RESUMEN
Purpose: Pulmonary surfactant proteins A (SP-A) and D (SP-D) are lectins, involved in host defense and regulation of pulmonary inflammatory response. However, studies on the assessment of COPD progress are limited. Patients and Methods: Pulmonary surfactant proteins were obtained from the COPD mouse model induced by cigarette and lipopolysaccharide, and the specimens of peripheral blood and bronchoalveolar lavage (BALF) in COPD populations. H&E staining and RT-PCR were performed to demonstrate the successfully established of the mouse model. The expression of SP-A and SP-D in mice was detected by Western Blot and immunohistochemistry, while the proteins in human samples were measured by ELISA. Pulmonary function test, inflammatory factors (CRP, WBC, NLR, PCT, EOS, PLT), dyspnea index score (mMRC and CAT), length of hospital stay, incidence of complications and ventilator use were collected to assess airway remodeling and progression of COPD. Results: COPD model mice with emphysema and airway wall thickening were more prone to have decreased SP-A, SP-D and increased TNF-α, TGF-ß, and NF-kb in lung tissue. In humans, SP-A and SP-D decreased in BALF, but increased in serum. The serum SP-A and SP-D were negatively correlated with FVC, FEV1, FEV1/FVC, and positively correlated with CRP, WBC, NLR, mMRC and CAT scores (P < 0.05, respectively). The lower the SP-A and SP-D in BALF, the worse the lung function and the increased probability of complications and ventilator use. Moreover, the same trend emerged in COPD patients grouped according to GOLD severity grade (Gold 1-2 group vs Gold 3-4 group). The worse the patient's condition, the more pronounced the change. Conclusion: This study suggests that SP-A and SP-D may be related to the progression and prognostic evaluation of COPD in terms of airway remodeling, inflammatory response and clinical symptoms, and emphasizes the necessity of future studies of surfactant protein markers in COPD.
Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica , Surfactantes Pulmonares , Remodelación de las Vías Aéreas (Respiratorias) , Animales , Biomarcadores , Ratones , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Proteína A Asociada a Surfactante Pulmonar/uso terapéutico , Proteína D Asociada a Surfactante Pulmonar/análisis , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Surfactantes Pulmonares/uso terapéuticoRESUMEN
Surfactant protein D (SP-D) is a collectin protein synthesized by alveolar type II cells in the lungs. SP-D participates in the innate immune defense of the lungs by helping to clear infectious pathogens and modulating the immune response. SP-D has shown an anti-inflammatory role by down-regulating the release of pro-inflammatory mediators in different signaling pathways such as the TLR4, decreasing the recruitment of inflammatory cells to the lung, and modulating the oxidative metabolism in the lungs. Recombinant human SP-D (rhSP-D) has been successfully produced mimicking the structure and functions of native SP-D. Several in vitro and in vivo experiments using different animal models have shown that treatment with rhSP-D reduces the lung inflammation originated by different insults, and that rhSP-D could be a potential treatment for bronchopulmonary dysplasia (BPD), a rare disease for which there is no effective therapy up to date. BPD is a complex disease in preterm infants whose incidence increases with decreasing gestational age at birth. Lung inflammation, which is caused by different prenatal and postnatal factors like infections, lung hyperoxia and mechanical ventilation, among others, is the key player in BPD. Exacerbated inflammation causes lung tissue injury that results in a deficient gas exchange in the lungs of preterm infants and frequently leads to long-term chronic lung dysfunction during childhood and adulthood. In addition, low SP-D levels and activity in the first days of life in preterm infants have been correlated with a worse pulmonary outcome in BPD. Thus, SP-D mediated functions in the innate immune response could be critical aspects of the pathogenesis in BPD and SP-D could inhibit lung tissue injury in this preterm population. Therefore, administration of rhSP-D has been proposed as promising therapy that could prevent BPD.
Asunto(s)
Células Epiteliales Alveolares/efectos de los fármacos , Displasia Broncopulmonar/tratamiento farmacológico , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Fármacos del Sistema Respiratorio/uso terapéutico , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Animales , Displasia Broncopulmonar/diagnóstico , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/fisiopatología , Humanos , Mediadores de Inflamación/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Proteína D Asociada a Surfactante Pulmonar/metabolismo , Proteínas Recombinantes/uso terapéutico , Transducción de SeñalRESUMEN
Preterm infants, particularly those who born between 23 and 28 weeks' gestation, suffer from a very high incidence of respiratory distress syndrome (RDS) related to pulmonary immaturity and inability to make Pulmonary Surfactant (PS). These infants are supported by the use of oxygen, ventilators, and routine administration of surfactant replacement. The currently commercial surfactant replacement therapies do not contain hydrophilic surfactant proteins such as Surfactant Protein D (SP-D). These proteins have a key role in the innate lung host defense, thus the development of a sustained release vehicle that provides SP-D for long periods in preterm infants' lungs would exploit the therapeutic potential of SP-D and other pulmonary medications. The proposed SP-D delivery system is based on nanoparticles (NPs) composed of poly (lactic acid-co-glycolic acid) (PLGA), a biodegradable, FDA approved biopolymer. The resulted NPs were spherical with high Zeta potential value, were not toxic to A-549 lungs cells, and did not induce any inflammatory response in mouse's lungs for short and long-term periods. Moreover, SP-D released from NPs showed biological activity for several days and in vivo release experiment of SP-D loaded NPs revealed that SP-D was released from NPs in mouse lungs with different NPs delivery doses.
Asunto(s)
Portadores de Fármacos/administración & dosificación , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Proteína D Asociada a Surfactante Pulmonar/administración & dosificación , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Animales , Línea Celular , Química Farmacéutica/métodos , Portadores de Fármacos/uso terapéutico , Estabilidad de Medicamentos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Recién Nacido , Recien Nacido Prematuro , Ratones , Ratones Endogámicos C57BL , Tamaño de la Partícula , Proteína D Asociada a Surfactante Pulmonar/uso terapéuticoRESUMEN
The objective of this study is to investigate the mechanism whereby innate immune molecule surfactant protein D (SP-D) attenuates sepsis-induced acute kidney injury (AKI) through modulating apoptosis and nuclear factor kappa-B (NFκB)-mediated inflammation. In the present study, a mouse sepsis model was established by cecal ligation and puncture in SP-D knockout (KO) mice and wild-type (WT) mice. A sham-operated group was included as the control. The experimental materials were extracted 6 and 24 hours postoperatively. The plasma levels of tumour necrosis factor alpha (TNF-α) and MCP-1 were determined by enzyme-linked immunosorbent assay (ELISA). Apoptosis was measured by double staining with Annexin V/propidium iodide and flow cytometry. The levels of NFκB in renal tissues were measured by ELISA and Western blotting assay. Apoptosis was detected by TUNEL assays. There were no significant differences in plasma TNF-α levels between the WT sham group and the KO sham group at 6 and 24 hours postoperatively (P < .05), but the levels of TNF-α in the WT sepsis and KO sepsis groups were significantly higher than those in controls (P < .05). The levels of TNF-α in the KO sepsis group were significantly higher than those of the WT sepsis group (P < .05). TNF-α levels in the WT sepsis group and the KO sepsis group at 24 hours postoperatively were significantly higher than those at 6 hours postoperatively (P < .05). The levels of MCP-1 in the WT sepsis group and the KO sepsis group at 6 and 24 hours postoperatively were significantly higher than those in the control group (P < .05), and MCP-1 levels in the KO sepsis group were significantly higher than those in the WT sepsis group (P < .05). MCP-1 levels in the WT sepsis group and the KO sepsis group at 24 hours postoperatively were significantly higher than those at 6 hours postoperatively (P < .05). The expression of SP-D in WT kidneys was significantly lower at 6 and 24 hours postoperatively (P < .05). The number of TUNEL-positive cells in the kidneys from septic SP-D KO mice was significantly higher (P < .05). The levels of NFκB in septic mice were significantly increased at 6 and 24 hours after induction of sepsis compared with the sham-operated group compared with those of septic SP-D KO mice and WT mice (P < .05). Innate immune molecule SP-D significantly decreased plasma levels of inflammatory cytokines in mice and attenuated sepsis-induced AKI by inhibiting NFκB activity and apoptosis.
Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/inmunología , Apoptosis/efectos de los fármacos , Inflamación/inmunología , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Surfactantes Pulmonares/uso terapéutico , Sepsis/complicaciones , Animales , Modelos Animales de Enfermedad , Inmunidad Innata/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , FN-kappa B/inmunologíaRESUMEN
BACKGROUND: Surfactant protein D (SPD) is a member of the collectin family that lines the airway epithelial cells with host defense. However, the role of SPD in the pathogenesis of aspirin-exacerbated respiratory disease (AERD) is still unclear. METHODS: The serum SPD level was measured in patients with AERD (n = 336), those with aspirin-tolerant asthma (ATA, n = 442), and healthy controls (HC, n = 104). Polymorphisms of SFTPD in the study subjects were analyzed. The effect of LTE4 on SPD production through eosinophil infiltration was investigated in BALB/c mice. The protective function of SPD against eosinophils inducing inflammation and remodeling was assessed in vitro/vivo. The potential efficacy of nintedanib against airway remodeling through the production of SPD was evaluated. RESULTS: The serum SPD level was significantly lower (P < .001) in AERD compared with ATA patients, and negatively correlated with fall in FEV1 (%) after lysine-aspirin bronchoprovocation test and/or the urinary LTE4 level. In addition, polymorphism of SFTPD at rs721917 was significantly different in the study subjects (odds ratio, 1.310; 95% confidence intervals, 2.124-3.446; P = .002). LTE4-exposed mice showed an increased eosinophil count with a decreased SPD level in bronchoalveolar lavage fluid. Eosinophils increased α-smooth muscle actin expression in airway epithelial cells, which was attenuated by SPD treatment. Furthermore, nintedanib protected the airway epithelial cells against eosinophils by enhancing the production of SPD. CONCLUSION: The decreased level of SPD in AERD was associated with airway inflammation/remodeling under the eosinophilic condition, suggesting that modulation of SPD may provide a potential benefit in AERD.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Asma Inducida por Aspirina/sangre , Eosinófilos/inmunología , Inflamación/tratamiento farmacológico , Proteína D Asociada a Surfactante Pulmonar/farmacología , Sistema Respiratorio/patología , Adulto , Animales , Asma Inducida por Aspirina/tratamiento farmacológico , Eosinófilos/efectos de los fármacos , Femenino , Humanos , Indoles/farmacología , Indoles/uso terapéutico , Inflamación/patología , Leucotrieno E4/farmacología , Leucotrieno E4/orina , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Proteína D Asociada a Surfactante Pulmonar/sangre , Proteína D Asociada a Surfactante Pulmonar/genética , Proteína D Asociada a Surfactante Pulmonar/uso terapéuticoRESUMEN
BACKGROUND: Periventricular leukomalacia (PVL) is the leading cause of neurocognitive deficits in children with prematurity. We previously hypothesized that surfactant protein D (SPD) with its ability to bind toll-like receptors may have a possible ameliorating effect in PVL. METHODS: Three groups were defined as: LPS-administered and postnatal intranasal saline administered group, LPS-administered and postnatal intranasal SPD-treated group, and control group. Twenty-eight offspring rats were reared with their dams until their sacrifice for histological evaluation on day 7. RESULTS: A significant loss of brain weight occurred in the LPS group compared with controls. The postnatal intranasal SPD treatment significantly reduced the number of TUNEL-positive cells in the periventricular white matter as compared with the LPS-treated group. Compared with the control group, LPS injection in the rat brain significantly reduced the MBP-positive staining. Postnatal SPD treatment greatly prevented LPS-stimulated loss of MBP staining. CONCLUSIONS: Present study demonstrated a neuroprotective effect of SPD in a rat model of PVL. Our results offer future implications towards increasing our understanding about multifactorial mechanisms underlying periventricular leukomalacia and developing plausible therapeutic strategies in order to prevent neurocognitive deficits in preterm infants.
Asunto(s)
Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Leucomalacia Periventricular/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Administración Intranasal , Animales , Animales Recién Nacidos , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Modelos Animales de Enfermedad , Femenino , Leucomalacia Periventricular/patología , Fármacos Neuroprotectores/metabolismo , Embarazo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Método Simple Ciego , Estadísticas no ParamétricasRESUMEN
Surfactant protein D (SP-D) is a pulmonary collectin important in lung immunity. SP-D-deficient mice (Sftpd(-/-)) are reported to be susceptible to ovalbumin (OVA)- and fungal allergen-induced pulmonary inflammation, while treatment with exogenous SP-D has therapeutic effects in such disease models. ß-Glucans are a diverse group of polysaccharides previously suggested to serve as fungal ligands for SP-D. We set out to investigate if SP-D could interact with 1,3-ß-glucan and attenuate allergic pulmonary inflammation in the presence of 1,3-ß-glucan. Allergic airway disease was induced in Sftpd(-/-) and Sftpd(+/+) mice by OVA sensitization and subsequent challenge with OVA, 1,3-ß-glucan, or OVA/1,3-ß-glucan together. Mice in the combined treatment group were further treated with a high dose of recombinant fragment of human SP-D (rfhSP-D). We demonstrated direct interaction between SP-D and 1,3-ß-glucan. OVA-induced mucous cell metaplasia was increased in Sftpd(-/-) mice, supporting previously reported protective effects of endogenous SP-D in allergy. OVA-induced parenchymal CCL11 levels and eosinophilic infiltration in bronchoalveolar lavage were unaffected by 1,3-ß-glucan, but were reversed with rfhSP-D treatment. 1,3-ß-Glucan treatment did, however, induce pulmonary neutrophilic infiltration and increased TNF-α levels in bronchoalveolar lavage, independently of OVA-induced allergy. This infiltration was also reversed by treatment with rfhSP-D. 1,3-ß-Glucan reduced OVA-induced mucous cell metaplasia, T helper 2 cytokines, and IFN-γ production. rfhSP-D treatment further reduced mucous metaplasia and T helper 2 cytokine secretion to background levels. In summary, rfhSP-D treatment resulted in attenuation of both allergic inflammation and 1,3-ß-glucan-mediated neutrophilic inflammation. Our data suggest that treatment with high-dose SP-D protects from mold-induced exacerbations of allergic asthma.
Asunto(s)
Hipersensibilidad/complicaciones , Hipersensibilidad/tratamiento farmacológico , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , beta-Glucanos/metabolismo , Animales , Quimiocina CCL11/metabolismo , Citocinas/metabolismo , Femenino , Humanos , Hipersensibilidad/patología , Inmunoglobulina E/metabolismo , Inflamación/patología , Ligandos , Metaplasia , Ratones Endogámicos C57BL , Microbiota/efectos de los fármacos , Ovalbúmina , Sustancias Protectoras/farmacología , Proteoglicanos , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/patología , Proteína D Asociada a Surfactante Pulmonar/farmacología , Hipersensibilidad Respiratoria/complicacionesRESUMEN
In the recent years, a large number of potential biomarkers for Chronic Obstructive Pulmonary Disease (COPD) have been described. One of the important biomarkers is Surfactant Protein D (SPD) since serum SPD levels have been associated with lung function or health status in patients with severe COPD. Several interesting evidences of the protein and gene polymorphisms have been described. The present review highlights the current literature, recent patents and, future prospects of this important collection.
Asunto(s)
Patentes como Asunto , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Proteína D Asociada a Surfactante Pulmonar/sangre , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Biomarcadores/sangre , Humanos , Modelos Biológicos , Polimorfismo Genético , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Proteína D Asociada a Surfactante Pulmonar/genética , Proteína D Asociada a Surfactante Pulmonar/fisiologíaRESUMEN
Influenza A viruses (IAV) cause respiratory tract infections annually associated with excess mortality and morbidity. Nonspecific, innate immune mechanisms play a key role in protection against viral invasion at early stages of infection. A soluble protein present in mucosal secretions of the lung, surfactant protein D (SP-D), is an important component of this initial barrier that helps to prevent and limit IAV infections of the respiratory epithelium. This collagenous C-type lectin binds IAVs and thereby inhibits attachment and entry of the virus but also contributes to enhanced clearance of SP-D-opsonized virus via interactions with phagocytic cells. In addition, SP-D modulates the inflammatory response and helps to maintain a balance between effective neutralization/killing of IAV, and protection against alveolar damage resulting from IAV-induced excessive inflammatory responses. The mechanisms of interaction between SP-D and IAV not only depend on the structure and binding properties of SP-D but also on strain-specific features of IAV, and both issues will be discussed. SP-D from pigs exhibits distinct anti-IAV properties and is discussed in more detail. Finally, the potential of SP-D as a prophylactic and/or therapeutic antiviral agent to protect humans against infections by IAV is discussed.
Asunto(s)
Inmunidad Innata , Virus de la Influenza A/inmunología , Gripe Humana/inmunología , Fagocitos/inmunología , Alveolos Pulmonares/inmunología , Proteína D Asociada a Surfactante Pulmonar/inmunología , Animales , Antivirales/inmunología , Antivirales/uso terapéutico , Humanos , Gripe Humana/prevención & control , Alveolos Pulmonares/virología , Proteína D Asociada a Surfactante Pulmonar/uso terapéuticoRESUMEN
Activation of microglia with an inflammatory insult, which plays a central role in periventricular leukomalacia (PVL), results in premyelinating oligodendrocyte death via release of certain cytokines, reactive oxygen and nitrogen species. Toll-like receptor (TLR) 4 is necessary for lipopolysaccharide (LPS) induced oligodenrocyte injury in the CNS. Having an ability to bind TLR 2, 4, and LPS receptor CD14, surfactant protein D (spD) may be a promising agent to counteract the pathways associated with PVL. Supplementation of surfactant treatment with spD may be the key point in prevention of PVL by supression of inflammation and preventing damage to pre-OLs in a vulnerable premature brain operating through TLRs.
Asunto(s)
Leucomalacia Periventricular/tratamiento farmacológico , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Humanos , Recién Nacido , Leucomalacia Periventricular/inmunología , Leucomalacia Periventricular/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
Whilst pulmonary surfactant therapy has been highly successful in reducing mortality from respiratory distress syndrome of the newborn, a significant proportion of infants born at less than 28 weeks' gestation develop neonatal chronic lung disease. This has a complex pathogenesis but infection, inflammation, oxygen toxicity and ventilator-induced lung injury in the premature infant are all recognised risk factors for its development. Current surfactant therapies in clinical use do not contain all surfactant components and lack the hydrophilic surfactant proteins A and D. These proteins are known to have important roles in surfactant homeostasis and in protecting the lung against inflammation. This review examines the evidence from animal models supporting a role for surfactant protein-D in particular in reducing inflammation in the lung and speculates that supplementation of current surfactant therapies with recombinant forms of surfactant protein-D may help offset the risk of development of chronic lung disease.
Asunto(s)
Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Surfactantes Pulmonares/uso terapéutico , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Humanos , Recién Nacido , Enfermedades del Recién Nacido/tratamiento farmacológico , Enfermedades del Recién Nacido/patología , Modelos Biológicos , Proteínas Recombinantes/uso terapéutico , Síndrome de Dificultad Respiratoria del Recién Nacido/patología , Tensoactivos/uso terapéuticoRESUMEN
BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a syndrome with multiple etiologies and is often deadly in lysinuric protein intolerance (LPI). At present, PAP is treated by whole lung lavage or with granulocyte/monocyte colony stimulating factor (GM-CSF); however, the effectiveness of GM-CSF in treating LPI associated PAP is uncertain. We hypothesized that GM-CSF and surfactant protein D (SP-D) would enhance the clearance of proteins and dying cells that are typically present in the airways of PAP lungs. METHODS: Cells and cell-free supernatant of therapeutic bronchoalveolar lavage fluid (BALF) of a two-year-old patient with LPI were isolated on multiple occasions. Diagnostic BALF samples from an age-matched patient with bronchitis or adult PAP patients were used as controls. SP-D and total protein content of the supernatants were determined by BCA assays and Western blots, respectively. Cholesterol content was determined by a calorimetic assay or Oil Red O staining of cytospin preparations. The cells and surfactant lipids were also analyzed by transmission electron microscopy. Uptake of Alexa-647 conjugated BSA and DiI-labelled apoptotic Jurkat T-cells by BAL cells were studied separately in the presence or absence of SP-D (1 microg/ml) and/or GM-CSF (10 ng/ml), ex vivo. Specimens were analyzed by light and fluorescence microscopy. RESULTS: Here we show that large amounts of cholesterol, and large numbers of cholesterol crystals, dying cells, and lipid-laden foamy alveolar macrophages were present in the airways of the LPI patient. Although SP-D is present, its bioavailability is low in the airways. SP-D was partially degraded and entrapped in the unusual surfactant lipid tubules with circular lattice, in vivo. We also show that supplementing SP-D and GM-CSF increases the uptake of protein and dying cells by healthy LPI alveolar macrophages, ex vivo. Serendipitously, we found that these cells spontaneously generated granulomas, ex vivo, and GM-CSF treatment drastically increased the number of granulomas whereas SP-D treatment counteracted the adverse effect of GM-CSF. CONCLUSIONS: We propose that increased GM-CSF and decreased bioavailability of SP-D may promote granuloma formation in LPI, and GM-CSF may not be suitable for treating PAP in LPI. To improve the lung condition of LPI patients with PAP, it would be useful to explore alternative therapies for increasing dead cell clearance while decreasing cholesterol content in the airways.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/terapia , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Granuloma/metabolismo , Lisina/metabolismo , Macrófagos Alveolares/fisiología , Proteína D Asociada a Surfactante Pulmonar , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/inmunología , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Preescolar , Colesterol/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Humanos , Pulmón/citología , Pulmón/metabolismo , Proteinosis Alveolar Pulmonar/inmunología , Proteinosis Alveolar Pulmonar/metabolismo , Proteinosis Alveolar Pulmonar/fisiopatología , Proteinosis Alveolar Pulmonar/terapia , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/fisiología , Proteína D Asociada a Surfactante Pulmonar/metabolismo , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Resultado del TratamientoRESUMEN
Aspergillus fumigatus (Afu) is an opportunistic fungal pathogen that can cause fatal invasive pulmonary aspergillosis (IPA) in immunocompromised individuals. Previously, surfactant protein D (SP-D), a surfactant-associated innate immune molecule, has been shown to enhance phagocytosis and killing of Afu conidia by phagocytic cells in vitro. An intranasal treatment of SP-D significantly increased survival in a murine model of IPA. Here we have examined mechanisms via which recombinant forms of full-length (hSP-D) or truncated human SP-D (rhSP-D) offer protection in a murine model of IPA that were immunosuppressed with hydrocortisone and challenged intranasally with Afu conidia prior to the treatment. SP-D or rhSP-D treatment increased the survival rate to 70% and 80%, respectively (100% mortality on day 7 in IPA mice), with concomitant reduction in the growth of fungal hyphae in the lungs, and increased levels of TNF-alpha and IFN-gamma in the lung suspension supernatants, as compared to untreated IPA mice. The level of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the lung cell suspension was also raised considerably following treatment with SP-D or rhSP-D. Our results appear to reaffirm the notion that under immunocompromised conditions, human SP-D or its truncated form can offer therapeutic protection against fatal challenge with Afu conidia challenge. Taken together, the SP-D-mediated protective mechanisms include enhanced phagocytosis by recruited macrophages and neutrophils and fungistatic properties, suppression of the levels of pathogenic Th2 cytokines (IL-4 and IL-5), enhanced local production of protective Th1 cytokines, TNF-alpha and IFN-gamma, and that of protective C-C chemokine, MIP-1 alpha.
Asunto(s)
Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Animales , Aspergillus fumigatus , Quimiocina CCL3/inmunología , Humanos , Interferón gamma/inmunología , Aspergilosis Pulmonar Invasiva/inmunología , Aspergilosis Pulmonar Invasiva/microbiología , Masculino , Ratones , Ratones Endogámicos BALB C , Mutación , Proteína D Asociada a Surfactante Pulmonar/genética , Proteína D Asociada a Surfactante Pulmonar/fisiología , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapéutico , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
BACKGROUND: Drug-resistant pathogens are an increasing threat, particularly for hospitalised patients. In search of a new approach in pathogen targeting, we developed bifunctional proteins that combine broad spectrum pathogen recognition with efficient targeting to phagocytes. Pathogen recognition is provided by a recombinant fragment of surfactant protein D (rfSP-D) while targeting to phagocytic cells is accomplished by coupling rfSP-D to F(ab') fragments directed against Fcalpha receptor I (FcalphaRI) or Fcgamma receptor I (FcgammaRI). FcalphaRI and FcgammaRI are expressed on myeloid cells, and induce rapid internalisation of particles after crosslinking. OBJECTIVE/METHODS: In this review we discuss the roles of SP-D and Fc receptors in host defence as a rationale for rfSP-D/anti-FcR bifunctional proteins. Furthermore we summarise the available data on rfSP-D/anti-FcR proteins as well as opportunities and considerations for future use of such bifunctional proteins. RESULTS/CONCLUSION: rfSP-D/anti-FcR bifunctional proteins could be of great value for the treatment of a variety of infectious diseases. The focus in the near future should be on proof-of-principle by testing the bifunctional proteins in different mouse models of infectious disease.
Asunto(s)
Enfermedades Transmisibles/terapia , Inmunidad Innata , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Inmunoterapia/métodos , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Animales , Antígenos CD/inmunología , Enfermedades Transmisibles/inmunología , Humanos , Fragmentos Fab de Inmunoglobulinas/inmunología , Fagocitos/inmunología , Proteína D Asociada a Surfactante Pulmonar/inmunología , Receptores Fc/inmunología , Receptores de IgG/inmunología , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
BACKGROUND: Surfactant protein D (SP-D) deficient mice develop emphysema-like pathology associated with focal accumulations of foamy alveolar macrophages, an excess of surfactant phospholipids in the alveolar space and both hypertrophy and hyperplasia of alveolar type II cells. These findings are associated with a chronic inflammatory state. Treatment of SP-D deficient mice with a truncated recombinant fragment of human SP-D (rfhSP-D) has been shown to decrease the lipidosis and alveolar macrophage accumulation as well as production of proinflammatory chemokines. The aim of this study was to investigate if rfhSP-D treatment reduces the structural abnormalities in parenchymal architecture and type II cells characteristic of SP-D deficiency. METHODS: SP-D knock-out mice, aged 3 weeks, 6 weeks and 9 weeks were treated with rfhSP-D for 9, 6 and 3 weeks, respectively. All mice were sacrificed at age 12 weeks and compared to both PBS treated SP-D deficient and wild-type groups. Lung structure was quantified by design-based stereology at the light and electron microscopic level. Emphasis was put on quantification of emphysema, type II cell changes and intracellular surfactant. Data were analysed with two sided non-parametric Mann-Whitney U-test. MAIN RESULTS: After 3 weeks of treatment, alveolar number was higher and mean alveolar size was smaller compared to saline-treated SP-D knock-out controls. There was no significant difference concerning these indices of pulmonary emphysema within rfhSP-D treated groups. Type II cell number and size were smaller as a consequence of treatment. The total volume of lamellar bodies per type II cell and per lung was smaller after 6 weeks of treatment. CONCLUSION: Treatment of SP-D deficient mice with rfhSP-D leads to a reduction in the degree of emphysema and a correction of type II cell hyperplasia and hypertrophy. This supports the concept that rfhSP-D might become a therapeutic option in diseases that are characterized by decreased SP-D levels in the lung.
Asunto(s)
Alveolos Pulmonares/patología , Enfisema Pulmonar/patología , Enfisema Pulmonar/prevención & control , Proteína D Asociada a Surfactante Pulmonar/genética , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Eliminación de Secuencia/genética , Animales , Humanos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Macrófagos Alveolares/ultraestructura , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/ultraestructura , Enfisema Pulmonar/metabolismo , Proteína D Asociada a Surfactante Pulmonar/deficiencia , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologíaRESUMEN
It has become increasingly evident that pulmonary surfactant proteins, SP-A and SP-D, present in the alveolar and bronchial epithelial fluid linings, not only play significant functions in the innate defense mechanism against pathogens, but also are involved in immunomodulatory roles, which result in the protection against, and resolution of, allergen-induced airway inflammation. Studies on allergen-sensitized murine models, and asthmatic patients, show that SP-A and SP-D can: specifically bind to aero-allergens; inhibit mast cell degranulation and histamine release; and modulate the activation of alveolar macrophages and dendritic cells during the acute hypersensitive phase of allergic response. They also can alleviate chronic allergic inflammation by inhibiting T-lymphocyte proliferation as well as increasing phagocytosis of DNA fragments and clearance of apoptotic cell debris. Furthermore, it has emerged, from the studies on SP-D-deficient mice, that, when these mice are challenged with allergen, they develop increased eosinophil infiltration, and abnormal activation of lymphocytes, leading to the production of Th2 cytokines. Intranasal administration of SP-D significantly attenuated the asthmatic-like symptoms seen in allergen-sensitized wild-type, and SP-D-deficient, mice. These important findings provide a new insight of the role that surfactant proteins play in handling environmental stimuli and in their immunoregulation of airway inflammatory disease.
Asunto(s)
Alérgenos/inmunología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Proteína A Asociada a Surfactante Pulmonar/inmunología , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Proteína D Asociada a Surfactante Pulmonar/inmunología , Proteína D Asociada a Surfactante Pulmonar/metabolismo , Animales , Asma/tratamiento farmacológico , Asma/inmunología , Asma/metabolismo , Asma/fisiopatología , Hiperreactividad Bronquial/tratamiento farmacológico , Hiperreactividad Bronquial/patología , Humanos , Hipersensibilidad/genética , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Hipersensibilidad/patología , Inmunidad Innata/inmunología , Inflamación/inmunología , Inflamación/metabolismo , Proteína A Asociada a Surfactante Pulmonar/uso terapéutico , Proteína D Asociada a Surfactante Pulmonar/uso terapéuticoRESUMEN
A significant proportion of bronchial asthma patients have underlying pulmonary fungal infections that contribute to persistent inflammation and allergic reactions. Aspergillus fumigatus is a ubiquitous opportunistic fungal pathogen causing a spectrum of allergic and infectious diseases. Currently, oral corticosteroids form the first line of treatment for allergic aspergillosis and use of antifungals such as itraconazole has been indicated in non-responders. In view of the protective role of innate immunity in host defense against Aspergillus fumigatus, we aimed to identify the relevant innate immune proteins In a series of studies, we identified and established the therapeutic potential of pulmonary collectins SP-A and SP-D and serum collectin MBL in murine models of allergic and invasive aspergillosis. Use of SP-D for diagnosis and therapy of lung disorders and MBL for therapy of various infections including invasive aspergillosis has been patented. Genetic polymorphisms in these genes may result in partial or total loss of function and may increase the host's susceptibility to aspergillosis. Candidate gene association studies showed SNPs in SP-A2 and MBL significantly associate with patients of allergic bronchopulmonary aspergillosis and bronchial asthma with rhinitis. The patients carrying either one or both of GCT and AGG alleles of SP-A2 and patients with A allele at position 1011 of MBL had markedly higher eosinophilia, total IgE antibodies and lower FEV1 (the clinical markers of ABPA). These SNPs may be useful for predicting susceptibility to allergic aspergillosis and bronchial asthma with allergic rhinitis and have been patented. Elucidation of the immunoregulatory role of SP-A, SP-D and MBL in mechanisms of allergy and inflammation suggests that they may also be potentially useful for predisposition diagnosis and therapy of non-fungal bronchial asthma.
Asunto(s)
Antifúngicos/uso terapéutico , Aspergilosis Broncopulmonar Alérgica/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Lectina de Unión a Manosa/uso terapéutico , Proteína A Asociada a Surfactante Pulmonar/uso terapéutico , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Fármacos del Sistema Respiratorio/uso terapéutico , Animales , Aspergilosis Broncopulmonar Alérgica/genética , Aspergilosis Broncopulmonar Alérgica/inmunología , Aspergilosis Broncopulmonar Alérgica/microbiología , Aspergillus fumigatus/inmunología , Predisposición Genética a la Enfermedad , Humanos , Inmunidad Innata , Aspergilosis Pulmonar Invasiva/genética , Aspergilosis Pulmonar Invasiva/inmunología , Aspergilosis Pulmonar Invasiva/microbiología , Lectina de Unión a Manosa/genética , Patentes como Asunto , Polimorfismo de Nucleótido Simple , Proteína A Asociada a Surfactante Pulmonar/genética , Proteína D Asociada a Surfactante Pulmonar/genética , Proteínas Recombinantes/uso terapéutico , Factores de RiesgoRESUMEN
BACKGROUND: The surfactant protein SP-D has been reported to reduce bronchial hyper-responsiveness, blood eosinophilia, and T-helper type 2 cytokines in models of allergic asthma. However, little is known about the functional effect of SP-D on the early airway response upon allergen inhalation, which is an important feature of this disease. OBJECTIVE: We investigated whether SP-D is able to reduce the immediate allergen-induced mediator release and the early bronchial obstruction in addition to its effects on airway inflammation and bronchial hyperresponsiveness in an Aspergillus fumigatus mouse asthma model. METHODS: A. fumigatus-sensitized mice were treated with a recombinant fragment of human SP-D or placebo. Lung functions were measured in orotracheally intubated, spontaneously breathing animals using body plethysmography. In addition, passively sensitized precision-cut lung slices (PCLS) were used to determine the effect of SP-D on allergen-induced histamine release. RESULTS: SP-D inhibited the allergen-induced early airway response and reduced airway hyperresponsiveness compared with placebo. Eosinophilia in bronchoalveolar lavage and lung tissue was reduced after SP-D treatment, possibly by reducing eotaxin levels in the lung. Furthermore, SP-D treatment reduced the allergen-induced histamine release from PCLS. CONCLUSION: These data suggest that SP-D not only reduces allergen-induced eosinophilic inflammation and airway hyperresponsiveness but also provides protection against early airway obstruction by inhibition of early mediator release.
Asunto(s)
Alérgenos/inmunología , Aspergillus fumigatus/inmunología , Asma/prevención & control , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Administración por Inhalación , Animales , Antígenos Fúngicos/inmunología , Asma/inmunología , Asma/metabolismo , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Hiperreactividad Bronquial/prevención & control , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Quimiocina CCL11 , Quimiocinas CC/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Eosinofilia/prevención & control , Femenino , Liberación de Histamina/efectos de los fármacos , Inmunoglobulina E/sangre , Interleucina-5/metabolismo , Pulmón/metabolismo , Rendimiento Pulmonar , Ratones , Ratones Endogámicos BALB C , Proteína D Asociada a Surfactante Pulmonar/farmacocinética , Proteínas Recombinantes/uso terapéuticoRESUMEN
The lung is repeatedly exposed to inhaled particles and pathogens that are cleared by the actions of a multi-component innate host defense system. The pulmonary collectins--surfactant proteins A (SP-A) and D (SP-D)--play important roles in innate host defense by binding and clearing invading microbes from the lung. SP-A and SP-D also influence surfactant homeostasis, contributing to the physical structures of lipids in the alveoli and to the regulation of surfactant function and metabolism. In addition to binding and opsonizing infectious pathogens, SP-A and SP-D bind to the surfaces of host defense cells, promoting or inhibiting immune cell activity through multiple cellular pathways. As a consequence of their physiologic functions, SP-A- and SP-D-dependent pathways are targets for clinical therapies designed to limit the proliferation of microoorgansims and to ameliorate inflammation following pulmonary infection.
Asunto(s)
Antiinflamatorios/inmunología , Pulmón/inmunología , Proteína A Asociada a Surfactante Pulmonar/inmunología , Proteína D Asociada a Surfactante Pulmonar/inmunología , Infecciones del Sistema Respiratorio/inmunología , Animales , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Humanos , Inmunidad Innata , Conformación Proteica , Proteína A Asociada a Surfactante Pulmonar/uso terapéutico , Proteína D Asociada a Surfactante Pulmonar/uso terapéutico , Hipersensibilidad Respiratoria/tratamiento farmacológico , Infecciones del Sistema Respiratorio/tratamiento farmacológicoRESUMEN
RATIONALE: The susceptibility of neonates to pulmonary and systemic infection has been associated with the immaturity of both lung structure and the immune system. Surfactant protein (SP) D is a member of the collectin family of innate immune molecules that plays an important role in innate host defense of the lung. OBJECTIVES: We tested whether treatment with recombinant human SP-D influenced the response of the lung and systemic circulation to intratracheally administered Escherichia coli lipopolysaccharides. METHODS: After intratracheal lipopolysaccharide instillation, preterm newborn lambs were treated with surfactant and ventilated for 5 h. MEASUREMENT: Survival rate, physiologic lung function, lung and systemic inflammation, and endotoxin level in plasma were evaluated. MAIN RESULTS: In control lambs, intratracheal lipopolysaccharides caused septic shock and death associated with increased endotoxin in plasma. In contrast, all lambs treated with recombinant human SP-D were physiologically stable and survived. Leakage of lipopolysaccharides from the lungs to the systemic circulation was prevented by intratracheal recombinant human SP-D. Recombinant human SP-D prevented systemic inflammation and decreased the expression of IL-1beta, IL-8, and IL-6 in the spleen and liver. Likewise, recombinant human SP-D decreased IL-1beta and IL-6 in the lung and IL-8 in the plasma. Recombinant human SP-D did not alter pulmonary mechanics following endotoxin exposure. Recombinant human SP-D was readily detected in the lung 5 h after intratracheal instillation. CONCLUSIONS: Intratracheal recombinant human SP-D prevented shock caused by endotoxin released from the lung during ventilation in the premature newborn.