Drug-induced interstitial lung disease(DILD)is the most common pulmonary adverse event of anticancer drugs.In recent years,the incidence of anticancer DILD has gradually increased with the rapid development of novel a...Drug-induced interstitial lung disease(DILD)is the most common pulmonary adverse event of anticancer drugs.In recent years,the incidence of anticancer DILD has gradually increased with the rapid development of novel anticancer agents.Due to the diverse clinical manifestations and the lack of specific diagnostic criteria,DILD is difficult to diagnose and may even become fatal if not treated properly.Herein,a multidisciplinary group of experts from oncology,respiratory,imaging,pharmacology,pathology,and radiology departments in China has reached the“expert consensus on the diagnosis and treatment of anticancer DILD”after several rounds of a comprehensive investigation.This consensus aims to improve the awareness of clinicians and provide recommendations for the early screening,diagnosis,and treatment of anticancer DILD.This consensus also emphasizes the importance of multidisciplinary collaboration while managing DILD.展开更多
Objective:Acute respiratory distress syndrome (ARDS) is an acute and lethal clinical syndrome that is characterized by hypoxemic respiratory failure and diffuse alveolar inflammatory damage.This review aimed to sea...Objective:Acute respiratory distress syndrome (ARDS) is an acute and lethal clinical syndrome that is characterized by hypoxemic respiratory failure and diffuse alveolar inflammatory damage.This review aimed to search and discuss the mass spectrometry (MS)-based proteomic studies on different subsets of ARDS patients.Data Sources:Original research articles were collected from the PubMed database published in English up to December 2015.Study Selection:The literature search was done using the term "(acute lung injury OR acute respiratory distress syndrome)AND (proteomics OR proteome OR mass spectrum OR differential in-gel electrophoresis OR two-dimensional polyacrylamide gel electrophoresis)".Related original research articles were included and were carefully analyzed.Results:Eight original proteomic researches on ARDS patients were found.The common proteomic modalities were two-dimensional (2D)high-performance liquid chromatography-based electronic spray ion-MS/MS and 2D-polyacrylamide gel electrophoresis/differential in-gel electrophoresis-based matrix-assisted laser desorption ionization-time of flight/MS.They compared the proteome between ARDS patients and normal controls and analyzed the dynamic changes ofproteome at different ARDS stages or severity.The disturbed proteome in ARDS patients includes plasma acute-phase proteins,inflammatory/immune-associated proteins,and coagulation proteins.Conclusions:Although several previous studies have provided some useful information about the lung proteome in ARDS patients and gained several interesting disease-associated biomarkers,clinical proteomic studies in ARDS patients are still in the initial stage.An increased cooperation is still needed to establish a global and faithful database containing disease-specific proteome from the largest ARDS subsets.展开更多
Background: Pulmonary hypertension (PH) frequently complicates the course of idiopathic pulmonary fibrosis (IPF) patients and is associated with significantly worse outcomes. The aim of the present study was to i...Background: Pulmonary hypertension (PH) frequently complicates the course of idiopathic pulmonary fibrosis (IPF) patients and is associated with significantly worse outcomes. The aim of the present study was to investigate the incidence of PH in IPF patients and evaluate the correlation between clinical parameters and systolic pulmonary artery pressure (sPAP). Methods: Hospitalized patients with IPF, who were evaluated for sPAP by Doppler echocardiography from January 2004 to December 2011, were enrolled in our study. Patients were defined as PH by an estimated sPAP 〉 50 mmHg and graded as PH likely, PH possible and PH unlikely, based on the 2009 European Society of Cardiology/European Respiratory Society PH Guidelines. The correlations between clinical parameters and sPAP were analyzed by multiple linear regression. Results: Totally, 119 IPF patients were enrolled in our study and 28 (23.5%), 20 (16.8%) and 71 (59.7%) patients were PH likely, PH possible and PH unlikely, respectively. Borg dyspnea score was positively correlated with sPAP, r = 0.467, P 〈 0.001. Oxygen saturation was negatively correlated with sPAP, r = -0.416, P 〈 0.001. Diffusing capacity of the lung for carbon monoxide percentage predicted was negatively correlated with sPAP, r = -0.424, P = 0.003. N-terminal fragment of pro-brain natriuretic peptide and pulmonary artery width was positively correlated with sPAP, r = 0.452, P = 0.011 and r= 0.513, P 〈 0.001, respectively. Conclusions: The incidence of PH in IPF patients was 23.5% in a single center of China. PH may worsen the dyspnea, right heart dysfunction and decrease the life quality of the patients with IPF.展开更多
Background: Follistatin-like I (FSTL 1) is a novel profibrogenic factor that induces pulmonary fibrosis (PF) through the transforming growth factor-beta 1 (TGF-[B 1 )/Smad signaling. Little is known about its e...Background: Follistatin-like I (FSTL 1) is a novel profibrogenic factor that induces pulmonary fibrosis (PF) through the transforming growth factor-beta 1 (TGF-[B 1 )/Smad signaling. Little is known about its effects on PF through the non-Smad signaling, like the mitogen-activated protein kinase (MAPK) pathway. Therefore, this study aimed to investigate the role ofFSTL 1 in PF through the MAPK signaling pathway and its mechanisms in lung fibrogenesis. Methods: PF was induced in Fstll~ and wild-type (WT) C57BL/6 mice with bleomycin. After 14 days, the mice were sacrificed, and lung tissues were stained with hematoxylin and eosin; the hydroxyproline content was measured to confirm PF. The mRNA and protein level of FSTLI and the change of MAPK phosphorylation were measured by quantitative polymerase chain reaction and Western blotting. The effect of Fst11 deficiency on fibroblasts differentiation was measured by Western blotting and cell immunofluorescence. MAPK signaling activation was measured by Western blotting in Fst11+/ and WT fibroblasts treated with recombinant human FSTLI protein. We pretreated mouse lung fibroblast cells with inhibitors of the extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal kinase (JNK) signaling and analyzed their differentiation, proliferation, migration, and invasion by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and transwell assays. The Student's t-test was used to compare the differences between two groups. Results: Fstll deficiency attenuated phosphorylation of the ERK, p38, and JNK signaling in bleomycin-induced fibrotic lung tissue 14 days after injury (0.67 ± 0.05 vs. 1.22 ± 0.03, t = 14.92, P = 0.0001; 0.41 ± 0.01 vs. 1.15 ± 0.07; t = 11.19; P = 0.0004; and 0.41 ± 0.01 vs. 1.07± 0.07, t = 8.92, P = 0.0009; respectively), compared with WT lungs at the same time and in primary lung fibroblasts (0.82 ± 0.01 vs. 1.01 ±0.04, t = 4.06, P = 0.0150; 1.04 ±0.03 vs. 1.24 ± 0.03, t= 4.44, P = 0.0100: and 0.76 ±0.05 vs. 0.99± 0.05, t = 4.48, P = 0.0100; respectively), compared with TGF-β1-stimulated WT group. Recombinant human FSTLI protein in lung fibroblasts enhanced TG F-β1 -mediated phosphorylation of the ERK ( 1.19± 0.08 vs, 0.55 ± 0.04, t = 6.99, P = 0.0020), p38 ( 1.18 ±0.04 vs. 0.66 ± 0.03, t = 11.20, P = 0.0020), and .INK ( 1,11± 0.01 vs. 0.84 ± 0.04, t = 6.53, P = 0.0030), compared with the TGF-β1-stimulated WT group. Fstll-deficient fibroblasts showed reduced alpha-smooth muscle actin (α-SMA) expression (0.70 ± 0.06 vs. 1.28 ±0.11, t = 4.65, P = 0.0035, compared with the untreated WT group; 1.40 ± 0.05 vs. 1.76± 0.02, t = 6.31, P = 0.0007; compared with the TGF-β1-treated WT group). Compared with the corresponding condition in the control group, the TGF-β1/FSTL 1-mediated α-SMA expression was significantly suppressed by pretreatment with an inhibitor of p38 (0.73± 0.01 vs. 1.13 ± 0.10, t = 3.92, P = 0.0078) and JNK (0.78 ± 0.03 vs. 1.08 ± 0.06, t = 4.40,P = 0.0046) signaling. The proliferation of mouse lung fibroblast cells (MLgs) significantly decreased after treatment of an inhibitor of p38 (0.30 ±0.01 vs. 0.46 ±0.03, t = 4.64, P = 0.0009), JNK (0.30 ± 0.01 vs. 0.49 ± 0.01, t = 12.84, P = 0.0001), and Smad2/3 (0.18 ± 0.02 vs. 0.46 ±0.02, t = 12.69, P = 0.0001) signaling compared with the dimethylsulibxide group. The migration and invasion cells of MLgs significantly decreased in medium pretreated with an inhibitor of p38 (70.17 ±3.28 vs. 116.30 ± 7.11, t = 5.89, P = 0.0042 for the migratory cells; 19.87 ± 0.84 vs. 32.70 i 0.95, t =10.14, P = 0.0005 for the invasive cells), JNK (72.30 ±3.85 vs. 116.30 ± 7.11, t = 5.44, P = 0.0056 for the migratory cells; 18.03 ± 0.94 vs. 32.70 ± 0.95, t = 11.00, P = 0.0004 for the invasive cells), and Smad2/3 (64.76 ± 1.41 vs. 116.30 ± 7.11, t = 7.11, P = 0.0021 for the migratory cells; 18.03 ± 0.94 vs. 32.70 ±0.95, t = 13.29, P = 0.0002 for the invasive cells) signaling compared with the corresponding condition in the dimethylsulfoxide group. Conclusion: FSTL1 affects lung fibroblast differentiation, proliferation, migration, and invasion through p38 and JNK signaling, and in this way, it might influence the development of PF.展开更多
Pulmonary nocardiosis is an opportunistic infection,especially in immunocompromised patients.Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease.We report a case of pulmonary nocardiosis...Pulmonary nocardiosis is an opportunistic infection,especially in immunocompromised patients.Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease.We report a case of pulmonary nocardiosis with secondary HLH.展开更多
Idiopathic pulmonary fibrosis(IPF)is a chronic,progressive,and generally fatal fibrotic lung disease with a median survival of 2 to 3 years after diagnosis.[1,2]Acute exacerbation of IPF(AE-IPF)is defined as an acute,...Idiopathic pulmonary fibrosis(IPF)is a chronic,progressive,and generally fatal fibrotic lung disease with a median survival of 2 to 3 years after diagnosis.[1,2]Acute exacerbation of IPF(AE-IPF)is defined as an acute,clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality.Nearly 46%of deaths in IPF are caused by AE-IPF,and the median survival of patients with AE-IPF is approximately 3 to 4 months.[3]Over the past 27 years,great efforts have been paid to find therapies that might work for patients with this condition.We herein summarize current therapies for patients with AE-IPF.展开更多
An outbreak of coronavirus disease 2019(COVID-19)has caught global attention and caused enormous damage.2019 novel coronavirus,also known as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),shares remarkabl...An outbreak of coronavirus disease 2019(COVID-19)has caught global attention and caused enormous damage.2019 novel coronavirus,also known as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),shares remarkable homology with severe acute respiratory syndrome(SARS)coronavirus and Middle East respiratory syndrome(MERS)coronavirus.In the follow-up studies,62%of SARS and 33%of MERS patients,who tended to be older and have longer intensive care unit admissions,had radiographic evidence of pulmonary fibrosis(PF)after hospital discharge.11,21 The repercussions of COVID-19 may also lead to PF,impair pulmonary function,and threaten life quality.展开更多
Idiopathic pulmonary fibrosis(IPF)incidence shows wide variations in different countries,ranging from 3 to 9 per 100,000 inhabitants per year in North America and Europe,while in South America and Asia,incidence is lo...Idiopathic pulmonary fibrosis(IPF)incidence shows wide variations in different countries,ranging from 3 to 9 per 100,000 inhabitants per year in North America and Europe,while in South America and Asia,incidence is lower,ranging from 1.2 to 4.16 per 100,000 inhabitants per year.展开更多
To the Editor: Chronic obstructive puhnonary disease (COPD) is a common preventable and treatable disease, characterized by persistent and progressive airflow limitation due to abnormal inflammation in the airways ...To the Editor: Chronic obstructive puhnonary disease (COPD) is a common preventable and treatable disease, characterized by persistent and progressive airflow limitation due to abnormal inflammation in the airways and lung to noxious particles or gases. Exacerbation of COPD is rarely induced by foreign body aspiration. In the present report, we described a male patient with acute exacerbation of COPD caused by foreign body aspiration.展开更多
基金supported by grants from CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2021-I2M-1-014)and National Key R&D Program of China(No.2021YFC2500700).
文摘Drug-induced interstitial lung disease(DILD)is the most common pulmonary adverse event of anticancer drugs.In recent years,the incidence of anticancer DILD has gradually increased with the rapid development of novel anticancer agents.Due to the diverse clinical manifestations and the lack of specific diagnostic criteria,DILD is difficult to diagnose and may even become fatal if not treated properly.Herein,a multidisciplinary group of experts from oncology,respiratory,imaging,pharmacology,pathology,and radiology departments in China has reached the“expert consensus on the diagnosis and treatment of anticancer DILD”after several rounds of a comprehensive investigation.This consensus aims to improve the awareness of clinicians and provide recommendations for the early screening,diagnosis,and treatment of anticancer DILD.This consensus also emphasizes the importance of multidisciplinary collaboration while managing DILD.
基金This work was supported by grants from National Natural Science Foundation of China (No. 81490534, No. 81490530, and No. 81270123).
文摘Objective:Acute respiratory distress syndrome (ARDS) is an acute and lethal clinical syndrome that is characterized by hypoxemic respiratory failure and diffuse alveolar inflammatory damage.This review aimed to search and discuss the mass spectrometry (MS)-based proteomic studies on different subsets of ARDS patients.Data Sources:Original research articles were collected from the PubMed database published in English up to December 2015.Study Selection:The literature search was done using the term "(acute lung injury OR acute respiratory distress syndrome)AND (proteomics OR proteome OR mass spectrum OR differential in-gel electrophoresis OR two-dimensional polyacrylamide gel electrophoresis)".Related original research articles were included and were carefully analyzed.Results:Eight original proteomic researches on ARDS patients were found.The common proteomic modalities were two-dimensional (2D)high-performance liquid chromatography-based electronic spray ion-MS/MS and 2D-polyacrylamide gel electrophoresis/differential in-gel electrophoresis-based matrix-assisted laser desorption ionization-time of flight/MS.They compared the proteome between ARDS patients and normal controls and analyzed the dynamic changes ofproteome at different ARDS stages or severity.The disturbed proteome in ARDS patients includes plasma acute-phase proteins,inflammatory/immune-associated proteins,and coagulation proteins.Conclusions:Although several previous studies have provided some useful information about the lung proteome in ARDS patients and gained several interesting disease-associated biomarkers,clinical proteomic studies in ARDS patients are still in the initial stage.An increased cooperation is still needed to establish a global and faithful database containing disease-specific proteome from the largest ARDS subsets.
基金This work was supported by grants from the National Key Technology R&D Program, the Ministry of Science and Technology of China (No. 2012BAI05B02) and the Key Program of Beijing Nature Science Foundation (No. 7131008).
文摘Background: Pulmonary hypertension (PH) frequently complicates the course of idiopathic pulmonary fibrosis (IPF) patients and is associated with significantly worse outcomes. The aim of the present study was to investigate the incidence of PH in IPF patients and evaluate the correlation between clinical parameters and systolic pulmonary artery pressure (sPAP). Methods: Hospitalized patients with IPF, who were evaluated for sPAP by Doppler echocardiography from January 2004 to December 2011, were enrolled in our study. Patients were defined as PH by an estimated sPAP 〉 50 mmHg and graded as PH likely, PH possible and PH unlikely, based on the 2009 European Society of Cardiology/European Respiratory Society PH Guidelines. The correlations between clinical parameters and sPAP were analyzed by multiple linear regression. Results: Totally, 119 IPF patients were enrolled in our study and 28 (23.5%), 20 (16.8%) and 71 (59.7%) patients were PH likely, PH possible and PH unlikely, respectively. Borg dyspnea score was positively correlated with sPAP, r = 0.467, P 〈 0.001. Oxygen saturation was negatively correlated with sPAP, r = -0.416, P 〈 0.001. Diffusing capacity of the lung for carbon monoxide percentage predicted was negatively correlated with sPAP, r = -0.424, P = 0.003. N-terminal fragment of pro-brain natriuretic peptide and pulmonary artery width was positively correlated with sPAP, r = 0.452, P = 0.011 and r= 0.513, P 〈 0.001, respectively. Conclusions: The incidence of PH in IPF patients was 23.5% in a single center of China. PH may worsen the dyspnea, right heart dysfunction and decrease the life quality of the patients with IPF.
文摘Background: Follistatin-like I (FSTL 1) is a novel profibrogenic factor that induces pulmonary fibrosis (PF) through the transforming growth factor-beta 1 (TGF-[B 1 )/Smad signaling. Little is known about its effects on PF through the non-Smad signaling, like the mitogen-activated protein kinase (MAPK) pathway. Therefore, this study aimed to investigate the role ofFSTL 1 in PF through the MAPK signaling pathway and its mechanisms in lung fibrogenesis. Methods: PF was induced in Fstll~ and wild-type (WT) C57BL/6 mice with bleomycin. After 14 days, the mice were sacrificed, and lung tissues were stained with hematoxylin and eosin; the hydroxyproline content was measured to confirm PF. The mRNA and protein level of FSTLI and the change of MAPK phosphorylation were measured by quantitative polymerase chain reaction and Western blotting. The effect of Fst11 deficiency on fibroblasts differentiation was measured by Western blotting and cell immunofluorescence. MAPK signaling activation was measured by Western blotting in Fst11+/ and WT fibroblasts treated with recombinant human FSTLI protein. We pretreated mouse lung fibroblast cells with inhibitors of the extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal kinase (JNK) signaling and analyzed their differentiation, proliferation, migration, and invasion by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and transwell assays. The Student's t-test was used to compare the differences between two groups. Results: Fstll deficiency attenuated phosphorylation of the ERK, p38, and JNK signaling in bleomycin-induced fibrotic lung tissue 14 days after injury (0.67 ± 0.05 vs. 1.22 ± 0.03, t = 14.92, P = 0.0001; 0.41 ± 0.01 vs. 1.15 ± 0.07; t = 11.19; P = 0.0004; and 0.41 ± 0.01 vs. 1.07± 0.07, t = 8.92, P = 0.0009; respectively), compared with WT lungs at the same time and in primary lung fibroblasts (0.82 ± 0.01 vs. 1.01 ±0.04, t = 4.06, P = 0.0150; 1.04 ±0.03 vs. 1.24 ± 0.03, t= 4.44, P = 0.0100: and 0.76 ±0.05 vs. 0.99± 0.05, t = 4.48, P = 0.0100; respectively), compared with TGF-β1-stimulated WT group. Recombinant human FSTLI protein in lung fibroblasts enhanced TG F-β1 -mediated phosphorylation of the ERK ( 1.19± 0.08 vs, 0.55 ± 0.04, t = 6.99, P = 0.0020), p38 ( 1.18 ±0.04 vs. 0.66 ± 0.03, t = 11.20, P = 0.0020), and .INK ( 1,11± 0.01 vs. 0.84 ± 0.04, t = 6.53, P = 0.0030), compared with the TGF-β1-stimulated WT group. Fstll-deficient fibroblasts showed reduced alpha-smooth muscle actin (α-SMA) expression (0.70 ± 0.06 vs. 1.28 ±0.11, t = 4.65, P = 0.0035, compared with the untreated WT group; 1.40 ± 0.05 vs. 1.76± 0.02, t = 6.31, P = 0.0007; compared with the TGF-β1-treated WT group). Compared with the corresponding condition in the control group, the TGF-β1/FSTL 1-mediated α-SMA expression was significantly suppressed by pretreatment with an inhibitor of p38 (0.73± 0.01 vs. 1.13 ± 0.10, t = 3.92, P = 0.0078) and JNK (0.78 ± 0.03 vs. 1.08 ± 0.06, t = 4.40,P = 0.0046) signaling. The proliferation of mouse lung fibroblast cells (MLgs) significantly decreased after treatment of an inhibitor of p38 (0.30 ±0.01 vs. 0.46 ±0.03, t = 4.64, P = 0.0009), JNK (0.30 ± 0.01 vs. 0.49 ± 0.01, t = 12.84, P = 0.0001), and Smad2/3 (0.18 ± 0.02 vs. 0.46 ±0.02, t = 12.69, P = 0.0001) signaling compared with the dimethylsulibxide group. The migration and invasion cells of MLgs significantly decreased in medium pretreated with an inhibitor of p38 (70.17 ±3.28 vs. 116.30 ± 7.11, t = 5.89, P = 0.0042 for the migratory cells; 19.87 ± 0.84 vs. 32.70 i 0.95, t =10.14, P = 0.0005 for the invasive cells), JNK (72.30 ±3.85 vs. 116.30 ± 7.11, t = 5.44, P = 0.0056 for the migratory cells; 18.03 ± 0.94 vs. 32.70 ± 0.95, t = 11.00, P = 0.0004 for the invasive cells), and Smad2/3 (64.76 ± 1.41 vs. 116.30 ± 7.11, t = 7.11, P = 0.0021 for the migratory cells; 18.03 ± 0.94 vs. 32.70 ±0.95, t = 13.29, P = 0.0002 for the invasive cells) signaling compared with the corresponding condition in the dimethylsulfoxide group. Conclusion: FSTL1 affects lung fibroblast differentiation, proliferation, migration, and invasion through p38 and JNK signaling, and in this way, it might influence the development of PF.
文摘Pulmonary nocardiosis is an opportunistic infection,especially in immunocompromised patients.Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease.We report a case of pulmonary nocardiosis with secondary HLH.
基金This work was supported by grants from the Chinese Academy of Medical Sciences Fund(No.2018-12M-1-001 and No.2019PT320021).
文摘Idiopathic pulmonary fibrosis(IPF)is a chronic,progressive,and generally fatal fibrotic lung disease with a median survival of 2 to 3 years after diagnosis.[1,2]Acute exacerbation of IPF(AE-IPF)is defined as an acute,clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality.Nearly 46%of deaths in IPF are caused by AE-IPF,and the median survival of patients with AE-IPF is approximately 3 to 4 months.[3]Over the past 27 years,great efforts have been paid to find therapies that might work for patients with this condition.We herein summarize current therapies for patients with AE-IPF.
文摘An outbreak of coronavirus disease 2019(COVID-19)has caught global attention and caused enormous damage.2019 novel coronavirus,also known as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),shares remarkable homology with severe acute respiratory syndrome(SARS)coronavirus and Middle East respiratory syndrome(MERS)coronavirus.In the follow-up studies,62%of SARS and 33%of MERS patients,who tended to be older and have longer intensive care unit admissions,had radiographic evidence of pulmonary fibrosis(PF)after hospital discharge.11,21 The repercussions of COVID-19 may also lead to PF,impair pulmonary function,and threaten life quality.
基金the grants from the National Key Technologies R&D Program Precision Medicine Research(No.2016YFC0901101)CAMS Innovation Fund for Medical Sciences(CIFMS,No.2018-12M-1-001)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2019PT320021).
文摘Idiopathic pulmonary fibrosis(IPF)incidence shows wide variations in different countries,ranging from 3 to 9 per 100,000 inhabitants per year in North America and Europe,while in South America and Asia,incidence is lower,ranging from 1.2 to 4.16 per 100,000 inhabitants per year.
文摘To the Editor: Chronic obstructive puhnonary disease (COPD) is a common preventable and treatable disease, characterized by persistent and progressive airflow limitation due to abnormal inflammation in the airways and lung to noxious particles or gases. Exacerbation of COPD is rarely induced by foreign body aspiration. In the present report, we described a male patient with acute exacerbation of COPD caused by foreign body aspiration.