test this hypothesis, rats were randomized to one of three groups, nonventilated controls, control ventilation, and high tidal volume ventilation (VILI). Following physiological assessment to confirm lung injury, isolated lamellar bodies were tested for surfactant function on a constrained sessile drop surfactometer. A separate cohort of animals was used to fix the lungs followed by examination of lamellar body numbers and morphology using transmission electron microscopy. The results showed an impaired ability of reducing surface tension for the lamellar bodies isolated from the VILI group as compared with the two other groups. The morphological assessment revealed that the number, and the relative area covered by, lamellar bodies were significantly decreased in animals with VILI animals as compared with the other groups. It is concluded that VILI causes significant alterations to lamellar bodies. It is speculated that increased secretion causes a depletion of lamellar bodies that cannot be compensated by de novo synthesis of surfactant in these injured lungs.
Assuntos
Lisossomos/patologia , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/ultraestrutura , Animais , Colesterol/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Lisossomos/efeitos dos fármacos , Lisossomos/ultraestrutura , Masculino , Oxigênio/metabolismo , Fosfolipídeos/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Surfactantes Pulmonares/farmacologia , Ratos Sprague-Dawley , Tensão Superficial/efeitos dos fármacos , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologiaRESUMO
Acute respiratory distress syndrome (ARDS) is a disease with a variety of causes and is defined by severe hypoxemia. Whereas ARDS carries a mortality of approximately 30 %, patients that survive may ultimately regain near normal pulmonary physiology. The critical pathophysiological processes in ARDS are alveolar barrier dysfunction and overwhelming inflammation. This encompasses damage to the epithelial and endothelial layers, thickening of the interstitial matrix, edema with inactivation of pulmonary surfactant at the alveolar surface and marked inflammation mediated by infiltrating neutrophils and pro-inflammatory macrophages. For patients that survive the disease, these are the critical processes that require repair and remodeling to allow for the recovery of ARDS. As such, the current review focuses on the experimental studies that have begun to elucidate the mechanisms involved in restoring the alveolar barrier following injury.
Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Pulmão/fisiopatologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/terapia , Animais , Humanos , Pulmão/patologia , Modelos Biológicos , Regeneração , Resultado do TratamentoRESUMO
BACKGROUND: The acute respiratory distress syndrome (ARDS) is a complex pulmonary disorder in which the local release of cytokines and chemokines appears central to the pathophysiology. OBJECTIVE: Based on the known role of matrix metalloproteinase-3 (MMP3) in inflammatory processes, the objective was to examine the role of MMP3 in the pathogenesis of ARDS through the modulation of pulmonary inflammation. MATERIALS AND METHODS: Female and male, wild type (MMP3+/+) and knock out (MMP3-/-) mice were exposed to two, clinically relevant models of ARDS including (i) lipopolysaccharide (LPS)-induced lung injury, and (ii) hydrochloric acid-induced lung injury. Parameters of lung injury and inflammation were assessed through measurements in lung lavage including total protein content, inflammatory cell influx, and concentrations of mediators such as TNF-α, IL-6, G-CSF, CXCL1, CXCL2, and CCL2. Lung histology and compliance were also evaluated in the LPS model of injury. RESULTS: Following intra-tracheal LPS instillation, all mice developed lung injury, as measured by an increase in lavage neutrophils, and decrease in lung compliance, with no overall effect of genotype observed. Increased concentrations of lavage inflammatory cytokines and chemokines were also observed following LPS injury, however, LPS-instilled female MMP3-/- mice had lower levels of inflammatory mediators compared to LPS-instilled female MMP3+/+ mice. This effect of the genotype was not observed in male mice. Similar findings, including the MMP3-related sex differences, were also observed after acid-induced lung injury. CONCLUSION: MMP3 contributes to the pathogenesis of ARDS, by affecting the pulmonary inflammatory response in female mice in relevant models of lung injury.
Assuntos
Metaloproteinase 3 da Matriz/farmacologia , Pneumonia/induzido quimicamente , Síndrome do Desconforto Respiratório/etiologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Feminino , Humanos , Ácido Clorídrico/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Metaloproteinase 3 da Matriz/genética , Camundongos , Fatores SexuaisRESUMO
The acute respiratory distress syndrome (ARDS) is characterized by arterial hypoxemia accompanied by severe inflammation and alterations to the pulmonary surfactant system. Published data has demonstrated a protective effect of matrix metalloproteinase-3 (Mmp3) deficiency against the inflammatory response associated with ARDS; however, the effect of Mmp3 on physiologic parameters and alterations to surfactant have not been previously studied. It was hypothesized that Mmp3 deficient (Mmp3(-/-)) mice would be protected against lung dysfunction associated with ARDS and maintain a functional pulmonary surfactant system. Wild type (WT) and Mmp3(-/-) mice were subjected to acid-aspiration followed by mechanical ventilation. Mmp3(-/-) mice maintained higher arterial oxygenation compared with WT mice at the completion of ventilation. Significant increase in functional large aggregate surfactant forms were observed in Mmp3(-/-) mice compared with WT mice. These findings further support a role of Mmp3 as an attractive therapeutic target for drug development in the setting of ARDS.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Modelos Animais de Doenças , Metaloproteinase 3 da Matriz/deficiência , Surfactantes Pulmonares/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distribuição Aleatória , Síndrome do Desconforto Respiratório/patologiaRESUMO
Acute respiratory distress syndrome (ARDS) is a pulmonary disorder associated with alterations to the pulmonary surfactant system. Recent studies showed that supra-physiological levels of cholesterol in surfactant contribute to impaired function. Since cholesterol is incorporated into surfactant within the alveolar type II cells which derives its cholesterol from serum, it was hypothesized that serum hypercholesterolemia would predispose the host to the development of lung injury due to alterations of cholesterol content in the surfactant system. Wistar rats were randomized to a standard lab diet or a high cholesterol diet for 17-20 days. Animals were then exposed to one of three models of lung injury: i) acid aspiration ii) ventilation induced lung injury, and iii) surfactant depletion. Following physiological monitoring, lungs were lavaged to obtain and analyze the surfactant system. The physiological results showed there was no effect of the high cholesterol diet on the severity of lung injury in any of the three models of injury. There was also no effect of the diet on surfactant cholesterol composition. Rats fed a high cholesterol diet had a significant impairment in surface tension reducing capabilities of isolated surfactant compared to those fed a standard diet exposed to the surfactant depletion injury. In addition, only rats that were exposed to ventilation induced lung injury had elevated levels of surfactant associated cholesterol compared to non-injured rats. It is concluded that serum hypercholesterolemia does not predispose rats to altered surfactant cholesterol composition or to lung injury. Elevated cholesterol within surfactant may be a marker for ventilation induced lung damage.
RESUMO
Antibiotic-resistant bacterial infections represent an emerging health concern in clinical settings, and a lack of novel developments in the pharmaceutical pipeline is creating a "perfect storm" for multidrug-resistant bacterial infections. Antimicrobial peptides (AMPs) have been suggested as future therapeutics for these drug-resistant bacteria, since they have potent broad-spectrum activity, with little development of resistance. Due to the unique structure of the lung, bacterial pneumonia has the additional problem of delivering antimicrobials to the site of infection. One potential solution is coadministration of AMPs with exogenous surfactant, allowing for distribution of the peptides to distal airways and opening of collapsed lung regions. The objective of this study was to test various surfactant-AMP mixtures with regard to maintaining pulmonary surfactant biophysical properties and bactericidal functions. We compared the properties of four AMPs (CATH-1, CATH-2, CRAMP, and LL-37) suspended in bovine lipid-extract surfactant (BLES) by assessing surfactant-AMP mixture biophysical and antimicrobial functions. Antimicrobial activity was tested against methillicin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. All AMP/surfactant mixtures exhibited an increase of spreading compared to a BLES control. BLES+CATH-2 mixtures had no significantly different minimum surface tension versus the BLES control. Compared to the other cathelicidins, CATH-2 retained the most bactericidal activity in the presence of BLES. The BLES+CATH-2 mixture appears to be an optimal surfactant-AMP mixture based on in vitro assays. Future directions involve investigating the potential of this mixture in animal models of bacterial pneumonia.