Pulmonary Drug Delivery Systems For The Treatment Of Lung Injury Induced By Haze

The process of social industrialization usually brings serious environmental pollution,among which haze is especially prominent.Now,haze has become an important public health problem.In the last century,serious air pollution events occurred in the process of rapid industrialization in the western developed countries.To this day,the ambient air pollution is still a prominent problems in developing countries and a great challenge to human health.The lungs communicate directly with the external environment.Without physical protection,the lungs are the main organ injured by air pollution.According to the survey data,fine particulate matter（PM 2.5）has been shown to cause the production and aggravation of respiratory diseases and the increasing of morbidity and mortality.However,people are not very aware of the health threat of haze at present.In addition to physical protection,the appropriate medical intervention is limited.In this paper,we propose a theory about the lung injuries caused by haze,which can be divided into three types,including（a）the physical lung injury caused by inorganic particulate matter in haze without degradation,the early manifestation of injury include inflammation,oxidative stress;（b）the chemical lung injury caused by the soluble components and organics in the haze,e.g.,the acid injury caused by sulfur dioxide and oxidative injury caused by ozone;（c）the biological lung injury and infection caused by the pathogen attached to the haze particles.The pulmonary drug delivery system（PDDS）can directly deliver the drugs to the lungs and play a role quickly,which is benifit to the treatment of lung injury induced by haze.The side effects will reduce due to the less distribution of drugs in other tissues.Therefore,PDDS is highly effective and safe for the treatment of lung injury induced by haze.In this study,the animal lung injury models caused by different components of haze were established.According to the injury mechanism,the appropriate drugs were screened.Based on their properties,drugs were prepared into dosage forms,such as liposome,inclusion complex,and further into PDDS,such as dry powder inhaler（DPI）.The characterization and pharmacodynamics were evaluated,and the mechanism of PDDS for the treatment of lung injury caused by haze was illuminated.The treatment options for different types of lung injury were provide.1.Treatment of physical lung injuryNano-Si O₂ was used to represent the inorganic particles in haze and was sprayed via airway.The hemorrhage of rat tissues were examined and the increase of IL-6 and TGF-βwere determined.The rat physical lung injury model were established by 0.1 mg nano-SiO₂/rat.Different types of drugs were selected and the appropriate dosage forms for pulmonary delivery were prepared according to their properties.The therapeutic effect of chloroquine phosphate solution,L-cysteine solution,clodronate disodium solution,fluoxetine hydrochloride solution,curcumin liposome and SB203580 solution were investigated.They could alleviate lung injury to some extent.Fluoxetine significantly alleviated lung hemorrhage and decreased the levels of IL-6,IL-1βand TNF-αin bronchoalveolar lavage fluids（BALF）.Fluoxetine is an excellent inhalation for the treatment of physical lung injury caused by haze.2.Treatment of chemical lung injuryHydrochloric acid（HCl）was used to represent the acid component of the haze.The rat model of acid lung injury was established by spraying HCl through airway.Chloroquine phosphate was prepared into DPI.The fine particle dose（FPD）,fine particle fraction（FPF）,respirable fraction（RF）and emitted dose（ED）were 2.86mg,22.49%,12.70%and 92.98%,respectively,which was suitable for pulmonary delivery.After administration of chloroquine DPI,the levels of TNF-α,IL-6 and total protein were decreased,and the expressions of NF-κB p65,p21 and sPLA₂IIA were significantly inhibited.The effect of chloroquine DPI was better than that of the positive drug dexamethasone in the treatment of chemical lung injury.Hydrogen peroxide（H₂O₂）was used to represent the oxidative components of haze and was sprayed via airway.The pathological sections of lung tissues were examined and the rat oxidative lung injury model were established by 0.2 mL of 10 mM H₂O₂.The SOD liposomes,chloroquine liposomes and the SOD/chloroquine liposomes were prepared.The size of the above liposomes were all less than 100 nm.The effects of SOD solution,liposomes and DPIs,chloroquine solution,liposomes and DPIs,SOD/chloroquine liposomes and DPIs on lung injury were investigated.The solution or liposomes were the appropriate formulations.According to the pathological sections of lung tissue and inflammatory cytokines（total protein,GSH,TNF-α,and IL-6）in BALF,the appropriate dose were 500 U SOD,0.5 mg chloroquine,250 U SOD/0.25 mg chloroquine,respectively.The effects of the combined two drugs with different doses showed that they could play anti-lung injury effect together with different mechanisms,but there was no synergistic effct.Lipopolysaccharide（LPS）was used to built acute lung injury（ALI）.The chloroquine DPI could significantly attenuate lung injury through decreasing the level of inflammatory cytokines（total protein,TNF-α,and IL-6）in BALF,inhibiting the expressions of NF-κB p65,p21 and sPLA₂IIA.The anti-ALI effect was similar to that of the positive drug dexamethasone in3.Treatment of biological lung injuryAcinetobacter baumannii and Candida albicans was used to represent the microorganisms in haze and was sprayed via airway for the bacterial and fungal pneumonia rat model to simulate the biological injury caused by haze.The tea tree oil-β-cyclodextrin inclusion complexes（TTO-β-CD）were prepared and characterized.The powder was irregular according to scanning electron microscopy（SEM）.The mass median aerodynamic diameters（MMAD）,emptying rate and FPF were 5.59μm,98.0%and 51.22%,respectively,which was suitable for pulmonary delivery.The inhibitory effect of TTO-β-CD on fungi or bacteria was similar to that of the positive drugs（fluconazole and penicillin）.TTO-β-CD reduced the amounts of leukocytes and neutrophils in BALF,decreased the levels of inflammatory cytokines and down regulated the expression of COX-2.The effect of anti-fungal pneumonia was better than that of fluconazole,and the effect of anti-bacterial pneumonia was similar to penicillin.Staphylococcus aureus was used to represent microbes in haze,and the bacterial pneumonia model was obtained in the same way.Andrographolide（AG）liposomes were prepared by ethanol injection method.The particle size of AG liposomes was77.91 nm.Mannitol was added and the liposomes were freeze-dried to obtain andrographolide liposome dry powder inhaler（LADPI）.The powder was irregular according to SEM.The MMAD and FPF were 4.87μm and 23.03%,respectively.The entrapment efficiency and drug loading of reconstruction of LADPI were 94.8%and6.70%,respectively.LADPI showed almost no in vitro antibacterial activity.However,after pulmonary administration LADPI significantly decreased the colony-forming units（CFUs）,reduced the levels of IL-1,TGF-β,total protein,ICAM1 and IFN-γin pneumonia rats,inhibited the phosphorylation of IκB-α,thereby inhibited NF-κB pathway and attenuated inflammation.LADPI regulated the levels of immune cells（e.g.leukocytes and neutrophils）.Therefore,LADPI exhibited anti-bacterial pneumonia effect by inhibiting the local inflammatory response and regulating the immune response.4.Treatment of lung injury caused by particulate matters in hazeThe particulate matters less than 2.5μm（PM 2.5）in the ground atmosphere were collected,and their structures and properties were characterized.The PM 2.5 were black solid.The main elements in PM 2.5 were C,O,Si based on the energy spectrum analysis.PM 2.5 was mainly composed of hydrocarbons and dust.Microbial community diversity cloud analysis showed that PM 2.5 contained fungi and bacteria.The suspension of PM 2.5 was prepared and sprayed through air way to establish the lung injury rat model caused by PM 2.5 with the dose of 3 mg/rat.The effects of fluoxetine solution,L-cysteine solution,chloroquine solution and curcumin liposomes on lung injury were investigated after pulmonary delivery.They all could alleviate the lung injury,and significantly reduce the levels of IL-1βand TNF-α.They are promising pulmonary delivery medicine for the treatment of lung injury caused by PM 2.5.We focus on the public health problems and clinical requirement.PDDS is applied for the therapy of lung injury caused by haze with high efficiency and safety.This study meets the needs of public health and provides a reasonable and effective solution for health problems caused by haze.