Increased levels of surfactant protein D (SP-D) and lipid-laden foamy macrophages (FMs) are frequently found under oxidative stress conditions and/or in patients with chronic obstructive pulmonary disease (COPD) who a...Increased levels of surfactant protein D (SP-D) and lipid-laden foamy macrophages (FMs) are frequently found under oxidative stress conditions and/or in patients with chronic obstructive pulmonary disease (COPD) who are also chronically exposed to cigarette smoke (CS). However, the roles and molecular mechanisms of SP-D and FMs in COPD have not yet been determined. In this study, increased levels of SP-D were found in the bronchoalveolar lavage fluid (BALF) and sera of ozone- and CS-exposed mice. Furthermore, SP-D-knockout mice showed increased lipid-laden FMs and airway inflammation caused by ozone and CS exposure, similar to that exhibited by our study cohort of chronic smokers and COPD patients. We also showed that an exogenous recombinant fragment of human SP-D (rfhSP-D) prevented the formation of oxidized low-density lipoprotein (oxLDL)-induced FMs in vitro and reversed the airway inflammation and emphysematous changes caused by oxidative stress and CS exposure in vivo. SP-D upregulated bone marrow-derived macrophage (BMDM) expression of genes involved in countering the oxidative stress and lipid metabolism perturbations induced by CS and oxLDL. Our study demonstrates the crucial roles of SP-D in the lipid homeostasis of dysfunctional alveolar macrophages caused by ozone and CS exposure in experimental mouse emphysema, which may provide a novel opportunity for the clinical application of SP-D in patients with COPD.展开更多
Importance:Surfactant protein C(SP-C)dysfunction is a rare disease associated with interstitial lung disease.Early therapies may improve outcomes but the diagnosis is often delayed owing to variability of manifestatio...Importance:Surfactant protein C(SP-C)dysfunction is a rare disease associated with interstitial lung disease.Early therapies may improve outcomes but the diagnosis is often delayed owing to variability of manifestations.Objective:To investigate the manifestations and outcomes of SP-C dysfunction.Methods:We retrospectively analyzed the records of five pediatric patients who were diagnosed with SP-C dysfunction between February 2014 and April 2017 at Beijing Children's Hospital.Results:The five patients included two boys and three girls with a median age at diagnosis of 1.3 years.All patients presented with interstitial lung disease and had a heterozygous SFTPC mutation,including an I73T mutation in three patients,a V39L mutation in one patient,and a Y 104H mutation in one patient.In addition to common respiratory manifestations,hemoptysis and anemia were observed in one patient with the I73T mutation.Elevated levels of autoantibodies and a large number of hemosiderin-laden macrophages in bronchoalveolar lavage fluid were found in two patients with the I73T mutation,suggesting the presence of diffuse alveolar hemorrage and autoimmunity.Chest high-resolution computed tomography features included ground-glass opacities,reticular opacities,cysts,and pleural thickening.Transbronchial lung biopsy was performed in one patient with the I73T mutation,which revealed the presence of some hemosiderin-laden macrophages in alveolar spaces.All patients received treatment with corticosteroids;two received combined treatment with hydroxychloroquine.During follow-up,the two patients who received hydroxychloroquine showed improved symptoms;of the remaining three patients,two died after their families refused further treatment,while the final patient was lost to follow-up.Interpretation:This is the first report to describe a new phenotype of diffuse alveolar hemorrhage with autoimmunity in patients with I73T SFTPC mutation.Treatment with hydroxychloroquine should be considered for patients with SP-C dysfunction.展开更多
基金supported by the Ministry of Science and Technology(MOST)of Taiwan(grant numbers 103-2321-B-006-030 and 104-2321-B-006-008),funding received in part from the Headquarters of University Advancement at the National Cheng Kung University,which is sponsored by the Ministry of Education in Taiwan,and a research grant(1JA8)from the Center for Allergy,Immunology,and Microbiome(A.I.M.),China Medical University Hospital,Taichung,Taiwan.
文摘Increased levels of surfactant protein D (SP-D) and lipid-laden foamy macrophages (FMs) are frequently found under oxidative stress conditions and/or in patients with chronic obstructive pulmonary disease (COPD) who are also chronically exposed to cigarette smoke (CS). However, the roles and molecular mechanisms of SP-D and FMs in COPD have not yet been determined. In this study, increased levels of SP-D were found in the bronchoalveolar lavage fluid (BALF) and sera of ozone- and CS-exposed mice. Furthermore, SP-D-knockout mice showed increased lipid-laden FMs and airway inflammation caused by ozone and CS exposure, similar to that exhibited by our study cohort of chronic smokers and COPD patients. We also showed that an exogenous recombinant fragment of human SP-D (rfhSP-D) prevented the formation of oxidized low-density lipoprotein (oxLDL)-induced FMs in vitro and reversed the airway inflammation and emphysematous changes caused by oxidative stress and CS exposure in vivo. SP-D upregulated bone marrow-derived macrophage (BMDM) expression of genes involved in countering the oxidative stress and lipid metabolism perturbations induced by CS and oxLDL. Our study demonstrates the crucial roles of SP-D in the lipid homeostasis of dysfunctional alveolar macrophages caused by ozone and CS exposure in experimental mouse emphysema, which may provide a novel opportunity for the clinical application of SP-D in patients with COPD.
文摘Importance:Surfactant protein C(SP-C)dysfunction is a rare disease associated with interstitial lung disease.Early therapies may improve outcomes but the diagnosis is often delayed owing to variability of manifestations.Objective:To investigate the manifestations and outcomes of SP-C dysfunction.Methods:We retrospectively analyzed the records of five pediatric patients who were diagnosed with SP-C dysfunction between February 2014 and April 2017 at Beijing Children's Hospital.Results:The five patients included two boys and three girls with a median age at diagnosis of 1.3 years.All patients presented with interstitial lung disease and had a heterozygous SFTPC mutation,including an I73T mutation in three patients,a V39L mutation in one patient,and a Y 104H mutation in one patient.In addition to common respiratory manifestations,hemoptysis and anemia were observed in one patient with the I73T mutation.Elevated levels of autoantibodies and a large number of hemosiderin-laden macrophages in bronchoalveolar lavage fluid were found in two patients with the I73T mutation,suggesting the presence of diffuse alveolar hemorrage and autoimmunity.Chest high-resolution computed tomography features included ground-glass opacities,reticular opacities,cysts,and pleural thickening.Transbronchial lung biopsy was performed in one patient with the I73T mutation,which revealed the presence of some hemosiderin-laden macrophages in alveolar spaces.All patients received treatment with corticosteroids;two received combined treatment with hydroxychloroquine.During follow-up,the two patients who received hydroxychloroquine showed improved symptoms;of the remaining three patients,two died after their families refused further treatment,while the final patient was lost to follow-up.Interpretation:This is the first report to describe a new phenotype of diffuse alveolar hemorrhage with autoimmunity in patients with I73T SFTPC mutation.Treatment with hydroxychloroquine should be considered for patients with SP-C dysfunction.
