Calcium-activated Chloride Channel Inhibitor Research Articles

Involvement of interstitial cells of Cajal in nicotinic acetylcholine receptor-induced relaxation of the porcine lower esophageal sphincter

The interstitial cells of Cajal (ICCs) play an important role in coordinated gastrointestinal motility. The present study aimed to elucidate whether or how ICCs are involved in the lower esophageal sphincter (LES) relaxation induced by stimulation of the nicotinic acetylcholine receptor. The application of 1,1-dimethyl-4-phenyl-piperazinium (DMPP; a nicotinic acetylcholine receptor agonist) induced a transient relaxation in the circular smooth muscle of the porcine LES. DMPP-induced relaxation was abolished by not only 1 μM tetrodotoxin but also the inhibition of ICC activity by pretreatment with 100 μM carbenoxolone (a gap junction inhibitor), pretreatment with 100 μM CaCCinh-A01 (an anoctamin-1 blocker acting as a calcium-activated chloride channel inhibitor), and pretreatment with Cl−-free solution. However, pretreatment with 100 μM Nω-nitro-L-arginine methyl ester had little effect on DMPP-induced relaxation. Furthermore, DMPP-induced relaxation was inhibited by pretreatment with 1 mM suramin, a purinergic P2 receptor antagonist, but not by 1 μM VIP (6–28), a vasoactive intestinal peptide (VIP) receptor antagonist. Stimulation of the purinergic P2 receptor with adenosine triphosphate (ATP) induced relaxation, which was abolished by the inhibition of ICC activity by pretreatment with CaCCinh-A01. In conclusion, membrane hyperpolarization of the ICCs via the activation of anoctamin-1 plays a central role in DMPP-induced relaxation. ATP may be a neurotransmitter for inhibitory enteric neurons, which stimulate the ICCs. The ICCs act as the interface of neurotransmission of nicotinic acetylcholine receptor in order to induce LES relaxation.

Distinct ion transport in the marsh rice rat (Oryzomys palustris) airway

Hypertonic solutions increase airway surface liquid (ASL) through cholinergically‐mediated epithelial cell ion transport and osmosis. Thus, mammals inhabiting salt marshes might have acquired adaptations, including greater dependence upon cholinergic mechanisms, for ASL regulation. To test this hypothesis, we investigated the airways of the rice rat, a medium‐sized rodent that inhabits salt marshes. We discovered unique ion transport properties, including minimal amiloride‐sensitive Na+ absorption and limited Cl− secretion through the cystic fibrosis transmembrane conductance regulator. In contrast, the cholinergic agonist carbachol induced a large Cl− secretory current that was blocked by the calcium‐activated chloride channel inhibitor CaCCinh‐A01. Rice rat airway cultures also secreted fluid in response to carbachol, and when challenged with 3.5% NaCl apically to mimic exposure to sea water aerosols, displayed a prolonged expansion of the ASL volume. These data suggest that the rice rat airway might possess unique ion transport mechanisms to facilitate survival in the harsh salt marsh environment.Support or Funding InformationHL119560, 0T2TR001983, DE0237863This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Antiestrogen- and tamoxifen-induced effects on calcium-activated chloride currents in epithelial cells carrying the \u2206F508-CFTR point mutation

BackgroundAlthough pharmacological treatment has increased the average life expectancy of patients with cystic fibrosis, the median survival of females is shorter than that of males. In vitro and in vivo studies have shown that estrogens play a relevant role in the disease progression.The aim of this study was to investigate the effects of 17β-estradiol and tamoxifen citrate (TMX) on calcium-activated chloride channel (CaCC) currents in human bronchial epithelial cells carrying the ΔPhe508-CFTR mutation both in homozygosis and in heterozygosis.MethodsPerforated patch clamp experiments were performed on single cells of the immortalized cell lines CFBE and IB3–1. Gramicidin (10 or 20 μM) was added to the electrode solution to reach the whole cell configuration. The electrical stimulation protocol consisted of square voltages ranging from − 80 to + 80 mV, in steps of 20 mV and with a duration of 800 msec.ResultsThe presence of 17β-estradiol significantly reduced the CaCC currents, both in basal conditions and in the presence of ATP (100 μM). The addition of TMX (10 μM) completely restored the currents abolished by 17β-estradiol, in basal conditions and after stimulation with ATP in both CFBE and IB3–1 cells. TMX had a strong, direct action on membrane current density, which significantly increased more than 4-fold in both cases. The membrane current stimulation produced by TMX was further enhanced by the addition of ATP. CFBE cells incubated for 24 h with 3 μM VX-809 (a CFTR corrector) and then acutely stimulated with VX-770 (a CFTR potentiator) in the presence of forskolin, showed an increase of chloride currents which were abolished by Inh-172. The chloride current density induced by TMX + ATP was, on average, greater than that obtained with VX-809 + VX-770 + forskolin. The currents elicited by TMX + ATP were abolished by the addition of NPPB, a CaCC inhibitor. The combined administration of TMX/ATP and VXs/FSK had an additional effect on chloride currents.ConclusionsOur results show that TMX restores CaCC currents inhibited by 17ß-estradiol and directly activates the transmembrane chloride currents potentiated by ATP, an effect which is mutation independent. The combined effect of TMX with current used treatments for cystic fibrosis could be of benefit to patients.

Elucidating the physiological role of platelet‐derived growth factor receptor‐alpha+ cells and characterization of ANO1 in the murine upper urinary tract.

Spontaneous electrical activity is necessary for driving peristalsis in the upper urinary tract (UUT) and is hypothesized to originate from the proximal renal pelvis. However, the mechanisms by which auto‐rhythmicity is generated remain undetermined. Specialized “atypical” smooth muscle cells have been implicated in pacing the pelvis due to the higher abundance of these cells in the area in which spontaneous contractions are generated. The calcium‐activated chloride channel (CaCC), anoctamin‐1 (ANO1) is essential for slow wave generation and normal gastrointestinal motility. In the pelvis, NFA‐sensitive Cl− currents have been observed in interstitial cells. To investigate the role of ANO1 in the renal pelvis, quantitative RT‐PCR analysis of Ano1 expression in the renal pelvis was assessed in mRNA extracted from single cell populations. Ano1 mRNA was detected in smooth muscle myosin heavy chain‐positive (smMHC+) cells, but was present more abundantly in platelet‐derived growth factor receptor alpha‐positive (PDGFRα+) cells. Furthermore, isolated Ano1eGFP+ cells confirmed the presence of cells co‐expressing both ANO1 and PDGFRα (~95%). Immunohistochemistry further validated this as coronal sections derived from the proximal renal pelvis exhibited dense ANO1 labeling on PDGFRα+ cells. An extensive network of PDGFRα+ cells populated the width of the proximal pelvic wall except the urothelium. Interestingly, smMHC+ “atypical” cells within this proximal region also co‐expressed PDGFRα+, identifying a novel marker of these specialized smooth muscle cells. Next, to determine if Ano1 possessed a physiological role in the pelvis, edge‐tracking and Ca2+ imaging experiments were performed on intact, renal pelvic tissue. Pharmacological inhibition of ANO1 with the CaCC inhibitor, CaCCinh‐A01 (5–10 μM) reduced the frequency of contractions and propagating Ca2+ waves in typical smooth muscle cells, indicating that Ano1 may be responsible for the generation of contractions. To probe underlying intracellular Ca2+ signals in PDGFRα+ and smMHC+ cells, confocal imaging experiments were conducted on the proximal extensions of the renal pelvis from PDGFRα+‐GCaMP6f mice on coronal vibratome sections (~150 μm thick) and flat‐sheet tissue. High frequency, spontaneous intracellular Ca2+ transients were visualized within PDGFRα+/smMHC+ specialized cells, that were abolished upon removal of extracellular Ca2+ but insensitive to L‐Type Ca2+ channel blockade by nicardipine (1 μM). PDGFRα+ cells presented irregular, often long duration Ca2+ transients that occasionally propagated into neighboring cells. Taken together, these data suggest a physiological role for PDGFRα+ cells, whereby activation of ANO1 channels, expressed on their plasma membrane, could contribute to depolarizing neighboring smMHC+ cells and ultimately regulate the propagating contractions in the renal pelvis.Support or Funding InformationR01 DK‐091336 (KMS)P01‐DK041315 (KMS)P30‐GM110767This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Pharmacological analysis of epithelial chloride secretion mechanisms in adult murine airways

Defective epithelial chloride secretion occurs in humans with cystic fibrosis (CF), a genetic defect due to loss of function of CFTR, a cAMP-activated chloride channel. In the airways, absence of an active CFTR causes a severe lung disease. In mice, genetic ablation of CFTR function does not result in similar lung pathology. This may be due to the expression of an alternative chloride channel which is activated by calcium. The most probable protein performing this function is TMEM16A, a calcium-activated chloride channel (CaCC). Our aim was to assess the relative contribution of CFTR and TMEM16A to chloride secretion in adult mouse trachea. For this purpose we tested pharmacological inhibitors of chloride channels in normal and CF mice. The amplitude of the cAMP-activated current was similar in both types of animals and was not affected by a selective CFTR inhibitor. In contrast, a CaCC inhibitor (CaCCinh-A01) strongly blocked the cAMP-activated current as well as the calcium-activated chloride secretion triggered by apical UTP. Although control experiments revealed that CaCCinh-A01 also shows inhibitory activity on CFTR, our results indicate that transepithelial chloride secretion in adult mouse trachea is independent of CFTR and that another channel, possibly TMEM16A, performs both cAMP- and calcium-activated chloride transport. The prevalent function of a non-CFTR channel may explain the absence of a defect in chloride transport in CF mice.

Effects of Small Molecule Calcium-Activated Chloride Channel Inhibitors on Structure and Function of Accessory Cholera Enterotoxin (Ace) of Vibrio cholerae.

Cholera pathogenesis occurs due to synergistic pro-secretory effects of several toxins, such as cholera toxin (CTX) and Accessory cholera enterotoxin (Ace) secreted by Vibrio cholerae strains. Ace activates chloride channels stimulating chloride/bicarbonate transport that augments fluid secretion resulting in diarrhea. These channels have been targeted for drug development. However, lesser attention has been paid to the interaction of chloride channel modulators with bacterial toxins. Here we report the modulation of the structure/function of recombinant Ace by small molecule calcium-activated chloride channel (CaCC) inhibitors, namely CaCCinh-A01, digallic acid (DGA) and tannic acid. Biophysical studies indicate that the unfolding (induced by urea) free energy increases upon binding CaCCinh-A01 and DGA, compared to native Ace, whereas binding of tannic acid destabilizes the protein. Far-UV CD experiments revealed that the α-helical content of Ace-CaCCinh-A01 and Ace-DGA complexes increased relative to Ace. In contrast, binding to tannic acid had the opposite effect, indicating the loss of protein secondary structure. The modulation of Ace structure induced by CaCC inhibitors was also analyzed using docking and molecular dynamics (MD) simulation. Functional studies, performed using mouse ileal loops and Ussing chamber experiments, corroborate biophysical data, all pointing to the fact that tannic acid destabilizes Ace, inhibiting its function, whereas DGA stabilizes the toxin with enhanced fluid accumulation in mouse ileal loop. The efficacy of tannic acid in mouse model suggests that the targeted modulation of Ace structure may be of therapeutic benefit for gastrointestinal disorders.

Four basic residues critical for the ion selectivity and pore blocker sensitivity of TMEM16A calcium-activated chloride channels

TMEM16A (transmembrane protein 16) (Anoctamin-1) forms a calcium-activated chloride channel (CaCC) that regulates a broad array of physiological properties in response to changes in intracellular calcium concentration. Although known to conduct anions according to the Eisenman type I selectivity sequence, the structural determinants of TMEM16A anion selectivity are not well-understood. Reasoning that the positive charges on basic residues are likely contributors to anion selectivity, we performed whole-cell recordings of mutants with alanine substitution for basic residues within the putative pore region and identified four residues on four different putative transmembrane segments that significantly increased the permeability of the larger halides and thiocyanate relative to that of chloride. Because TMEM16A permeation properties are known to shift with changes in intracellular calcium concentration, we further examined the calcium dependence of anion selectivity. We found that WT TMEM16A but not mutants with alanine substitution at those four basic residues exhibited a clear decline in the preference for larger anions as intracellular calcium was increased. Having implicated these residues as contributing to the TMEM16A pore, we scrutinized candidate small molecules from a high-throughput CaCC inhibitor screen to identify two compounds that act as pore blockers. Mutations of those four putative pore-lining basic residues significantly altered the IC50 of these compounds at positive voltages. These findings contribute to our understanding regarding anion permeation of TMEM16A CaCC and provide valuable pharmacological tools to probe the channel pore.

Novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids as calcium activated chloride channel inhibitors

Transmembrane protein 16A (TMEM16A) channels are recently discovered membrane proteins that functions as a calcium activated chloride channel (CaCC). CaCCs are major regulators of various physiological processes, such as sensory transduction, epithelial secretion, smooth muscle contraction and oocyte fertilization. Thirty novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids (B01–B30) were synthesized and evaluated for their TMEM16A inhibitory activity by using short circuit current measurements in Fischer rat thyroid (FRT) cells expressing human TMEM16A. IC50 values were calculated using YFP fluorescence plate reader assay. Final compounds, having free carboxylic group displayed significant inhibition. Eight of the novel compounds B02, B13, B21, B23, B25, B27, B28, B29 exhibit excellent CaCCs inhibition with IC50 value <6μM, with compound B25 exhibiting the lowest IC50 value of 2.8±1.3μM. None of the tested ester analogs of final benzofuran derivatives displayed TMEM16A/CaCCs inhibition.

TMEM16A and NHERF1 Regulate Ca2+ and cAMP Stimulated Cl‐ Secretion in Murine Colon

TMEM16A is a calcium activated chloride channel (CaCC). However, its role in colonic Cl secretion is unknown. By qPCR, we identified TMEM16A as the predominant CaCC in mouse colon and hypothesized that it was involved in basal and Ca2+‐ stimulated colonic Cl secretion. Because the NHERF family of PDZ domain containing proteins has been shown to regulate intestinal ion transporters, we tested whether NHERF1 and NHERF2 are involved in TMEM16A regulation. Colonic Cl secretion was measured as the change in short circuit current (ΔIsc) by Ussing chamber. Digallic acid, a CaCC inhibitor inhibited basal Isc by 50% (p&lt;0.05) and completely abolished carbachol (CCH) stimulated Isc in the wild type (WT) mouse colon. In TMEM16A+/− colon, basal, CCH and forskolin (FSK) stimulated Isc were reduced by 47% (p&lt;0.04), 67% (p&lt;0.001) and 75% (p&lt;0.001), respectively. In NHERF1−/− mice, basal and CCH stimulated Isc were reduced by 60% (P&lt;0.01) and 92% (P&lt;0.001), while there was no significant change in the FSK stimulated Isc. Basal, CCH and FSK stimulated Isc in NHERF2−/− colonic tissues were not different from WT. Our results suggest that in mouse colon (1) TMEM16A is a major contributor of basal, CCH and unexpectedly also cAMP stimulated Cl secretion; (2) NHERF1, but not NHERF2 plays an important role in basal and CCH stimulated Cl secretion. In conclusion, NHERF1 affects colonic Cl secretion via effects on TMEM16A.

Presence of the Ca2+-activated chloride channel anoctamin 1 in the urethra and its role in excitatory neurotransmission

We investigated the cellular distribution of the calcium-activated chloride channel (CaCC), anoctamin 1, in the urethra of mice, rats, and sheep by both immunofluorescence and PCR. We studied its role in urethral contractility by examining the effects of chloride-free medium and of several CaCC inhibitors on noradrenergic and cholinergic excitatory responses, and on nitrergic relaxations in urethral preparations. In all species analyzed, CaCC played a key role in urethral contractions, influencing smooth muscle cells activated by increases in intracellular calcium, probably due to calcium influx but with a minor contribution by IP(3)-mediated calcium release. The participation of CaCC in relaxant responses was negligible. Strong anoctamin 1 immunoreactivity was detected in the smooth muscle cells and urothelia of sheep, rat, and mouse urethra, but not in the interstitial cells of Cajal (ICC) in any of these species. RT-PCR confirmed the expression of anoctamin 1 mRNA in the rat urethra. This anoctamin 1 in urethral smooth muscle probably mediates the activity of chloride in contractile responses in different species, However, the lack of anoctamin 1 in ICCs challenges its proposed role in regulating urethral contractility in a manner similar to that observed in the gut.

Niflumic Acid Reduces Histamine-Induced MUC5AC Expression in Human Conjunctival Epithelial Cells

Background/Aims: Histamine is an important inflammatory mediator in allergic conjunctivitis. The aim of the present study was to explore whether histamine induced MUC5AC production in human conjunctival epithelial cells (HCECs), and to describe the relationship between human calcium-activated chloride channel 1 (hCLCA1) activity and MUC5AC expression. Methods: HCECs were isolated from human conjunctiva and cultured at an air-liquid interface. MUC5AC and hCLCA1 mRNA expression was examined by real-time PCR after exposure of the cells to histamine. MUC5AC secretion was quantitated by ELISA. hCLCA1 protein was detected by Western blot analysis. Results: Histamine upregulated MUC5AC expression and MUC5AC secretion in a dose-dependent manner. Histamine also upregulated hCLCA1 mRNA expression in a dose-dependent manner. Preincubation of histamine receptor 1 antagonist reduced histamine-induced MUC5AC and hCLCA1 mRNA expression. Niflumic acid, a chloride channel inhibitor, reduced histamine-induced MUC5ACand hCLCA1 expression. Conclusion: Histamine-induced MUC5AC production could be decreased by niflumic acid, a calcium-activated chloride channel inhibitor.

ANO1 amplification and expression in HNSCC with a high propensity for future distant metastasis and its functions in HNSCC cell lines

Background:Head and neck squamous cell carcinoma (HNSCC) is associated with poor survival. To identify prognostic and diagnostic markers and therapeutic targets, we studied ANO1, a recently identified calcium-activated chloride channel (CaCC).Methods:High-resolution genomic and transcriptomic microarray analysis and functional studies using HNSCC cell line and CaCC inhibitors.Results:Amplification and overexpression of genes within the 11q13 amplicon are associated with the propensity for future distance metastasis of HPV-negative HNSCC. ANO1 was selected for functional studies based on high correlations, cell surface expression and CaCC activity. ANO1 overexpression in cells that express low endogenous levels stimulates cell movement, whereas downregulation in cells with high endogenous levels has the opposite effect. ANO1 overexpression also stimulates attachment, spreading, detachment and invasion, which could account for its effects on migration. CaCC inhibitors decrease movement, suggesting that channel activity is required for the effects of ANO1. In contrast, ANO1 overexpression does not affect cell proliferation.Interpretation:ANO1 amplification and expression could be markers for distant metastasis in HNSCC. ANO1 overexpression affects cell properties linked to metastasis. Inhibitors of CaCCs could be used to inhibit the tumourigenic properties of ANO1, whereas activators developed to increase CaCC activity could have adverse effects.

Effect of Steroids, Acetyl‐cysteine and Calcium‐Activated Chloride Channel Inhibitors on Allergic Mucin Expression in Sinus Mucosa

Allergic inflammation of the upper airways is commonly associated with mucus hypersecretion. At present, there is no specific mucus regulating drug available. Our goal was to investigate the effect of glucocorticosteroids, acetyl-cysteine (ACC), and calcium-activated chloride channel (CLCA) inhibitors in a model of Th2 type cytokine induced mucin expression in human airway mucosa. Prospective. Explanted tissue from human sinus mucosa was stimulated with interleukin (IL)-4, IL-9, or IL-13. Different concentrations of dexamethasone, ACC, or CLCA inhibitors [niflumic acid (NFA) or MSI-2216] were added to stimulated tissue. Epithelial mucin expression was quantified using periodic acid-Schiff staining. IL-4, IL-9, and IL-13 significantly increased epithelial mucin expression (P < .05). Dexamethasone reduced Th2 type cytokine induced mucin expression in a dose-dependent manner being statistically significant at concentrations >or=4.0 micromol/L (IL-4) and >or=40.0 micromol/L (IL-9 and IL-13) (P < .05). ACC had no significant effect on IL-4 and IL-13 induced mucin expression, whereas IL-9 induced mucin expression was significantly decreased at concentrations >or=3.0 mmol/L (P < .05). NFA and MSI-2216 decreased Th2 type cytokine induced mucin expression in a dose-dependent manner. This effect was statistically significant at concentrations >or=100 micromol/L (NFA) and >or=50 micromol/L (MSI-2216) (P < .05). Th2 type cytokines can induce mucin expression in a model of explanted human airway mucosa. Th2 type cytokine induced mucin expression can be effectively reduced by either glucocorticosteroids or CLCA inhibitors ex vivo. Besides glucocorticosteroids CLCA inhibitors may offer an alternative therapeutic approach to treat allergic mucus hypersecretion.

Intracellular signalling pathways in the vasoconstrictor response of mouse afferent arterioles to adenosine

Adenosine causes vasoconstriction of afferent arterioles of the mouse kidney through activation of adenosine A(1) receptors and Gi-mediated stimulation of phospholipase C. In the present study, we further explored the signalling pathways by which adenosine causes arteriolar vasoconstriction. Adenosine (10(-7) M) significantly increased the intracellular calcium concentration in mouse isolated afferent arterioles measured by fura-2 fluorescence. Pre-treatment with thapsigargin (2 microM) blocked the vasoconstrictor action of adenosine (10(-7) M) indicating that release of calcium from the sarcoplasmic reticulum (SR), stimulated presumably by IP(3), is involved in the adenosine contraction mechanism of the afferent arteriole. In agreement with this notion is the observation that 2 aminoethoxydiphenyl borate (100 microM) blocked the adenosine-induced constriction whereas the protein kinase C inhibitor calphostin C had no effect. The calcium-activated chloride channel inhibitor IAA-94 (30 microM) inhibited the adenosine-mediated constriction. Patch clamp experiments showed that adenosine treatment induced a depolarizing current in preglomerular smooth muscle cells which was abolished by IAA-94. Furthermore, the vasoconstriction caused by adenosine was significantly inhibited by 5 microM nifedipine (control 8.3 +/- 0.2 microM, ado 3.6 +/- 0.6 microM, ado + nifedipine 6.8 +/- 0.2 microM) suggesting involvement of voltage-dependent calcium channels. We conclude that adenosine mediates vasoconstriction of afferent arterioles through an increase in intracellular calcium concentration resulting from release of calcium from the SR followed by activation of Ca(2+)-activated chloride channels leading to depolarization and influx of calcium through voltage-dependent calcium channels.

LPS-induced mucin expression in human sinus mucosa can be attenuated by hCLCA inhibitors

hCLCA1 is a member of the calcium-activated chloride channel family and is associated with disease-inducible mucus expression. Niflumic acid (NFA) and a closely related chemical structure are reported inhibitors of calcium-activated chloride channels and endotoxin-inducible mucus expression in the mouse. Therefore, we tested the hypothesis that hCLCA1 may be involved in lipopolysaccharide (LPS) induced mucin up-regulation in human airways. We also investigated the effect of NFA and MSI-2216 on LPS-induced mucin up-regulation. Explanted human airways and the muco-epidermoid cell line Calu-3 were stimulated with LPS. Different concentrations of NFA or MSI-2216 were added to LPS-stimulated airway mucosa and Calu-3 cells. Expression of hCLCA1 and MUC5AC mRNA and protein was quantified in human airways using real-time PCR and PAS staining. In addition, immunohistochemistry was performed for quantification of inflammatory cells (lymphocytes, monocytes, eosinophils, and neutrophils) in the submucosa of the airways. Expression of hCLCA1 protein in Calu-3 cells was analysed by FACS. LPS significantly induced hCLCA1 and MUC5AC mRNA and protein expression in human airway mucosa (P < 0.05). NFA and MSI-2216 significantly decreased LPS-induced mucus expression in explanted airway mucosa in a dose-dependent manner (P < 0.05). In Calu-3 cells, LPS significantly increased hCLCA1 surface expression whereas intracellular expression was significantly decreased (P < 0.05). In Calu-3 cells, NFA and MSI-2216 also significantly reduced MUC5AC mRNA expression (P < 0.05). These data suggest that hCLCA1 may play a role in LPS-induced mucin expression in human airway mucosa. Calcium-activated chloride channel inhibitors significantly decreased LPS-induced mucus expression both ex vivo and in vitro . Therefore, blocking of hCLCA1 may offer a therapeutic approach to reduce bacterial-induced mucus hypersecretion.

Retraction Notice: Emerging Targets for COPD Therapy

No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. However, several new treatments that target the inflammatory process are in clinical development. A group of specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD; these include adhesion molecule and chemokine-directed therapy, as well as therapies to combat tumour necrosis factor-alpha and augment interleukin-10. Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kappaB and phosphoinositide-3 kinase-gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase, and leukotriene B4 receptor antagonists. Epidermal growth factor receptor kinase inhibitors and calcium-activated chloride channel inhibitors have potential to combat mucus overproduction. Therapy to inhibit fibrosis is being developed against transforming growth factor-beta1 and protease activated receptor-2. There is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema, as well as drugs such as retinoids that may even reverse this process. Effective delivery of drugs to the sites of disease in the peripheral lung is an important consideration, and there is the need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD.

New approaches to COPD

No currently available treatments reduce the progression or suppress the inflammation of chronic obstructive pulmonary disease (COPD). However, with a better understanding of the inflammatory and destructive process, several targets have been identified, and new treatments are now in clinical development. Several specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, including adhesion molecule and chemokine-directed therapy, as well as therapies to inhibit tumour necrosis factor-α. Broad spectrum anti-inflammatory drugs are also in development, and include inhibitors of phosphodiesterase-4, p38 mitogen-activated protein kinase, nuclear factor-κB and phosphoinositide-3 kinase-γ. More specific approaches include antioxidants, inhibitors of inducible nitric oxide synthase, and leukotriene B 4 receptor antagonists. Inhibitors of epidermal growth factor receptor kinase and calcium-activated chloride channel inhibitors have the potential to inhibit mucus hypersecretion. Other therapies are targeted at the structural changes of COPD. Therapy to inhibit fibrosis is being developed against transforming growth factor-β 1 and protease activated receptor-2. There is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema, as well as drugs such as retinoids that may even reverse this process. There is the need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for chronic obstructive pulmonary disease.