Effects Of Ambient Temperature On Lung Function And Potential Roles Of Inflammation,Oxidative Damage,and Hormones

Ambient temperature is an important environmental physical factor,which is crucial to human survival and health.The respiratory system has the most frequent contact and the extensive contact area with the external environment,which is considered one of the most sensitive systems to respond to ambient temperature.Lung function is an important noninvasive index to reflect the health status of the respiratory system.In the context of global warming,it is necessary to deeply study the impact of ambient temperature on lung function and its possible pathways.The factors affecting lung function are complex and diverse.Previous studies have pointed out that a variety of individual characteristics(age,gender,etc.)and lifestyles(smoking,drinking,etc.)can affect lung function;environmental chemicals like airborne particles can be inhaled into the respiratory tract,and then also cause changes in lung function.These factors can enhance or weaken the actual effect of ambient temperature on lung function,which brings some difficulties in correctly identifying the effect of ambient temperature on lung function.The controlled exposure study is an experimental epidemiological method to directly explore the biological relationship between objective exposure and body response by controlling other potential confounders,which is widely used in the field of environmental epidemiology.But there are relatively few studies on the relationship between temperature and lung function.Previous studies have suggested that ambient temperature can cause inflammation,oxidative damage,and changes in the hypothalamic-pituitary-adrenal axis(HPA)and hypothalamic-pituitary-thyroid axis(HPT)hormones,and the three have also been confirmed to be involved in the occurrence and development of several respiratory diseases.However,whether the three are involved in the changes in lung function caused by ambient temperature needs to be further explored.To explore the effect of ambient temperature on lung function and the potential role of inflammation,oxidative damage,and HPA and HPT hormones,this study was carried out by the following three aspects.First,this study took all the subjects who completed questionnaire surveys,physical examinations,and lung function tests in Dongfeng General Hospital from the Dongfeng-Tongji cohort as the study subjects.The associations between ambient temperature and lung function were analyzed by collecting the basic information and lung function levels of the subjects and the ambient temperature data during the study period.Second,we recruited healthy volunteers to conduct a controlled exposure study.All volunteers were exposed to the middle(18℃),low(6℃),and high(30℃)temperatures for 12 hours,and maintained the same diet and other conditions.Their lung function levels under different temperatures were measured to further explore the direct relationship between temperature and lung function.On this basis,the inflammatory markers,oxidative damage markers,and HPA and HPT hormones in biological samples(blood or urine)of volunteers were measured to explore the potential role of the three in the temperature effect on lung function.All the studies were approved by the Ethics and Human Subject Committee of Tongji Medical College,Huazhong University of Science and Technology,and all subjects signed the informed consent.Part Ⅰ The association between ambient temperature and lung function Objective: To explore the association between ambient temperature and lung function,and the effect modification and the combined effects of individual characters and lifestyles on the association.Methods: A total of 13,818 and 11,693 participants who finished both lung function tests and semi-structured questionnaires in the first(2013)and second(2018)follow-ups of the Dongfeng-Tongji cohort were recruited in the Part,of which 6,383 subjects completed two lung function tests.The demographic information and lifestyles of the subjects were collected through structured questionnaires,and the lung function levels were measured according to the guidelines of the American Thoracic Association.The lung function parameters included forced vital capacity(FVC),forced expiratory volume in one second(FEV1),FEV1/FVC,peak expiratory flow(PEF),and maximum mid-expiratory flow(MMF).The data on ambient temperature during the study period were collected from the National Meteorological Information Centre.Generalized additive mixed models(GAMM)and linear mixed models(LMM)were used to analyze the nonlinear and linear relationships between ambient temperature with multi-day lag(lag01-lag07)and lung function,respectively.In addition,stratified analysis was used to explore the association between ambient temperature and lung function in different subgroups of individual characters,including sex(male or female),age(<65 years or ≥65 years),body mass index(BMI)(<24.0 kg/m2 or ≥24.0 kg/m2),body surface area(BSA)(<1.65 m2 or ≥1.65 m2),and lifestyles,including smoking status(yes or no),drinking status(yes or no),and physical activity(yes or no).Then we further explored the effect modification and the combined effects of these factors on the association.Results: A total of 19,128 subjects with 25,511 observations were included in the analyses,of which males were 10,604(41.35%).The mean age of all subjects was 65.13 years,FVC was 2,525.21 m L,FEV1 was 2,076.02 m L,FEV1/FVC was 82.84%,PEF was 4,771.98 m L/s,MMF was 2,309.25 m L/s.The temperature ranged from-0.4 to 32.7℃(average 21.5℃)during the study period.After adjusting for the covariates,we found inversely J-shaped associations for ambient temperatures(lag01-lag07)and FVC,FEV1,and PEF.The ambient temperature was positively associated with FVC,FEV1,and PEF in low temperatures(<18℃),and the effects of lag05 were strongest;the ambient temperature was negatively associated with FVC and FEV1 in high temperatures(≥18℃),and the effects of lag07 were strongest(all P<0.05).With each 1℃ increases in ambient temperature,FVC increased by 10.37 m L [95% confidence interval(CI): 2.83 to 17.91 m L],FEV1 increased by 10.83 m L(4.52 to 17.13 m L),and PEF increased by 57.54 m L/s(32.66 to 82.41 m L/s)in low temperature(lag05),while FVC decreased by 9.03 m L(-11.98 to-6.08 m L)and FEV1 decreased by 2.88 m L(-5.30 to-0.46 m L)in high temperature(lag07)(all P<0.05).FEV1/FVC and MMF were positively associated with ambient temperature(lag01-lag07).With each 1℃ increases in ambient temperature,FEV1/FVC and MMF increased significantly from lag01 to lag07,with the largest increase at lag02 [0.21%(0.18% to 0.25%)] and lag04 [11.66 m L/s(8.59 to 14.73 m L/s)],respectively(all P<0.05).We observed significant effect modification of gender,age,BMI,BSA,smoking status,drinking status,and physical activity on the associations(all Pmodification<0.05).The results showed that the low-temperature effects on lung function were more pronounced in males,subjects with age<65 years,BMI<24.0 kg/m2,and BSA≥1.65 m2,smokers,and drinkers;the high-temperature effects on lung function were more pronounced in females,subjects with BMI<24.0 kg/m2 and BSA<1.65 m2,smokers,drinkers,and non-exercisers(P<0.05).The combined effect results showed that females,subjects with age≥65 years and BSA<1.65m2,and smokers had combined effects with high temperature to reduce the lung function(P<0.05).Conclusion: Ambient temperature affects different lung function parameters differently.Ambient temperature showed inversely J-shaped associations with FVC,FEV1,and PEF and positive associations with FEV1/FVC and MMF.Several individual characters(gender,age,BMI,and BSA)and lifestyles(smoking status,drinking status,and physical activity)have effect modification and/or combined effects on the association.Part Ⅱ Temperature and lung function levels: a controlled exposure study Objective: To investigate the direct relationship between temperature and lung function through a controlled exposure study.Methods: A total of 47 healthy non-obese volunteers were recruited for the study.All subjects underwent three temperature exposures in sequence,namely middle(18℃),low(6℃),and high(30℃)temperatures,and each exposure duration was 12 hours.Lung function was performed every 2 hours for all subjects in each exposure.The collection or measurement methods of basic information,physical examination,and lung function are the same as Part Ⅰ.To minimize the influence of individual heterogeneity and circadian rhythm,the lung function measures at each time point under middle temperature were set as the baseline,and the corresponding values under low or high temperature were divided by the baseline,expressed as percentages of baseline.LMM was used to assess the changes in lung function parameters(FVC,FEV1,FEV1/FVC,PEF,and MMF)under low or high temperatures relative to the middle temperature.Stratified analysis was performed to explore the relationship between temperature and lung function in different gender groups and the effect modification of gender on the relationship.Results: A total of 43 volunteers(average 23.91 years)completed the entire experiment,of which males were 20.Compared to the middle temperature,the mean values of FVC,FEV1,and MMF decreased by 2.20%(95% CI:-3.34% to-1.07%),2.59%(-3.92% to-1.26%),and 4.36%(-7.41% to-1.32%),respectively,and the mean value of PEF increased by 5.68%(1.15% to 10.20%)under the low temperature for 12 hour;while under high temperature for 12 hour,the mean value of FVC decreased by 1.59%(-2.87% to-0.32%),the mean values of FEV1/FVC and PEF increased by 1.56%(0.35% to 2.77%)and 7.29%(2.34% to 12.24%),respectively(all P<0.05).Further analyses revealed that under low temperature,FVC decreased significantly after 2-8 hours of exposure;FEV1 decreased significantly after 2,6,and 8 hours of exposure;PEF increased significantly after 2-8 and 12 hours of exposure;MMF decreased significantly after 8-10 hours of exposure(all P<0.05).Under high temperature,FEV1/FVC increased significantly after 6 hours of exposure;PEF increased significantly after 2-8 and 12 hours of exposure(all P<0.05).A significant effect modification of gender on the relationship was observed(all Pmodification<0.05).The low-temperature effect was more pronounced on PEF in females and on MMF in males,whereas the high-temperature effect was more pronounced on FVC,FEV1/FVC,PEF,and MMF in females(P<0.05).Conclusion: Except for PEF,the trends of the temperature effect on lung function in this Part are similar to Part I.Low temperature can reduce FVC,FEV1,and MMF,and increase PEF,while the high temperature can reduce FVC,and increase FEV1/FVC and PEF.Gender has effect modification on the effect of low temperature on PEF and MMF,and high temperature on FVC,FEV1/FVC,PEF,and MMF.Part Ⅲ The potential roles of inflammation,oxidative damage,and hormones in the temperature effect on lung function Objective: To explore the relationship of temperature with inflammatory markers,oxidative damage markers,and HPA and HPT hormones,and to analyze the potential role of the latter on the effect of temperature on lung function.Methods: The subjects were based on Part Ⅱ.blood and urine samples of the subjects were collected after each temperature exposure,but one refused to provide and was excluded.The blood levels of C-reactive protein(CRP),procalcitonin(PCT)as well as the platelet-lymphocyte ratio(PLR),and neutrophil-lymphocyte ratio(NLR)as inflammatory markers were measured by fully automated blood/biochemistry analyzers;The levels of protein carbonylation(PCO)in plasma as protein oxidative damage marker were measured by the colorimetric method.The levels of urinary 8-iso-prostaglandin-F2α(8-iso PGF2α)and 8-hydroxy-2-deoxyguanosine(8-OHd G),as lipid and DNA oxidative damage markers,respectively,were measured by solid-phase extraction-high performance liquid chromatography-mass spectrometry.Blood levels of HPA hormones,including adrenocorticotropic hormone(ACTH)and cortisol(CORT),and of HPT hormones,including thyroid-stimulating hormone(TSH),triiodothyronine(T3),tetraiodothyronine (T4),free triiodothyronine(FT3)and free tetraiodothyronine(FT4)were measured by a fully automated biochemical analyzer.To minimize the influence of individual heterogeneity,the levels of inflammatory markers,oxidative damage markers,and HPA and HPT hormones under middle temperature(18℃)were set as the baseline,and the corresponding values under low(6℃)or high(30℃)temperatures were divided by the baseline,expressed as percentages of baseline.LMM was used to assess the changes in the markers under low or high temperatures relative to the middle temperature,as well as their associations with lung function(FVC,FEV1,FEV1/FVC,PEF,and MMF).Results: A total of 42 healthy volunteers were included in the study,including 19 males.Compared with middle temperature,several inflammatory markers,oxidative damage markers,and T4 were increased under low-temperature exposure.Of them,PCT,PLR and NLR increased by 46.73%(95% CI: 8.26% to 85.19%),9.85%(1.05% to 18.64%)and 19.98%(4.37% to 35.60%),respectively;8-iso PGF2α and 8-OHd G were increased by 93.79%(14.06% to 173.53%)and 38.21%(14.45% to 61.96%),respectively;and T4 increased by 5.11%(1.93% to 8.28%)(all P<0.05).Under high-temperature exposure,CORT,T4,FT3,and FT4 decreased by 15.16%(-29.24% to-1.08%),12.50%(-15.77% to-9.24%),4.78%(-7.07% to-2.49%)and 3.34%(-6.34% to-0.34%),respectively,while ACTH increased by 278.16%(207.42% to 348.90%)(all P<0.05).Further association analysis showed that for every 10% increase in 8-OHd G,FVC decreased by 0.007%(-0.013% to-0.002%),FEV1 decreased by 0.016%(-0.022% to-0.010%)and FEV1/FVC decreased by 0.009%(-0.014% to-0.005%);For every 10% increase in ACTH,PEF increased by 0.101%(0.003% to 0.198%);For every 10% increase in FT3,FVC increased by 1.066%(0.194% to 1.939%),FEV1/FVC was decreased by 0.970%(-1.729% to-0.210%)(all P<0.05).Conclusion: Low temperature can cause inflammation,lipid,and DNA oxidative damage,and promote T4 release.High temperature can promote ACTH release and inhibits the release of CORT,T4,FT3,and FT4.DNA oxidative damage marker and some hormones may be involved in the temperature effect on lung function.