Microarray profiling identifies extracellular circulating miRNAs dysregulated in cystic fibrosis.

Sci Rep. 2019 Oct 29;9(1):15483

Authors: Ideozu JE, Zhang X, Rangaraj V, McColley S, Levy H

Abstract
Extracellular circulating miRNAs (ECmiRNAs) play a crucial role in cell-to-cell communication and serve as non-invasive biomarkers in a wide range of diseases, but their abundance and functional relevance in cystic fibrosis (CF) remain poorly understood. In this study, we employed microarray technology to identify aberrantly expressed plasma ECmiRNAs in CF and elucidate the functional relevance of their targets. Overall, we captured several ECmiRNAs abundantly expressed in CF. Expression levels of 11 ECmiRNAs differed significantly between CF and healthy control (HC) samples (FDR < 0.05, log2 FC≥2). Among these, 10 were overexpressed while only hsa-miR-598-3p was underexpressed in CF. The overexpressed miRNAs included three let-7 family members (hsa-let-7b-5p, hsa-let-7c-5p and hsa-let-7d-5p), three 103/107 family members (hsa-mir-103a-3p; hsa-mir-103b; hsa-mir-107), hsa-miR-486-5p, and other miRNAs. Using in silico methods, we identified 2,505 validated targets of the 11 differentially expressed miRNAs. Hsa-let-7b-5p was the most important hub in the network analysis. The top-ranked validated targets were involved in miRNA biogenesis and gene expression, including AGO1, DICER1, HMGA1, and MYC. The top pathways influenced by all targets were primarily signal transduction pathways associated with CF, including PI3K/Akt-, Wnt/β catenin-, glucocorticoid receptor-, and mTor signaling pathways. Our results suggest ECmiRNAs may be clinically relevant in CF and warrant further study.

PMID: 31664087 [PubMed - in process]

Transcriptomic profile of cystic fibrosis airway epithelial cells undergoing repair.

Sci Data. 2019 Oct 29;6(1):240

Authors: Zoso A, Sofoluwe A, Bacchetta M, Chanson M

Abstract
Pathological remodeling of the airway epithelium is commonly observed in Cystic Fibrosis (CF). The different cell types that constitute the airway epithelium are regenerated upon injury to restore integrity and maintenance of the epithelium barrier function. The molecular signature of tissue repair in CF airway epithelial cells has, however, not well been investigated in primary cultures. We therefore collected RNA-seq data from well-differentiated primary cultures of bronchial human airway epithelial cells (HAECs) of CF (F508del/F508del) and non-CF (NCF) origins before and after mechanical wounding, exposed or not to flagellin. We identified the expression changes with time of repair of genes, the products of which are markers of the different cell types that constitute the airway epithelium (basal, suprabasal, intermediate, secretory, goblet and ciliated cells as well as ionocytes). Researchers in the CF field may benefit from this transcriptomic profile, which covers the initial steps of wound repair and revealed differences in this process between CF and NCF cultures.

PMID: 31664037 [PubMed - in process]

Reclassification of CLSI criteria for ciprofloxacin and levofloxacin susceptibility against Pseudomonas aeruginosa: Implications for patients with cystic fibrosis(CF).

Clin Respir J. 2019 Oct 30;:

Authors: Millar BC, Malnarcic CM, McCaughan J, Moore JE

Abstract
Employment of the fluoroquinolones is an important antibiotic treatment against the Gram-negative bacterium, Pseudomonas aeruginosa (PA), in chronic lung infections in patients with cystic fibrosis (CF).1 Ciprofloxacin is the only oral antibiotic that is commonly employed in treating PA infections in CF.

PMID: 31663261 [PubMed - as supplied by publisher]

Interactions of the effector ExoU from Pseudomonas aeruginosa with short-chain phosphatidylinositides provide insights into ExoU targeting to host membranes.

J Biol Chem. 2019 Oct 29;:

Authors: Springer TI, Reid TE, Gies SL, Feix JB

Abstract
Pseudomonas aeruginosa is an opportunistic multidrug-resistant pathogen and a common cause of infection in cystic fibrosis and ventilator-associated pneumonia, and in burn and wound patients. P. aeruginosa uses its Type III secretion system (T3SS) to secrete various effector proteins directly into mammalian host cells. ExoU is a potent T3SS effector that after secretion localizes to the inner cytoplasmic membrane of eukaryotic cells where it exerts its phospholipase A2 activity upon interacting with ubiquitin and/or ubiquitinated proteins. In this study, we used site-directed spin labeling (SDSL) EPR spectroscopy to examine the interaction of ExoU with soluble analogs of phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2). We found that dioctanoyl (diC8) PI(4,5)P2 binds to and induces conformational changes in a C-terminal four-helix bundle (4HB) domain of ExoU previously implicated in membrane binding.  Other soluble phosphoinositides also interacted with the 4HB, but less effectively. Molecular modeling and ligand docking studies indicated the potential for numerous hydrogen-bond interactions within and between interhelical loops of the 4HB and suggested several potential interaction sites for PI(4,5)P2.  Site-directed mutagenesis experiments confirmed that the side chains of Gln-623 and Arg-661 play important roles in mediating PI(4,5)P2-induced conformational changes in ExoU. These results support a mechanism in which direct interactions with phosphatidylinositol-containing lipids play an essential role in targeting ExoU to host membrane bilayers. Molecules or peptides that block this interaction may prove useful in preventing the cytotoxic effects of ExoU to mitigate the virulence of P. aeruginosa strains that express this potent phospholipase toxin.

PMID: 31662432 [PubMed - as supplied by publisher]

Alternative chloride transport pathways as pharmacological targets for the treatment of cystic fibrosis.

J Cyst Fibros. 2019 Oct 26;:

Authors: Quesada R, Dutzler R

Abstract
Cystic fibrosis is a hereditary disease that originates from mutations in the epithelial chloride channel CFTR. Whereas established therapies for the treatment of cystic fibrosis target CFTR to repair its function, alternative therapeutic strategies aim for the restoration of chloride transport by the activation of other chloride transport proteins such as TMEM16A or SLC26A9 or by the application of synthetic anionophores. TMEM16A is an anion-selective channel that is activated by the binding of Ca2+ from the cytoplasm. Pharmacological efforts aim for the increase of its open probability at resting Ca2+ concentrations. SLC26 is an uncoupled chloride transporter, which shuttles chloride across the membrane by an alternate-access mechanism. Its activation requires its mobilization from intracellular stores. Finally, anionophores are small synthetic molecules that bind chloride to form lipid-soluble complexes, which shuttle the anion across the membrane. All three approaches are currently pursued and have provided promising initial results.

PMID: 31662238 [PubMed - as supplied by publisher]

Rebuttal from Stephen M. Stick and André Schultz.

J Physiol. 2018 08;596(16):3445-3446

Authors: Stick SM, Schultz A

PMID: 30014473 [PubMed - indexed for MEDLINE]

19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2019/10/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2019/10/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Impact of genetic testing and family health history of cystic fibrosis in the early prenatal diagnosis and prevention of a new case of genetic disorder.

Rom J Morphol Embryol. 2019;60(2):667-671

Authors: Albu CC, Stancu IG, Grigore LG, Albu DF, Albu ŞD, Pătraşcu A, Gogănău AM

Abstract
Cystic fibrosis (CF) is a multi-system autosomal recessive disorder, results of mutations in the CF transmembrane conductance regulator (CFTR) gene, located on the long arm of chromosome 7. We present a special family couple with particular medical history of CF, who comes to our Clinic for genetic tests and a prenatal genetic counseling, to prevent the birth of a new affected CF child. Genetic analysis showed that the first affected child, a daughter, is compound heterozygous for two clinically significant recessive mutations: c.1521_1523delCTT; p.Phe508del, inherited from her mother, who carries the same CFTR mutation, and c.1853_1863delTTTTGCATGAA; p.IIe618Argfs 2, inherited from her father, who is heterozygous, healthy carrier, for the same CFTR mutation. In our case report, early prenatal genetic testing, pre- and post-test genetic counseling was crucial in the management of the present pregnancy, to prevent the birth of a new affected CF child.

PMID: 31658342 [PubMed - in process]

Slowing ribosome velocity restores folding and function of mutant CFTR.

J Clin Invest. 2019 Oct 28;:

Authors: Oliver KE, Rauscher R, Mijnders M, Wang W, Wolpert MJ, Maya J, Sabusap CM, Kesterson RA, Kirk KL, Rab A, Braakman I, Hong JS, Hartman JL, Ignatova Z, Sorscher EJ

Abstract
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), with approximately 90% of patients harboring at least one copy of the disease-associated variant F508del. We utilized a yeast phenomic system to identify genetic modifiers of F508del-CFTR biogenesis, from which ribosomal protein L12 (RPL12/uL11) emerged as a molecular target. In the present study, we investigated mechanism(s) by which suppression of RPL12 rescues F508del protein synthesis and activity. Using ribosome profiling, we found that rates of translation initiation and elongation were markedly slowed by RPL12 silencing. However, proteolytic stability and patch-clamp assays revealed RPL12 depletion significantly increased F508del-CFTR steady-state expression, interdomain assembly, and baseline open-channel probability. We next evaluated whether Rpl12-corrected F508del-CFTR could be further enhanced with concomitant pharmacologic repair (e.g., using clinically approved modulators lumacaftor and tezacaftor) and demonstrated additivity of these treatments. Rpl12 knockdown also partially restored maturation of specific CFTR variants in addition to F508del, and WT Cftr biogenesis was enhanced in the pancreas, colon, and ileum of Rpl12 haplosufficient mice. Modulation of ribosome velocity therefore represents a robust method for understanding both CF pathogenesis and therapeutic response.

PMID: 31657788 [PubMed - as supplied by publisher]

Effect of salinity and temperature on the expression of genes involved in branchial ion transport processes in European sea bass.

J Therm Biol. 2019 Oct;85:102422

Authors: Masroor W, Farcy E, Blondeau-Bidet E, Venn A, Tambutté E, Lorin-Nebel C

Abstract
The responses of European sea bass to temperature increase and salinity decrease were investigated measuring mRNA expression levels of main genes involved in ion transport. Juvenile fish were pre-acclimated to seawater (SW) at 18 °C (temperate) or 24 °C (warm) for two weeks and then transferred for two weeks to either fresh water (FW) or SW at the respective temperature. Unlike temperate conditions, there is no change in Na+/K+-ATPase α1a (nka α1a) and Na+/H+ exchanger 3 (nhe3) mRNA expression following FW transfer in warm conditions. This is linked to the high expression of these genes in warm SW compared to temperate SW. Na+/Cl--cotransporter (ncc2a) expression however is increased following FW transfer in temperate and warm conditions. Main transporters involved in ion excretion (Na+/K+/2Cl--1 cotransporter, nkcc1 and cystic fibrosis transmembrane conductance regulator, cftr) as well as nitrogen excretion (Rh-glycoproteins, rhcg1 and rhbg) and acid-base regulation (V-H+-ATPase, vha-a and b) are highly expressed in SW warm conditions vs FW warm. Overall, our results suggest a higher activation of ion transport processes in warm conditions and more strikingly in SW. This is linked to a strong interplay between diverse ion transporters in order to coordinate physiological responses at the gill level.

PMID: 31657763 [PubMed - in process]

19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2019/10/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Inhaled Mucoactive Particles with Tailored Architecture for Enhanced Aerodynamicity, Stability and Efficacy.

Int J Pharm. 2019 Oct 21;:118740

Authors: Huey Lee S, Heng D, Teo JWP, Toh FKY, Tan RBH

Abstract
In respiratory and genetic disorders such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis and cystic fibrosis (CF), the lungs produce excess mucus, resulting in a thickened mass, which clogs up the airways and reduces airflow. Consequently, breathing becomes more difficult. Medications that break down the structure of mucus will be especially useful in managing the early symptoms of these diseases and preventing their progression into the more severe forms. This work therefore seeks to develop an inhaled mucoactive dry powder formulation that is efficacious on multiple fronts. As an innovative step, sodium chloride was used to tailor the surface architecture of ambroxol hydrochloride particles, such that the resulting angular features on the surfaces contributed to the creation of corrugated particles with enhanced aerodynamicity. The optimized spray-dried powder particles were of respirable-size (d50 of 2.85 ± 0.15 μm) and moderately corrugated. When the crystalline powder was dispersed via an Aerolizer® inhaler at 60 L/min, it gave a fine particle fraction (FPF) of ∼ 31%, which was a ten-fold improvement over the unmodified species (i.e. ambroxol hydrochloride alone). Tests on artificial sputum medium (ASM) showed that the optimized formulation was potentially useful in liquefying the mucus, which favorably pointed towards the effectiveness of the formulation. In addition, the formulation was also stable to moisture ingress (up to ∼ 60% RH) and had good flowability. Hence, the advent of angular adjuvant sodium chloride particles in a mucoactive formulation conferred a three-fold benefit to the product: 1) Improved aerodynamicity and flowability, 2) Enhanced moisture stability and 3) Synergistic mucolytic properties.

PMID: 31648015 [PubMed - as supplied by publisher]

Introduction to Purinergic Signaling.

Methods Mol Biol. 2020;2041:1-15

Authors: Burnstock G

Abstract
Purinergic signaling was proposed in 1972, after it was demonstrated that adenosine 5'-triphosphate (ATP) was a transmitter in nonadrenergic, noncholinergic inhibitory nerves supplying the guinea-pig taenia coli. Later, ATP was identified as an excitatory cotransmitter in sympathetic and parasympathetic nerves, and it is now apparent that ATP acts as a cotransmitter in most, if not all, nerves in both the peripheral nervous system and central nervous system (CNS). ATP acts as a short-term signaling molecule in neurotransmission, neuromodulation, and neurosecretion. It also has potent, long-term (trophic) roles in cell proliferation, differentiation, and death in development and regeneration. Receptors to purines and pyrimidines have been cloned and characterized: P1 adenosine receptors (with four subtypes), P2X ionotropic nucleotide receptors (seven subtypes) and P2Y metabotropic nucleotide receptors (eight subtypes). ATP is released from different cell types by mechanical deformation, and after release, it is rapidly broken down by ectonucleotidases. Purinergic receptors were expressed early in evolution and are widely distributed on many different nonneuronal cell types as well as neurons. Purinergic signaling is involved in embryonic development and in the activities of stem cells. There is a growing understanding about the pathophysiology of purinergic signaling and there are therapeutic developments for a variety of diseases, including stroke and thrombosis, osteoporosis, pain, chronic cough, kidney failure, bladder incontinence, cystic fibrosis, dry eye, cancer, and disorders of the CNS, including Alzheimer's, Parkinson's. and Huntington's disease, multiple sclerosis, epilepsy, migraine, and neuropsychiatric and mood disorders.

PMID: 31646477 [PubMed - in process]

Co-cultured microfluidic model of the airway optimized for microscopy and micro-optical coherence tomography imaging.

Biomed Opt Express. 2019 Oct 01;10(10):5414-5430

Authors: Liu Z, Mackay S, Gordon DM, Anderson JD, Haithcock DW, Garson CJ, Tearney GJ, Solomon GM, Pant K, Prabhakarpandian B, Rowe SM, Guimbellot JS

Abstract
We have developed a human bronchial epithelial (HBE) cell and endothelial cell co-cultured microfluidic model to mimic the in vivo human airway. This airway-on-a-chip was designed with a central epithelial channel and two flanking endothelial channels, with a three-dimensional monolayers of cells growing along the four walls of the channel, forming central clear lumens. These cultures mimic airways and microvasculature in vivo. The central channel cells are grown at air-liquid interface and show features of airway differentiation including tight-junction formation, mucus production, and ciliated cells. Combined with novel micro-optical coherence tomography, this chip enables functional imaging of the interior of the lumen, which includes quantitation of cilia motion including beat frequency and mucociliary transport. This airway-on-a chip is a significant step forward in the development of microfluidics models for functional imaging.

PMID: 31646055 [PubMed]

The anion transporter SLC26A9 localizes to tight junctions and is degraded by the proteasome when co-expressed with F508del-CFTR.

J Biol Chem. 2019 Oct 23;:

Authors: Sato Y, Thomas DY, Hanrahan JW

Abstract
Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) disrupt epithelial secretion and cause cystic fibrosis (CF). Available CFTR modulators provide only modest clinical benefits, so alternative therapeutic targets are being explored. The anion-conducting transporter solute carrier family 26 member 9 (SLC26A9) is a promising candidate, but its functional expression is drastically reduced in cells that express the most common CF-associated CFTR variant, F508del-CFTR, through mechanisms that remain incompletely understood. Here, we examined the metabolic stability and location of SLC26A9 and its relationship to CFTR. Compared with SLC26A9 levels in BHK cells expressing SLC26A9 alone or with wild-type CFTR (WT-CFTR), co-expression of SLC26A9 with F508del-CFTR reduced total and plasma membrane levels of SLC26A9. Proteasome inhibitors increased SLC26A9 immunofluorescence in primary human bronchial epithelial cells (pHBEs) homozygous for F508del-CFTR but not in non-CF pHBEs, suggesting that F508del-CFTR enhances proteasomal SLC26A9 degradation. Apical SLC26A9 expression increased when F508del-CFTR trafficking was partially corrected by low temperature or with the CFTR modulator VX-809. The immature glycoforms of SLC26A9 and CFTR co-immunoprecipitated, consistent with their interaction in the endoplasmic reticulum (ER). Transfection with increasing amounts of WT-CFTR cDNA progressively increased SLC26A9 levels in F508del-CFTR-expressing cells, suggesting that WT-CFTR competes with F508del-CFTR for SLC26A9 binding. Immunofluorescence staining of endogenous SLC26A9 and transfection of a 3HA-tagged construct into well-differentiated cells revealed that SLC26A9 is mostly present at tight junctions. We conclude that SLC26A9 interacts with CFTR in both the ER and Golgi and that its interaction with F508del-CFTR increases proteasomal SLC26A9 degradation.

PMID: 31645438 [PubMed - as supplied by publisher]

The importance of effective registries in pulmonary diseases and how to optimize their output.

Chron Respir Dis. 2019 Jan-Dec;16:1479973119881777

Authors: Chorostowska-Wynimko J, Wencker M, Horváth I

Abstract
Randomized controlled trials (RCTs) are essential for the approval of new therapies; however, because of their design, they provide little insight concerning disease epidemiology/etiology and current clinical practice. Particularly, in lung disease, rigid inclusion/exclusion criteria can limit the generalizability of pivotal trial data. Noninterventional studies (NIS), conducted through the well-established mechanism of patient registries, are undervalued as a means to close data gaps left by RCTs by providing essential data that can guide patient care at different levels from clinical decision-making to health-care policy. While NIS contribute valuable data in all disease areas, their importance in rare diseases cannot be underestimated. In respiratory disease, registries have been essential in understanding the natural history and different phenotypes of rare conditions, such as alpha 1 antitrypsin deficiency, cystic fibrosis, and idiopathic pulmonary fibrosis. Importantly, additional therapeutic outcome data were generated. While measures for enhancing data quality in RCTs have evolved significantly, the approach and effectiveness of registries is variable. Within this article, we review the contribution of registries to pulmonary disease and make recommendations for their effective management. Additionally, we assess limitations of registry data as well as challenges to registry operation, including the impact of the European Union General Data Protection Regulation.

PMID: 31645111 [PubMed - in process]

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

Book. 2012

Authors:

Abstract
Bile acids are a large family of molecules that have a steroidal structure and are synthesized from cholesterol in the liver and actively secreted along with cholesterol and phospholipids into the bile. Bile flowing from the liver is concentrated in the gallbladder and, in response to a meal, released into the upper intestine. In the intestines, bile acids act as detergents and help to emulsify fats, aiding in their digestion and absorption. After participating in digestion in the small bowel, bile acids are almost completely (95%) reabsorbed in the distal ileum and then retaken up from portal blood by the liver (enterohepatic circulation). The primary bile acids synthesized in the liver are cholic and chenodeoxycholic acid which are typically conjugated to glycine or taurine before secretion. In the intestine, the primary bile acids are often converted by colonic bacteria to the secondary bile acids, predominantly deoxycholic acid and lithocholic acid. The reabsorbed bile acids are transported to the liver in portal blood. Conjugated bile acids are then retaken up by hepatocytes via the sodium taurocholate cotransporter (NTCT), while unconjugated bile acids are taken up by organic anion transporters that also take up bilirubin and other anions. The total bile acid pool in humans is tightly controlled by a coordinated regulation of expression of genes involved with synthesis, secretion, reabsorption and reuptake of bile acids by the liver. The major components of the bile acid pool are cholic and chenodeoxycholic acid with lesser amounts deoxycholic and lithocholic acid and minor amounts of ursodeoxycholic acid. Bile acids also act as signaling molecules and are important in regulation of their own synthesis, uptake and secretion as well as control of cholesterol synthesis and regulation of lipid and glucose metabolism. Bile acid levels are increased in the serum and liver in patients with obstructive jaundice or cholestasis and, perhaps because of their inherent detergent activities, can cause hepatocyte injury. Thus, increased bile acid levels in hepatocytes may account for some of the liver damage in cholestatic liver diseases. Bile acids can be used as therapeutic agents, particularly in patients with cholestatic liver diseases where administered bile acids (such as ursodeoxycholic acid) replace the more lipophilic and toxic bile acids that accumulate during cholestasis. Bile acids are also useful for the medical treatment (dissolution) of gallstones by increasing bile acid and decreasing cholesterol concentrations in bile (causing a less saturated bile). Bile acids can also be useful as replacement therapy in patients with bile acid synthetic defects. Finally, the other metabolic effects of bile acids can be useful in treating metabolic diseases including nonalcoholic steatohepatitis. Four bile acids are currently approved for use in the United States and several others are under active investigation. Cholic acid is used for treatment of inherited defects in bile acid synthesis, chenodeoxycholic (chenodiol) and ursodeoxycholic (ursodiol) acid for gallstone dissolution, and obeticholic and ursodiol for chronic cholestatic liver diseases, specifically primary biliary cirrhosis. Obeticholic acid is under evaluation as therapy of other liver diseases including sclerosing cholangitis and nonalcoholic steatohepatitis. Ursodiol is used off label to prevent, treat or ameliorate several uncommon forms of liver disease, including intrahepatic cholestasis of pregnancy, sinusoidal obstruction syndrome, graft-vs-host disease, cystic fibrosis associated liver disease, parenteral nutrition related liver injury and even acute, drug induced liver injury. The long term efficacy in ameliorating the course of these diseases is, however, unproven. Separate documents are available in LiverTox for each of the currently available bile acids. References given in this overview section are limited to general publications on bile acid metabolism and use as therapeutic agents. Drug Class: Gastrointestinal Agents: Chenodiol (Chenodeoxycholic Acid). Cholic Acid. Obeticholic Acid. Ursodiol (Ursodeoxycholic Acid).

PMID: 31643938

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

Book. 2012

Authors:

Abstract
Ivacaftor, lumacaftor and tezacaftor are orally available potentiators or correctors of the cystic fibrosis transmembrane conductance regulator (CFTR) that are used to treat patients with cystic fibrosis with specific mutations of the CFTR. Ivacaftor alone or in combination with lumacaftor or tezacaftor has been associated with transient serum enzyme elevations during treatment, but neither agent has been convincingly implicated in cases of clinically apparent acute liver injury with jaundice.

PMID: 31643225

Rational particle design to overcome pulmonary barriers for obstructive lung diseases therapy.

J Control Release. 2019 Oct 20;:

Authors: He Y, Liang Y, Han R, Lu WL, Wo Mak JC, Zheng Y

Abstract
Pulmonary delivery of active drugs has been applied for the treatment of obstructive lung diseases, including asthma, chronic obstructive pulmonary disease and cystic fibrosis, for several decades and has achieved progress in symptom management by bronchodilator inhalation. However, substantial progress in anti-inflammation, prevention of airway remodeling and disease progression is limited, since the majority of the formulation strategies focus only on particle deposition, which is insufficient for pulmonary delivery of the drugs. The lack of knowledge on lung absorption barriers in obstructive lung diseases and on pathogenesis impedes the development of functional formulations by rational design. In this review, we describe the physiological structure and biological functions of the barriers in various regions of the lung, review the pathogenesis and functional changes of barriers in obstructive lung diseases, and examine the interaction of these barriers with particles to influence drug delivery efficiency. Subsequently, we review rational particle design for overcoming lung barriers based on excipients selection, particle size and surface properties, release properties and targeting ability. Additionally, useful particle fabrication strategies and commonly used drug carriers for pulmonary delivery in obstructive lung diseases are proposed in this article.

PMID: 31644935 [PubMed - as supplied by publisher]