Cell. 2022 Jan 6;185(1):158-168.e11. doi: 10.1016/j.cell.2021.12.009.

ABSTRACT

Small molecule chaperones have been exploited as therapeutics for the hundreds of diseases caused by protein misfolding. The most successful examples are the CFTR correctors, which transformed cystic fibrosis therapy. These molecules revert folding defects of the ΔF508 mutant and are widely used to treat patients. To investigate the molecular mechanism of their action, we determined cryo-electron microscopy structures of CFTR in complex with the FDA-approved correctors lumacaftor or tezacaftor. Both drugs insert into a hydrophobic pocket in the first transmembrane domain (TMD1), linking together four helices that are thermodynamically unstable. Mutating residues at the binding site rendered ΔF508-CFTR insensitive to lumacaftor and tezacaftor, underscoring the functional significance of the structural discovery. These results support a mechanism in which the correctors stabilize TMD1 at an early stage of biogenesis, prevent its premature degradation, and thereby allosterically rescuing many disease-causing mutations.

PMID:34995514 | DOI:10.1016/j.cell.2021.12.009

Int J Cardiovasc Imaging. 2022 Jan 7. doi: 10.1007/s10554-021-02496-6. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) transmembrane conductance regulator is expressed in myocardium, but cardiac involvement in CF remains poorly understood. The recent development of a combined cardiopulmonary magnetic resonance imaging technology allows for a simultaneous interrogation of cardiac and pulmonary structure and function. The aim of this study was to investigate myocardial manifestations in adults with CF, both in a stable state and during an acute respiratory exacerbation, and to investigate the relationship between cardiac and pulmonary disease. Healthy adult volunteers (n = 12) and adults with CF (n = 10) were studied using a multiparametric cardiopulmonary magnetic resonance protocol. CF patients were scanned during an acute respiratory exacerbation and re-scanned when stable. Stable CF was associated with left ventricular dilatation and hypertrophy (LVH; left ventricular mass: CF 59 ± 9 g/m2 vs. control 50 ± 8 g/m2; p = 0.028). LVH was predominantly driven by extracellular myocardial matrix expansion (extracellular matrix mass: CF 27.5 ± 3.4 g vs. control 23.6 ± 5.2 g; p = 0.006; extracellular volume [ECV]: CF 27.6 [24.7-29.8]% vs. control 24.8 [22.9-26.0]%; p = 0.030). Acute CF was associated with an acute reduction in left ventricular function (ejection fraction: acute 57 ± 3% vs. stable 61 ± 5%; p = 0.025) and there was a suggestion of myocardial oedema. Myocardial oedema severity was strongly associated with the severity of airflow limitation (r = - 0.726, p = 0.017). Multiparametric cardiopulmonary magnetic resonance technology allows for a simultaneous interrogation of cardiac and pulmonary structure and function. Stable CF is associated with adverse myocardial remodelling, including left ventricular systolic dilatation and hypertrophy, driven by myocardial fibrosis. CF exacerbation is associated with acute myocardial contractile dysfunction. There is also a suggestion of myocardial oedema in the acute period which is related to pulmonary disease severity.

PMID:34994881 | DOI:10.1007/s10554-021-02496-6

Front Biosci (Landmark Ed). 2021 Dec 30;26(12):1613-1620. doi: 10.52586/5054.

ABSTRACT

In recent years, advances in diagnosis and treatment have significantly modified the short- and long-term prognosis of cystic fibrosis (CF) patients. However, as in the past, the most important health problem that has significantly reduced the quality of life in CF patients is the progressive deterioration of lung structure and function. In recent years, Achromobacter species have emerged with increasing incidence in the respiratory secretions of CF subjects. The significance of this detection remains debated. In this review article, the characteristics of these pathogens, the importance of their presence in CF patients, and possible antibiotic treatment of treatments for colonization and infection are discussed. Literature analysis shows that Achromobacter species, mainly A. xylosoxidans, are pathogens with intrinsic characteristics that favour persistent lung colonization and several virulence factors and secretion systems that significantly interfere with respiratory cell survival. However, although it seems undebatable that Achromobacterspecies detection is a marker of CF severity, the role of these pathogens as a cause of lung structure and functional deterioration is not definitively established. Nonetheless, there is general agreement about the need for antibiotic therapy to eradicate these pathogens when they are detected in CF patients. Unfortunately, eradication is difficult, and no standard treatment is recommended by scientific societies. New possibilities are potentially offered by some recently developed drugs, such as cefiderocol, but further studies on the dosage, treatment duration and efficacy and safety of this new antibiotic in CF patients of different ages are urgently needed.

PMID:34994175 | DOI:10.52586/5054

Front Biosci (Landmark Ed). 2021 Dec 30;26(12):1396-1410. doi: 10.52586/5034.

ABSTRACT

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) has been associated with vascular tone and blood pressure (BP), however, its role in the genesis of hypertension remains elusive. In the present study, we investigated the regulating effect of CFTR on angiotensin II (Ang II) -induced hypertension and defined the molecular role of CFTR in vasoconstriction.

RESULTS: We found that CFTR mRNA and protein expression were markedly down-regulated in the arteries from Ang II induced hypertensive animals. During the development of hypertension, BP of Cftr-⁣/- mice was significantly higher than that of Cftr+⁣/+ mice. Arteries from Cftr-⁣/- mice or pre-incubated with CFTR specific inhibitor CFTR(inh)-172 exhibited a greater contractile response to Ang II. In vascular smooth muscle cells (VSMCs), the phosphorylation of myosin light chain (MLC), which is the core of VSMCs contraction, was negatively modulated by CFTR. Furthermore, intracellular Ca2+ concentration ([Ca2+]i) rise in response to Ang II was negatively modulated by CFTR, while no alteration was observed in resting VSMCs. Ras homolog family member A/Rho-associated protein kinase (RhoA/Rock) mediated phosphorylation of myosin phosphatase target subunit 1 (MYPT1), a regulator of MLC phosphorylation, was negatively modulated by CFTR in both resting and Ang II-stimulated VSMCs.

CONCLUSIONS: This study demonstrates that CFTR is a negative regulator of vasoconstriction and hypertension, and the underlying mechanism contains two possible pathways: (1) in resting VSMCs, CFTR altered MLC phosphorylation through RhoA/Rock pathway; (2) in Ang II stimulated VSMCs, the regulating effect was mediated by both Ca2+ influx and RhoA/Rock mediated pathway.

PMID:34994155 | DOI:10.52586/5034

Appl Biochem Biotechnol. 2022 Jan 6. doi: 10.1007/s12010-021-03746-y. Online ahead of print.

ABSTRACT

Alginate lyases are epitomized as prospective therapeutic mediators for treating Pseudomonas aeruginosa infections, particularly in the cystic fibrosis airway through alginate degradation thereby improving the efficacy of anti-pseudomonal antibiotics. Investigation of metal-binding residues is significant for expounding the ion specificity of an enzyme and will provide a broad understanding of the potential roles of metal ions in enzyme function and stability. However, experimental analysis of metal ion-binding sites in proteins is time consuming and expensive. Concerning the clinical importance of this therapeutic enzyme, the present study was focused on the prediction and characterization of metal ion-binding sites of different alginate lyases reported in the literature through a computational approach using a Metal Ion-Binding Site Prediction and Docking Server. 3D structures of different alginate lyase from different organisms were retrieved, and these retrieved proteins were docked with twelve different metal ions such as Ca2+, Cu2+, Fe3+, Mg2+, Mn2+, Zn2+, Cd2+, Fe2+, Ni2+, Hg2+, Co2+, and Cu+. The binding affinity and interacting amino acids for alginate lyases produced by different microorganisms were compared and analysed. Further analysis on active site residues of reported alginate lyase and subsequent experiments will reveal the function of different metal ions in enhancing or inhibiting the catalysis of alginate lyase and will help in exploiting the enzyme as an efficient therapeutic agent as well as for industrial applications.

PMID:34993770 | DOI:10.1007/s12010-021-03746-y

J Thorac Dis. 2021 Nov;13(11):6550-6563. doi: 10.21037/jtd-2021-10.

ABSTRACT

Lung transplantation is a very complex surgical procedure with many implications for the anesthetic care of these patients. Comprehensive preoperative evaluation is an important component of the transplant evaluation as it informs many of the decisions made perioperatively to manage these complex patients effectively and appropriately. These decisions may involve pre-emptive actions like pre-habilitation and nutrition optimization of these patients before they arrive for their transplant procedure. Appropriate airway and ventilation management of these patients needs to be performed in a manner that provides an optimal operating conditions and protection from ventilatory injury of these fragile post-transplant lungs. Pain management can be challenging and should be managed in a multi-modal fashion with or without the use of an epidural catheter while recognizing the risk of neuraxial technique in patients who will possibly be systemically anticoagulated. Complex monitoring is required for these patients involving both invasive and non-invasive including the use of transesophageal echocardiography (TEE) and continuous cardiac output monitoring. Management of the patient's hemodynamics can be challenging and involves managing the systemic and pulmonary vascular systems. Some patients may require extra-corporeal lung support as a planned part of the procedure or as a rescue technique and centers need to be proficient in instituting and managing this sophisticated method of hemodynamic support.

PMID:34992834 | PMC:PMC8662503 | DOI:10.21037/jtd-2021-10

J Thorac Dis. 2021 Nov;13(11):6514-6527. doi: 10.21037/jtd-2021-09.

ABSTRACT

Lung transplantation is an established treatment option that can improve quality of life and prolong survival for select patients diagnosed with end-stage lung disease. Given the gaps in organ donation and failures to make effective use of available organs, careful selection of candidates for lung transplant remains one of the most important considerations of the transplant community. Toward this end, we briefly reviewed recent trends in pretransplant evaluation, candidate selection, organ allocation, and organ preservation techniques. Since the latest consensus statement regarding appropriate selection of lung transplant candidates, many advances in the science and practice of lung transplantation have emerged and influenced our perspective of 'contraindications' to transplant. These advances have made it increasingly possible to pursue lung transplant in patients with risk factors for decreased survival-namely, older recipient age, increased body mass index, previous chest surgery, poorer nutritional status, and presence of chronic infection, cardiovascular disease, or extrapulmonary comorbid conditions. Therefore, we reviewed the updated evidence demonstrating the prognostic impact of these risk factors in lung transplant recipients. Lastly, we reviewed the salient evidence for current trends in disease-specific indications for lung transplantation, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, emphysema due to alpha-1 antitrypsin deficiency, and pulmonary arterial hypertension, among other less common end-stage diseases. Overall, lung transplant remains an exciting field with considerable hope for patients as they experience remarkable improvements in quality of life and survival in the modern era.

PMID:34992831 | PMC:PMC8662491 | DOI:10.21037/jtd-2021-09

Proc Natl Acad Sci U S A. 2022 Jan 11;119(2):e2116637119. doi: 10.1073/pnas.2116637119.

ABSTRACT

Bacterial behavior and virulence during human infection is difficult to study and largely unknown, as our vast knowledge of infection microbiology is primarily derived from studies using in vitro and animal models. Here, we characterize the physiology of Porphyromonas gingivalis, a periodontal pathogen, in its native environment using 93 published metatranscriptomic datasets from periodontally healthy and diseased individuals. P. gingivalis transcripts were more abundant in samples from periodontally diseased patients but only above 0.1% relative abundance in one-third of diseased samples. During human infection, P. gingivalis highly expressed genes encoding virulence factors such as fimbriae and gingipains (proteases) and genes involved in growth and metabolism, indicating that P. gingivalis is actively growing during disease. A quantitative framework for assessing the accuracy of model systems showed that 96% of P. gingivalis genes were expressed similarly in periodontitis and in vitro midlogarithmic growth, while significantly fewer genes were expressed similarly in periodontitis and in vitro stationary phase cultures (72%) or in a murine abscess infection model (85%). This high conservation in gene expression between periodontitis and logarithmic laboratory growth is driven by overall low variance in P. gingivalis gene expression, relative to other pathogens including Pseudomonas aeruginosa and Staphylococcus aureus Together, this study presents strong evidence for the use of simple test tube growth as the gold standard model for studying P. gingivalis biology, providing biological relevance for the thousands of laboratory experiments performed with logarithmic phase P. gingivalis Furthermore, this work highlights the need to quantitatively assess the accuracy of model systems.

PMID:34992142 | DOI:10.1073/pnas.2116637119

J Cyst Fibros. 2022 Jan 3:S1569-1993(21)02175-5. doi: 10.1016/j.jcf.2021.12.015. Online ahead of print.

ABSTRACT

BACKGROUND: Exaggerated neutrophil-dominated inflammation underlies progressive cystic fibrosis (CF) lung disease. Older studies reported a defective respiratory burst in CF, but more recent studies suggest neutrophil function is normal.

METHODS: We measured the amount and rate of reactive oxygen species (ROS) during PMA-stimulated respiratory burst activity in children [70 CF, 13 disease controls, 19 health controls] and adults [31 CF, 14 health controls] in neutrophils harvested from peripheral blood. Blood was collected from participants with CF when clinically stable (60 children, 9 adults) and on hospital admission (38 children, 24 adults) and discharge (18 children, 21 adults) for acute pulmonary exacerbations.

RESULTS: When clinically stable, children with CF had lower ROS production [median 318,633, 25% 136,810 - 75% 569,523 RLU] than disease controls [median 599,459, 25% 425,566 - 75% 730,527 RLU] and healthy controls [median 534,073, 25% 334,057 - 75% 738,593 RLU] (p = 0.008). The rate of ROS production was also lower (p = 0.029). In neither children nor adults with CF did ROS production increase on hospital admission for acute pulmonary exacerbation, nor fall prior to discharge. There were no associations between ROS production and high-sensitivity C-reactive protein (indicating systemic inflammation) in either children or adults with CF.

CONCLUSIONS: Our data do not support a role for exaggerated respiratory burst activity contributing to the exaggerated neutrophil-dominated inflammation seen with CF lung disease.

PMID:34991978 | DOI:10.1016/j.jcf.2021.12.015

J Biol Chem. 2022 Jan 3:101560. doi: 10.1016/j.jbc.2021.101560. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic human pathogen and a leading cause of chronic infection in the lungs of individuals with cystic fibrosis. After colonization, P. aeruginosa often undergoes a phenotypic conversion to mucoidy, characterized by overproduction of the alginate exopolysaccharide. This conversion is correlated with poorer patient prognoses. The majority of genes required for alginate synthesis, including the alginate lyase, algL, are located in a single operon. Previous investigations of AlgL have resulted in several divergent hypotheses regarding the protein's role in alginate production. To address these discrepancies, we determined the structure of AlgL and, using multiple sequence alignments, identified key active site residues involved in alginate binding and catalysis. In vitro enzymatic analysis of active site mutants highlights R249 and Y256 as key residues required for alginate lyase activity. In a genetically engineered P. aeruginosa strain where alginate biosynthesis is under arabinose control, we found that AlgL is required for cell viability and maintaining membrane integrity during alginate production. We demonstrate that AlgL functions as a homeostasis enzyme to clear the periplasmic space of accumulated polymer. Constitutive expression of the AlgU/T sigma factor mitigates the effects of an algL deletion during alginate production, suggesting that an AlgU/T-regulated protein or proteins can compensate for an algL deletion. Together, our study demonstrates the role of AlgL in alginate biosynthesis, explains the discrepancies observed previously across other P. aeruginosa ΔalgL genetic backgrounds, and clarifies the existing divergent data regarding the function of AlgL as an alginate degrading enzyme.

PMID:34990713 | DOI:10.1016/j.jbc.2021.101560

J Mol Biol. 2022 Jan 3:167436. doi: 10.1016/j.jmb.2021.167436. Online ahead of print.

ABSTRACT

An attractive approach to treat people with Cystic Fibrosis (CF), a life-shortening disease caused by mutant CFTR, is to compensate for the absence of this chloride/bicarbonate channel by activating alternative (non-CFTR) chloride channels. One obvious target for such "mutation-agnostic" therapeutic approach is TMEM16A (anoctamin-1/ANO1), a calcium-activated chloride channel (CaCC) which is also expressed in the airways of people with CF, albeit at low levels. To find novel TMEM16A regulators of both traffic and function, with the main goal of identifying candidate CF drug targets, we performed a fluorescence cell-based high-throughput siRNA microscopy screen for TMEM16A trafficking using a double-tagged construct expressed in human airway cells. About 700 genes were screened (2 siRNAs per gene) of which 262 were identified as candidate TMEM16A modulators (179 siRNAs enhanced and 83 decreased TMEM16A traffic), being G-protein coupled receptors (GPCRs) enriched on the primary hit list. Among the 179 TMEM16A traffic enhancer siRNAs subjected to secondary screening 20 were functionally validated. Further hit validation revealed that siRNAs targeting two GPCRs - ADRA2C and CXCR3 - increased TMEM16A-mediated chloride secretion in human airway cells, while their overexpression strongly diminished calcium-activated chloride currents in the same cell model. The knockdown, and likely also the inhibition, of these two TMEM16A modulators is therefore an attractive potential therapeutic strategy to increase chloride secretion in CF.

PMID:34990652 | DOI:10.1016/j.jmb.2021.167436

Pediatr Pulmonol. 2022 Jan 6. doi: 10.1002/ppul.25817. Online ahead of print.

ABSTRACT

OBJECTIVE: Pediatric cystic fibrosis (CF) patients possess unique pharmacokinetics and may benefit from prolonged beta-lactam infusions to optimize pharmacodynamics. This study compared adverse drug event (ADE) rates with cefepime prolonged (PI) and standard infusions (SI).

METHODS: This retrospective study included pediatric patients treated with cefepime for CF exacerbations between 2009 and 2019. One encounter per patient was analyzed with prioritization of SI encounters given sample size limitations. Baseline lab abnormalities, seizure disorders and bleeding were exclusion criteria. The primary outcome was a composite safety endpoint (acute kidney injury (AKI), hepatotoxicity, hematologic toxicity, neurotoxicity, and hypersensitivity).

RESULTS: Of 188 patients, 135 received PI and 53 received SI. Baseline characteristics were similar between groups. More PI patients used CFTR modulators (25% vs 0%, p<0.01) or had antibiotic allergies (62% vs 38%, p=0.02). Difference in rates of composite safety endpoint was not statistically significant between PI and SI [21 (15.6%) vs 6 (11.3%) p=0.46] nor was incidence of AKI [16 (11.8%) vs 6 (11.3%), p=0.92]. Other ADEs were rarely observed. Length of stay (12.2 vs 10.1 days, p=0.06), change in discharge ppFEV1 from admission (13 vs 12, p =0.91) or from baseline (-4 vs -6.5, p=0.33), and time to next exacerbation (249.7 vs 192.5 days, p=0.93) were similar.

CONCLUSIONS: No difference in risk of ADEs including AKI was seen with cefepime PI in pediatric CF patients. Clinical outcomes were not significantly different between groups, but sample size may have limited comparison. PI cefepime may be considered in pediatric CF patients to optimize pharmacodynamics. This article is protected by copyright. All rights reserved.

PMID:34989183 | DOI:10.1002/ppul.25817

J Clin Transl Endocrinol. 2021 Dec 6;27:100288. doi: 10.1016/j.jcte.2021.100288. eCollection 2022 Mar.

ABSTRACT

Over 30,000 people in the United States are diagnosed with cystic fibrosis (CF), and over 50% of those with CF are male. Men with CF face specific and sometimes difficult sexual and reproductive health (SRH) issues, including infertility and hypogonadism. Male infertility affects over 95% of men with CF, with obstructive azoospermia resulting from congenital bilateral absence of the vas deferens being the primary cause of infertility. SRH education for males with CF represents an important opportunity for clinical improvement, as the majority of men with CF know that their disease impacts their fertility, however the depth of this understanding varies significantly. Hypogonadism is a clinical syndrome that affects men with low testosterone level, a common finding among men with CF that has clinical implications and can significantly affect quality of life. Better understanding of SRH attitudes, the prevalence of hypogonadism, and management of infertility in men with CF should remain future research priorities.

PMID:34987977 | PMC:PMC8695349 | DOI:10.1016/j.jcte.2021.100288

Therap Adv Gastroenterol. 2021 Dec 21;14:17562848211062801. doi: 10.1177/17562848211062801. eCollection 2021.

ABSTRACT

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is not only a common aetiology but also accompanying comorbidity of non-cystic fibrosis bronchiectasis (bronchiectasis). However, the association between GORD and the disease burden of bronchiectasis has not been well evaluated. Our study aimed to evaluate whether GORD is associated with increased healthcare use and medical costs in patients with bronchiectasis.

METHODS: We analyzed the data from 44,119 patients with bronchiectasis using a large representative Korean population-based claim database between 2009 and 2017. We compared the healthcare use [outpatient department (OPD) visits and emergency room (ER) visits/hospitalizations] and medical costs in patients with bronchiectasis according to the presence or absence of GORD.

RESULTS: The prevalence of GORD in patients with bronchiectasis tended to increase during the study period, especially in the 50s and older population. GORD was associated with increased use of all investigated healthcare resources in patients with bronchiectasis. Healthcare use including OPD visits (mean 47.6/person/year versus 30.0/person/year), ER visits/hospitalizations (mean 1.7/person/year versus 1.1/person/year), and medical costs (mean 3564.5 Euro/person/year versus 2198.7 Euro/person/year) were significantly higher in bronchiectasis patients with GORD than in those without GORD (p < 0.001 for all). In multivariable analysis, bronchiectasis patients with GORD showed 1.44-fold (95% confidence interval = 1.37-1.50) and 1.26-fold (95% confidence interval = 1.19-1.33) increased all-cause and respiratory-related ER visits/hospitalizations relative to those without GORD, respectively. After adjusting for potential confounders, the estimated total medical costs (mean 4337.3 versus 3397.4 Euro/person/year) and respiratory disease-related medical costs (mean 920.7 versus 720.2 Euro/person/year) were significantly higher in bronchiectasis patients with GORD than in those without GORD (p < 0.001 for both).

CONCLUSION: In patients with bronchiectasis, GORD was associated with increased healthcare use and medical costs. Strategies to reduce the disease burden associated with GORD are needed in patients with bronchiectasis.

PMID:34987606 | PMC:PMC8721380 | DOI:10.1177/17562848211062801

Front Microbiol. 2021 Dec 20;12:789550. doi: 10.3389/fmicb.2021.789550. eCollection 2021.

ABSTRACT

Pseudomonas aeruginosa chronically infects in the lungs of people with cystic fibrosis and other forms of lung disease. Infections are treated with antibiotics, but over time, the bacteria acquire mutations that reduce their antibiotic susceptibility. The effects of inhibitory amounts of antibiotics in selecting for antibiotic-resistant mutants have been well studied. However, the concentrations of antibiotics that reach infecting bacteria can be sub-inhibitory and but may nonetheless promote emergence of antibiotic-resistant bacteria. Therefore, the aim of this research was to investigate the effects of sub-inhibitory concentrations of antibiotics on the antibiotic susceptibility of P. aeruginosa. Two P. aeruginosa reference strains, PAO1 and PA14, and six isolates from individuals with cystic fibrosis were studied. The bacteria were passaged in the presence of antibiotics (ceftazidime, ciprofloxacin, meropenem or tobramycin) at sub-inhibitory amounts. Fifteen populations of bacteria (up to five per strain) were exposed to each of the four antibiotics. Antibiotic susceptibility was determined following 10 passages on agar supplemented with antibiotic and compared with susceptibility prior to antibiotic exposure. Antibiotic exposure resulted in susceptibility being significantly (>2-fold) reduced for 13 of the 60 populations. Seven samples had reduced susceptibility to ciprofloxacin, three to tobramycin, two to ceftazidime and one to meropenem. Whole-genome sequencing revealed the mutations arising following antibiotic exposure. Mutants with reduced antibiotic susceptibility had mutations in genes known to affect antibiotic resistance, including regulators of efflux pumps (mexR, mexS, mexZ and nalC) and the fusA1 gene that is associated with aminoglycoside resistance. Genes not previously associated with resistance, including gacS, sigX and crfX and two genes with no known function, were also mutated in some isolates with reduced antibiotic susceptibility. Our results show that exposure to sub-inhibitory amounts of antibiotics can select for mutations that reduce the susceptibility of P. aeruginosa to antibiotics and that the profile of mutations is different from that arising during selection with inhibitory antibiotic concentrations. It is likely that exposure to sub-inhibitory amounts of antibiotics during infection contributes to P. aeruginosa becoming antibiotic-resistant.

PMID:34987489 | PMC:PMC8721600 | DOI:10.3389/fmicb.2021.789550

Pharmacol Rev. 2022 Jan;74(1):48-118. doi: 10.1124/pharmrev.120.000108.

ABSTRACT

The purpose of this review is to summarize essential pharmacological, pharmaceutical, and clinical aspects in the field of orally inhaled therapies that may help scientists seeking to develop new products. After general comments on the rationale for inhaled therapies for respiratory disease, the focus is on products approved approximately over the last half a century. The organization of these sections reflects the key pharmacological categories. Products for asthma and chronic obstructive pulmonary disease include β -2 receptor agonists, muscarinic acetylcholine receptor antagonists, glucocorticosteroids, and cromones as well as their combinations. The antiviral and antibacterial inhaled products to treat respiratory tract infections are then presented. Two "mucoactive" products-dornase α and mannitol, which are both approved for patients with cystic fibrosis-are reviewed. These are followed by sections on inhaled prostacyclins for pulmonary arterial hypertension and the challenging field of aerosol surfactant inhalation delivery, especially for prematurely born infants on ventilation support. The approved products for systemic delivery via the lungs for diseases of the central nervous system and insulin for diabetes are also discussed. New technologies for drug delivery by inhalation are analyzed, with the emphasis on those that would likely yield significant improvements over the technologies in current use or would expand the range of drugs and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of approved orally inhaled drug products for a variety of respiratory diseases and for systemic administration should be helpful in making judicious decisions about the development of new or improved inhaled drugs. These aspects include the choices of the active ingredients, formulations, delivery systems suitable for the target patient populations, and, to some extent, meaningful safety and efficacy endpoints in clinical trials.

PMID:34987088 | DOI:10.1124/pharmrev.120.000108

Am J Physiol Lung Cell Mol Physiol. 2022 Jan 5. doi: 10.1152/ajplung.00022.2021. Online ahead of print.

ABSTRACT

Several aspects of the cell biology of cystic fibrosis (CF) epithelial cells are altered including impaired lipid regulation, disrupted intracellular transport, and impaired microtubule regulation. It is unclear how the loss of cystic fibrosis transmembrane conductance regulator (CFTR) function leads to these differences. It is hypothesized that the loss of CFTR function leads to altered regulation of carbonic anhydrase (CA) activity resulting in cellular phenotypic changes. In this study, it is demonstrated that CA2 protein expression is reduced in CF model cells, primary mouse nasal epithelial (MNE) cells, excised MNE tissue, and primary human nasal epithelial cells (p<0.05). This corresponds to a decrease in CA2 RNA expression measured by qPCR as well as an overall reduction in CA activity in primary CF MNEs. The addition of CFTR-inhibitor-172 to WT MNE cells for ≥24 h mimics the significantly lower protein expression of CA2 in CF cells. Treatment of CF cells with L-Phenylalanine (L-Phe), an activator of CA activity, restores endosomal transport through an effect on microtubule regulation in a manner dependent on soluble adenylate cyclase (sAC). This effect can be blocked with the CA2-selective inhibitor dorzolamide. These data suggest the loss of CFTR function leads to the decreased expression of CA2 resulting in the downstream cell signaling alterations observed in CF.

PMID:34986321 | DOI:10.1152/ajplung.00022.2021

Cochrane Database Syst Rev. 2022 Jan 5;1:CD013254. doi: 10.1002/14651858.CD013254.pub2.

ABSTRACT

BACKGROUND: Bronchiectasis is a common but under-diagnosed chronic disorder characterised by permanent dilation of the airways arising from a cycle of recurrent infection and inflammation. Symptoms including chronic, persistent cough and productive phlegm are a significant burden for people with bronchiectasis, and the main aim of treatment is to reduce exacerbation frequency and improve quality of life. Prophylactic antibiotic therapy aims to break this infection cycle and is recommended by clinical guidelines for adults with three or more exacerbations a year, based on limited evidence. It is important to weigh the evidence for bacterial suppression against the prevention of antibiotic resistance and further evidence is required on the safety and efficacy of different regimens of intermittently administered antibiotic treatments for people with bronchiectasis.

OBJECTIVES: To evaluate the safety and efficacy of intermittent prophylactic antibiotics in the treatment of adults and children with bronchiectasis.

SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted searches on 6 September 2021, with no restriction on language of publication.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) of at least three months' duration comparing an intermittent regime of prophylactic antibiotics with placebo, usual care or an alternate intermittent regimen. Intermittent prophylactic administration was defined as repeated courses of antibiotics with on-treatment and off-treatment intervals of at least 14 days' duration. We included adults and children with a clinical diagnosis of bronchiectasis confirmed by high resolution computed tomography (HRCT), plain film chest radiograph, or bronchography and a documented history of recurrent chest infections. We excluded studies where participants received high dose antibiotics immediately prior to enrolment or those with a diagnosis of cystic fibrosis, allergic bronchopulmonary aspergillosis (ABPA), primary ciliary dyskinesia, hypogammaglobulinaemia, sarcoidosis, or a primary diagnosis of COPD. Our primary outcomes were exacerbation frequency and serious adverse events. We did not exclude studies on the basis of review outcomes.

DATA COLLECTION AND ANALYSIS: We analysed dichotomous data as odds ratios (ORs) or relative risk (RRs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures expected by Cochrane. We conducted GRADE assessments for the following primary outcomes: exacerbation frequency; serious adverse events and secondary outcomes: antibiotic resistance; hospital admissions; health-related quality of life.

MAIN RESULTS: We included eight RCTs, with interventions ranging from 16 to 48 weeks, involving 2180 adults. All evaluated one of three types of antibiotics over two to six cycles of 28 days on/off treatment: aminoglycosides, ß-lactams or fluoroquinolones. Two studies also included 12 cycles of 14 days on/off treatment with fluoroquinolones. Participants had a mean age of 63.6 years, 65% were women and approximately 85% Caucasian. Baseline FEV1 ranged from 55.5% to 62.6% predicted. None of the studies included children. Generally, there was a low risk of bias in the included studies. Antibiotic versus placebo: cycle of 14 days on/off. Ciprofloxacin reduced the frequency of exacerbations compared to placebo (RR 0.75, 95% CI 0.61 to 0.93; I2 = 65%; 2 studies, 469 participants; moderate-certainty evidence), with eight people (95% CI 6 to 28) needed to treat for an additional beneficial outcome. The intervention increased the risk of antibiotic resistance more than twofold (OR 2.14, 95% CI 1.36 to 3.35; I2 = 0%; 2 studies, 624 participants; high-certainty evidence). Serious adverse events, lung function (FEV1), health-related quality of life, and adverse effects did not differ between groups. Antibiotic versus placebo: cycle of 28 days on/off. Antibiotics did not reduce overall exacerbation frequency (RR 0.92, 95% CI 0.82 to 1.02; I2 = 0%; 8 studies, 1695 participants; high-certainty evidence) but there were fewer severe exacerbations (OR 0.59, 95% CI 0.37 to 0.93; I2 = 54%; 3 studies, 624 participants), though this should be interpreted with caution due to low event rates. The risk of antibiotic resistance was more than twofold higher based on a pooled analysis (OR 2.20, 95% CI 1.42 to 3.42; I2 = 0%; 3 studies, 685 participants; high-certainty evidence) and consistent with unpooled data from four further studies. Serious adverse events, time to first exacerbation, duration of exacerbation, respiratory-related hospital admissions, lung function, health-related quality of life and adverse effects did not differ between study groups. Antibiotic versus usual care. We did not find any studies that compared intermittent antibiotic regimens with usual care. Cycle of 14 days on/off versus cycle of 28 days on/off. Exacerbation frequency did not differ between the two treatment regimens (RR 1.02, 95% CI 0.84 to 1.24; I2 = 71%; 2 studies, 625 participants; moderate-certainty evidence) However, inconsistencies in the results from the two trials in this comparison indicate that the apparent aggregated similarities may not be reliable. There was no evidence of a difference in antibiotic resistance between groups (OR 1.00, 95% CI 0.68 to 1.48; I2 = 60%; 2 studies, 624 participants; moderate-certainty evidence). Serious adverse events, adverse effects, lung function and health-related quality of life did not differ between the two antibiotic regimens.

AUTHORS' CONCLUSIONS: Overall, in adults who have frequent chest infections, long-term antibiotics given at 14-day on/off intervals slightly reduces the frequency of those infections and increases antibiotic resistance. Intermittent antibiotic regimens result in little to no difference in serious adverse events. The impact of intermittent antibiotic therapy on children with bronchiectasis is unknown due to an absence of evidence, and further research is needed to establish the potential risks and benefits.

PMID:34985761 | DOI:10.1002/14651858.CD013254.pub2

Biochem Biophys Rep. 2021 Dec 16;29:101188. doi: 10.1016/j.bbrep.2021.101188. eCollection 2022 Mar.

ABSTRACT

Multi-drug resistant infections caused by the opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa), are a continuing problem that contribute to morbidity and mortality in immunocompromised hosts such as cystic fibrosis (CF), wound and burn patients. The bacterial toxin ExoU is one of four potent toxins that P. aeruginosa secretes into the epithelial cells of hosts. In this study, NMR Saturation Transfer Difference (STD) and in silico Schrödinger Computational Modeling were used to identify a possible binding site of a novel ligand methoctramine targeting ExoU. Future project goals will be to design a structure activity relationship (SAR) study of methoctramine and ExoU and lead to a new drug solving ExoU toxicity P. aeruginosa exerts in the clinical environment.

PMID:34984240 | PMC:PMC8693347 | DOI:10.1016/j.bbrep.2021.101188

ERJ Open Res. 2021 Dec 27;7(4):00411-2021. doi: 10.1183/23120541.00411-2021. eCollection 2021 Oct.

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes.

METHODS: In this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis.

RESULTS: Up to December 31, 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0-18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6; 95% CI: 22.7-35.5) versus non-lung-transplanted pwCF (16.6; 95% CI: 15.4-17.8) (p≤0.001).SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation and pancreatic insufficiency.Overall, 23.7% of pwCF were admitted to hospital, 2.5% of those to intensive care, and regretfully 11 (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2- to 6-fold more frequent in lung-transplanted versus non-lung-transplanted pwCF.Factors associated with hospitalisation and oxygen therapy were lung transplantation, cystic fibrosis-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function).

CONCLUSION: SARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s <70% predicted, CFRD and those with lung transplants are at particular risk of more severe outcomes.

PMID:34984210 | PMC:PMC8557394 | DOI:10.1183/23120541.00411-2021