Revised Korean Cough Guidelines, 2020: Recommendations and Summary Statements.

Cough is the most common respiratory symptom that can have various causes. It is a major clinical problem that can reduce a patient's quality of life. Thus, clinical guidelines for the treatment of cough were established in 2014 by the cough guideline committee under the Korean Academy of Tuberculosis and Respiratory Diseases. From October 2018 to July 2020, cough guidelines were revised by members of the committee based on the first guidelines. The purpose of these guidelines is to help clinicians efficiently diagnose and treat patients with cough. This article highlights the recommendations and summary of the revised Korean cough guidelines. It includes a revised algorithm for the evaluation of acute, subacute, and chronic cough. For a chronic cough, upper airway cough syndrome (UACS), cough variant asthma (CVA), and gastroesophageal reflux disease (GERD) should be considered in differential diagnoses. If UACS is suspected, first-generation antihistamines and nasal decongestants can be used empirically. In cases with CVA, inhaled corticosteroids are recommended to improve cough. In patients with suspected chronic cough due to symptomatic GERD, proton pump inhibitors are recommended. Chronic bronchitis, bronchiectasis, bronchiolitis, lung cancer, aspiration, intake of angiotensin-converting enzyme inhibitor, intake of dipeptidyl peptidase-4 inhibitor, habitual cough, psychogenic cough, interstitial lung disease, environmental and occupational factors, tuberculosis, obstructive sleep apnea, peritoneal dialysis, and unexplained cough can also be considered as causes of a chronic cough. Chronic cough due to laryngeal dysfunction syndrome has been newly added to the guidelines.

Clinical Characteristics of Chronic Cough in Korea.

BACKGROUND: Chronic cough is defined as a cough lasting more than 8 weeks and socio-economic burden of chronic cough is enormous. The characteristics of chronic cough in Korea are not well understood. The Korean Academy of Tuberculosis and Respiratory Diseases (KATRD) published guidelines on cough management in 2014. The current study evaluated the clinical characteristics of chronic cough in Korea and the efficacy of the KATRD guidelines. METHODS: This was a multi-center, retrospective observational study conducted in Korea. The participants were over 18 years of age. They had coughs lasting more than 8 weeks. Subjects with current pulmonary diseases, smokers, ex-smokers with more than 10 pack-years or who quit within the past 1 year, pregnant women, and users of cough-inducing medications were excluded. Evaluation and management of cough followed the KATRD cough-management guidelines. RESULTS: Participants with chronic cough in Korea showed age in the late forties and cough duration of more than 1 year. Upper airway cough syndrome was the most common cause of cough, followed by cough-variant asthma (CVA). Gastro-esophageal reflux diseases and eosinophilic bronchitis were less frequently observed. Following the KATRD cough-management guidelines, 91.2% of the subjects improved after 4 weeks of treatment. Responders were younger, had a longer duration of cough, and an initial impression of CVA. In univariate and multivariate analyses, an initial impression of CVA was the only factor related to better treatment response. CONCLUSION: The causes of chronic cough in Korea differed from those reported in other countries. The current Korean guidelines proved efficient for treating Korean patients with chronic cough.

Development and validation of the COugh Assessment Test (COAT).

BACKGROUND AND OBJECTIVE: A cough-specific quality-of-life questionnaire is recommended to assess the impact of cough; however, a simple instrument to quantify cough is required for everyday clinical practice. This study was aimed to develop a short patient-completed questionnaire (COugh Assessment Test, COAT). METHODS: The COAT was developed and validated by comparison with the Korean version of Leicester Cough Questionnaire (K-LCQ) and cough numeric rating scale (NRS, 0-10, 11-point scale) for chronic cough patients. RESULTS: Item selection identified five items regarding cough frequency, daily activity, sleep disturbance, fatigue and cough hypersensitivity (0-4 scaling of items, 0-20 score range) through reliability test cohort (n = 78). Test-retest reliability was strong (intra-class correlation coefficient = 0.88). The final COAT was compared with K-LCQ and cough NRS in a validation cohort (n = 323). In Rasch analysis, COAT fitted well to a unidimensional model. Pearson correlations of COAT versus K-LCQ (i) before treatment, (ii) after treatment; COAT versus cough NRS (iii) before treatment, (iv) after treatment; (v) delta-COAT versus delta-cough NRS, (vi) delta-COAT versus delta-K-LCQ were (i) -0.71, (ii) -0.81, (iii) 0.69, (iv) 0.82, (v) -0.66 and (vi) 0.72, respectively. CONCLUSION: The COAT is a useful, simple questionnaire for assessing and monitoring cough.

Development of Prediction Equation of Diffusing Capacity of Lung for Koreans.

BACKGROUND: The diffusing capacity of the lung is influenced by multiple factors such as age, sex, height, weight, ethnicity and smoking status. Although a prediction equation for the diffusing capacity of Korea was proposed in the mid-1980s, this equation is not used currently. The aim of this study was to develop a new prediction equation for the diffusing capacity for Koreans. METHODS: Using the data of the Korean National Health and Nutrition Examination Survey, a total of 140 nonsmokers with normal chest X-rays were enrolled in this study. RESULTS: Using linear regression analysis, a new predicting equation for diffusing capacity was developed. For men, the following new equations were developed: carbon monoxide diffusing capacity (DLco)=-10.4433-0.1434×age (year)+0.2482×heights (cm); DLco/alveolar volume (VA)=6.01507-0.02374×age (year)-0.00233×heights (cm). For women the prediction equations were described as followed: DLco=-12.8895-0.0532×age (year)+0.2145×heights (cm) and DLco/VA=7.69516-0.02219×age (year)-0.01377×heights (cm). All equations were internally validated by k-fold cross validation method. CONCLUSION: In this study, we developed new prediction equations for the diffusing capacity of the lungs of Koreans. A further study is needed to validate the new predicting equation for diffusing capacity.

Prevalence of chronic cough and possible causes in the general population based on the Korean National Health and Nutrition Examination Survey.

Although chronic cough is very common, its prevalence and causes have been rarely reported in the large general population including smokers. This study aimed to identify the prevalence of possible causes of chronic cough and their clinical impact.From Korean National Health and Nutrition Examination Survey (KNHANES) data including 119,280 adults aged over 40 years, 302 individuals with chronic cough were recruited irrespective of smoking status. Data from questionnaire, laboratory tests including spirometry, chest radiographs, and otorhinolaryngologic examination were analyzed.The prevalence of chronic cough in adults was 2.5% ±â€Š0.2%. Current smokers occupied 47.7% ±â€Š3.8% of study population and 46.8% ±â€Š3.9% of the subjects showed upper airway cough syndrome (UACS). Based on spirometry, chronic obstructive pulmonary disease (COPD) was identified in 26.4% ±â€Š3.5%. Asthma explained for 14.5% ±â€Š2.8% of chronic cough. Only 4.1% ±â€Š1.6% showed chronic laryngitis suggesting gastro-esophageal reflux-related cough. Abnormalities on chest radiography were found in 4.0% ±â€Š1.2%. Interestingly, 50.3% ±â€Š4.5% of study subjects had coexisting causes. In multivariate analysis, only current smoking (odds ratio [OR] 3.16, P < 0.001), UACS (OR 2.50, P < 0.001), COPD (OR 2.41, P < 0.001), asthma (OR 8.89, P < 0.001), and chest radiographic abnormalities (OR 2.74, P = 0.003) were independent risk factor for chronic cough. This pattern was not different according to smoking status excepting the prevalence of COPD.Smoking, COPD, and chest radiographic abnormalities should be considered as causes of chronic cough, along with UACS and asthma. Gastro-esophageal reflux-related cough is not prevalent in study population.

The Korean Cough Guideline: Recommendation and Summary Statement.

Cough is one of the most common symptom of many respiratory diseases. The Korean Academy of Tuberculosis and Respiratory Diseases organized cough guideline committee and cough guideline was developed by this committee. The purpose of this guideline is to help clinicians to diagnose correctly and treat efficiently patients with cough. In this article, we have stated recommendation and summary of Korean cough guideline. We also provided algorithm for acute, subacute, and chronic cough. For chronic cough, upper airway cough syndrome (UACS), cough variant asthma (CVA), and gastroesophageal reflux disease (GERD) should be considered. If UACS is suspicious, first generation anti-histamine and nasal decongestant can be used empirically. In CVA, inhaled corticosteroid is recommended in order to improve cough. In GERD, proton pump inhibitor is recommended in order to improve cough. Chronic bronchitis, bronchiectasis, bronchiolitis, lung cancer, aspiration, angiotensin converting enzyme inhibitor, habit, psychogenic cough, interstitial lung disease, environmental and occupational factor, tuberculosis, obstructive sleep apnea, peritoneal dialysis, and idiopathic cough can be also considered as cause of chronic cough. Level of evidence for treatment is mostly low. Thus, in this guideline, many recommendations are based on expert opinion. Further study regarding treatment for cough is mandatory.

Vitamin D Inhibits Expression and Activity of Matrix Metalloproteinase in Human Lung Fibroblasts (HFL-1) Cells.

BACKGROUND: Low levels of serum vitamin D is associated with several lung diseases. The production and activation of matrix metalloproteinases (MMPs) may play an important role in the pathogenesis of emphysema. The aim of the current study therefore is to investigate if vitamin D modulates the expression and activation of MMP-2 and MMP-9 in human lung fibroblasts (HFL-1) cells. METHODS: HFL-1 cells were cast into three-dimensional collagen gels and stimulated with or without interleukin-1ß (IL-1ß) in the presence or absence of 100 nM 25-hydroxyvitamin D (25(OH)D) or 1,25-dihydroxyvitamin D (1,25(OH)2D) for 48 hours. Trypsin was then added into the culture medium in order to activate MMPs. To investigate the activity of MMP-2 and MMP-9, gelatin zymography was performed. The expression of the tissue inhibitor of metalloproteinase (TIMP-1, TIMP-2) was measured by enzyme-linked immunosorbent assay. Expression of MMP-9 mRNA and TIMP-1, TIMP-2 mRNA was quantified by real time reverse transcription polymerase chain reaction. RESULTS: IL-1ß significantly stimulated MMP-9 production and mRNA expression. Trypsin converted latent MMP-2 and MMP-9 into their active forms of MMP-2 (66 kDa) and MMP-9 (82 kDa) within 24 hours. This conversion was significantly inhibited by 25(OH)D (100 nM) and 1,25(OH)2D (100 nM). The expression of MMP-9 mRNA was also significantly inhibited by 25(OH)D and 1,25(OH)2D. CONCLUSION: Vitamin D, 25(OH)D, and 1,25(OH)2D play a role in regulating human lung fibroblast functions in wound repair and tissue remodeling through not only inhibiting IL-1ß stimulated MMP-9 production and conversion to its active form but also inhibiting IL-1ß inhibition on TIMP-1 and TIMP-2 production.

Epidemiological aspects of pertussis among adults and adolescents in a Korean outpatient setting: a multicenter, PCR-based study.

Epidemiological data of Bordetella pertussis infection among adolescents and adults are limited in Korea. Patients (≥ 11 yr of age) with a bothersome cough for less than 30 days were enrolled during a 1-yr period at 22 hospitals in Korea. Nasopharyngeal swabs were collected for polymerase chain reaction (PCR) and for bacteriologic culture. In total, 490 patients were finally enrolled, and 34 (6.9%) patients tested positive for B. pertussis; cough duration (14.0 days [7.0-21.0 days]) and age distribution were diverse. The incidence was the highest in secondary referral hospitals, compared to primary care clinics or tertiary referral hospitals (24/226 [10.6%] vs. 3/88 [3.4%] vs. 7/176 [4.0%], P = 0.012), and the peak incidence was observed in February and August (15.8% and 15.9%), with no confirmed cases between March and June. In the multivariate analysis, post-tussive vomiting was significantly associated with pertussis (odds ratio, 2.508; 95% confidence interval, 1.146-5.486) and secondary referral hospital showed a borderline significance. In conclusion, using a PCR-based method, 6.9% of adolescent and adult patients with an acute cough illness had pertussis infection in an outpatient setting. However, hospital levels and seasonal trends must be taken into account to develop a better strategy for controlling pertussis.

A Multicenter Study of Pertussis Infection in Adults with Coughing in Korea: PCR-Based Study.

BACKGROUND: Limited data on the incidence and clinical characteristics of adult pertussis infections are available in Korea. METHODS: Thirty-one hospitals and the Korean Centers for Disease Control and Prevention collaborated to investigate the incidence and clinical characteristics of pertussis infections among adults with a bothersome cough in non-outbreak, ordinary outpatient settings. Nasopharyngeal aspirates or nasopharyngeal swabs were collected for polymerase chain reaction (PCR) and culture tests. RESULTS: The study enrolled 934 patients between September 2009 and April 2011. Five patients were diagnosed as confirmed cases, satisfying both clinical and laboratory criteria (five positive PCR and one concurrent positive culture). Among 607 patients with cough duration of at least 2 weeks, 504 satisfied the clinical criteria of the US Centers for Disease Control and Prevention (i.e., probable case). The clinical pertussis cases (i.e., both probable and confirmed cases) had a wide age distribution (45.7±15.5 years) and cough duration (median, 30 days; interquartile range, 18.0~50.0 days). In addition, sputum, rhinorrhea, and myalgia were less common and dyspnea was more common in the clinical cases, compared to the others (p=0.037, p=0.006, p=0.005, and p=0.030, respectively). CONCLUSION: The positive rate of pertussis infection may be low in non-outbreak, ordinary clinical settings if a PCR-based method is used. However, further prospective, well-designed, multicenter studies are needed.

Dermatomyositis, complicated with pneumomediastinum, successfully treated with cyclosporine A: a case report and review of literature.

We report a rare case of patient with dermatomyositis (DM) who developed spontaneous pneumomediastinum (PnM) and subcutaneous emphysema. She was successfully treated with oral prednisolone and cyclosporine A (CsA). We reviewed the cases of PnM in patients with DM treated with CsA. A review of four previously reported cases revealed that treatment with systemic glucocorticoid and CsA was effective for the DM and PnM. We indicate that initial and early treatment of the patients with DM and PnM with CsA enabled rapid tapering of the dose of glucocorticoid and improved the disease.

Sphingosine 1-phosphate potentiates human lung fibroblast chemotaxis through the S1P2 receptor.

Migration of fibroblasts plays an essential role in tissue repair after injury. Sphingosine 1-phosphate (S1P) is a multifunctional mediator released by many cells that can be released in inflammation and after injury. This study evaluated the effect of S1P on fibroblast chemotaxis toward fibronectin. S1P alone did not affect fibroblast migration, but S1P enhanced fibronectin-directed chemotaxis in a concentration-dependent manner. The effect of S1P was not mimicked by dihydro (dh) S1P or the S1P(1) receptor agonist SEW2871. S1P augmentation of fibroblast chemotaxis, however, was completely blocked by JTE-013, an S1P(2) antagonist, but not by suramin, an S1P(3) antagonist. Suppression of the S1P(2) receptor by small interfering (si)RNA also completely blocked S1P augmentation of fibroblast chemotaxis to fibronectin. S1P stimulated Rho activation and focal adhesion kinase (FAK) phosphorylation, and these were also significantly inhibited by the S1P(2) receptor antagonist (JTE-013) or by S1P(2) siRNA. Further, the potentiation of S1P signaling was blocked by the Rho-kinase inhibitor Y-27632 in a concentration-dependent manner. Inhibition of FAK with siRNA reduced basal chemotaxis toward fibronectin slightly but significantly, and almost completely blocked S1P augmented chemotaxis. These results suggest that S1P-augmented fibroblast chemotaxis toward fibronectin depends on the S1P(2) receptor and requires Rho and Rho-kinase, and FAK phosphorylation. By augmenting fibroblast recruitment, S1P has the potential to modulate tissue repair after injury. The pathways by which S1P mediates this effect, therefore, represent a potential therapeutic target to affect tissue repair and remodeling.

TGF-beta1 and serum both stimulate contraction but differentially affect apoptosis in 3D collagen gels.

Apoptosis of fibroblasts may be key for the removal of cells following repair processes. Contraction of three-dimensional collagen gels is a model of wound healing and remodeling. Here two potent inducers of contraction, TGF-beta1 and fetal calf serum (FCS) were evaluated for their effect on fibroblast apoptosis in contracting collagen gels. Human fetal lung fibroblasts were cultured in floating type I collagen gels, exposed to TGF-beta1 or FCS, and allowed to contract for 5 days. Apoptosis was evaluated using TUNEL and confirmed by DNA content profiling. Both TGF-beta1 and serum significantly augmented collagen gel contraction. TGF-beta1 also increased apoptosis assessed by TUNEL positivity and DNA content analysis. In contrast, serum did not affect apoptosis. TGF-beta1 induction of apoptosis was associated with augmented expression of Bax, a pro-apoptotic member of the Bax/Bcl-2 family, inhibition of Bcl-2, an anti-apoptotic member of the same family, and inhibition of both cIAP-1 and XIAP, two inhibitors of the caspase cascade. Serum was associated with an increase in cIAP-1 and Bcl-2, anti-apoptotic proteins. Interestingly, serum was also associated with an apparent increase in Bax, a pro-apoptotic protein. Blockade of Smad3 with either siRNA or by using murine fibroblasts deficient in Smad3 resulted in a lack of TGF-beta induction of augmented contraction and apoptosis. Contraction induced by different factors, therefore, may be differentially associated with apoptosis, which may be related to the persistence or resolution of the fibroblasts that accumulate following injury.

Smad3 mediates TGF-beta1 induction of VEGF production in lung fibroblasts.

Transforming growth factor-beta1 (TGF-beta1) is a key factor in a variety of physiological and pathological processes. Vascular endothelial growth factor (VEGF) is a key angiogenic factor, and vascular change is one of the features of airway remodeling. We examined the effect of TGF-beta1 on VEGF production by fibroblasts from mice lacking expression of Smad2 or Smad3 as well as human lung fibroblasts treated with or without Smad2 or Smad3 siRNA. TGF-beta1 stimulated VEGF production by fibroblasts from Smad2 deficient animals and wildtype animals. In contrast, TGF-beta1 did not affect VEGF production by fibroblasts from Samd3 deficient mice. Similarly, TGF-beta1 failed to stimulate VEGF production by HFL-1 cells treated with Samd3 siRNA but significantly increased VEGF production by the cells treated with Smad2 siRNA. These result suggest that TGF-beta1 stimulation of VEGF production by fibroblasts is regulated by Smad3 but not by Smad2 signaling.

Cigarette smoke extract inhibits chemotaxis and collagen gel contraction mediated by human bone marrow osteoprogenitor cells and osteoblast-like cells.

Cell migration and matrix remodeling are key events in tissue repair and restructuring. Osteoblasts are responsible for the production of new bone matrix during bone remodeling. The activity of these cells can be modulated by a number of factors. The current study evaluated the hypothesis that cigarette smoke extract can alter repair and remodeling responses of human osteoprogenitor cells and osteoblast-like cells and, therefore, could explain one mechanism by which cigarette smoking leads to osteoporosis. Human osteoprogenitor cells were isolated from normal human bone marrow and maintained in culture under either control conditions or conditions that induced differentiation into osteoblast-like cells. Both cell types migrated toward fibronectin and PDGF-BB as chemoattractants. Neither responded to TGF-beta1. The osteoprogenitor cells were more active in their chemotactic response. The chemotactic response of both cell types was inhibited by cigarette smoke extract in a concentration-dependent manner. Both cell types, when cultured in three-dimensional native collagen gels maintained in floating culture, induced contraction of their surrounding matrices. Contraction was augmented by serum, PDGF-BB, and TGF-beta1. Osteoprogenitor cells were less active in inducing contraction than were osteoblast-like cells. Contraction of both cell types was inhibited by cigarette smoke extract. Cigarette smoke extract also inhibited the production of fibronectin by both cell types maintained in three-dimensional culture. Addition of exogenous fibronectin partially restored the ability of the cells to contract three-dimensional collagen gels. The current study demonstrates that cigarette smoke can interfere with the ability of bone cells to participate in repair and remodeling events. Such an effect may be one mechanism leading to the development of osteoporosis.

Effect of cigarette smoke on fibroblast-mediated gel contraction is dependent on cell density.

Cigarette smoke exposure has been associated with a variety of diseases, including emphysema. The current study evaluated the interaction of cell density and cigarette smoke extract (CSE) on fibroblast contraction of collagen gels. Protein levels of transforming growth factor (TGF)-beta1, fibronectin, PGE(2), and TGF-beta1 mRNA were quantified. Although both 5 and 10% CSE inhibited contraction by low-density fibroblasts (1 x 10(5) cell/ml), only 5% CSE augmented contraction in higher-density cultures (3-5 x 10(5) cells/ml). CSE also inhibited fibronectin and TGF-beta1 production in low-density cultures but stimulated fibronectin production in high-density cultures. Active TGF-beta1 was readily detectable only in higher-density cultures and was markedly augmented by 5% CSE. In contrast, although TGF-beta1 mRNA expression was inhibited in high-density cultures by 10% CSE, expression was increased in the presence of 5% CSE. These results suggest that CSE-induced inhibition of low-density fibroblast contraction is due to inhibition of fibronectin production, whereas CSE's stimulatory effect on high-density cells is the result of increased release of TGF-beta1. These effects may help explain the varied pathologies associated with exposure to cigarette smoke.

PGD(2) modulates fibroblast-mediated native collagen gel contraction.

Repair of tissues is a necessary step in restoring tissue function following injury consequent to inflammation. Many inflammatory mediators are capable of modulating not only the activity of "inflammatory cells" but also of modulating functions of parenchymal cells that may contribute to repair. Disordered repair is believed to contribute to tissue dysfunction in many inflammatory diseases, including bronchial asthma. The current study evaluated the ability of prostaglandin D(2) (PGD(2)) to modulate fibroblast repair using the in vitro contraction of three-dimensional native collagen gels as a model system. PGD(2) stimulated gel contraction in a concentration- and time-dependent manner. In contrast, the PGD(2) analog BW245C inhibited contraction. Both effects were blocked by a DP-receptor blocker (AH6809). Neither TP receptor blocker SQ29548 nor protein kinase (PK) A antagonist KT5720 hand an effect on PGD(2)-stimulated contraction, suggesting action through a novel prostaglandin D receptor. PKC inhibitor calphostin-C (10(-6) M) blocked the PGD(2) stimulation of gel contraction. A calcium-independent PKC-epsilon inhibitor (Ro31-8220), but not calcium-dependent PKC-alpha and -beta inhibitors, also blocked the PGD(2) effect on contraction, implying a role for a calcium-independent pathway. This study, therefore, supports a role for PGD(2) in tissue repair and remodeling. These effects of PGD(2) appear to be mediated through receptor-signal transduction pathways different from the cAMP-PKA pathways mediating the proinflammatory activity of PGD(2), creating the possibility for selective therapeutic manipulation.

Glutathione prevents inhibition of fibroblast-mediated collagen gel contraction by cigarette smoke.

Cigarette smoke, the major risk factor for the development of emphysema, contains over 4,700 chemical compounds, including free radicals and other oxidants (10(14)/puff). An imbalance between oxidants and antioxidants has been proposed in the pathogenesis of chronic obstructive pulmonary disease. Inhibition of repair processes has been suggested to be one pathway contributing to the development of emphysema. We hypothesized that cigarette smoke inhibition of repair might result from a shift of the oxidant/antioxidant balance in favor of oxidants. To evaluate this hypothesis, N-acetyl-L-cysteine (NAC), which serves as a substrate for glutathione (GSH) production, and buthionine sulfoximine (BSO), which inhibits GSH production, were incubated in the presence and absence of cigarette smoke extract (CSE) with fibroblasts in three-dimensional collagen gels. Neither agent alone altered gel contraction. CSE inhibition of gel contraction, however, was mitigated by NAC and potentiated by BSO. Parallel effects were observed on cigarette smoke inhibition of fibronectin production and mRNA expression as well as by changes in intracellular GSH content. Pretreatment of fibroblasts with NAC or BSO resulted in similar effects, suggesting that neither agent was acting directly on smoke but, rather, was altering cellular response to smoke. In conclusion, smoke inhibition of fibroblast repair, as reflected by collagen gel contraction and fibronectin production, may be modulated by intracellular GSH levels.

Prostacyclin analogs inhibit fibroblast migration.

The controlled accumulation of fibroblasts to sites of inflammation is crucial to effective tissue repair after injury. Either inadequate or excessive accumulation of fibroblasts could result in abnormal tissue function. Prostacyclin (PGI(2)) is a potent mediator in the coagulation and inflammatory processes. The aim of this study was to investigate the effect of PGI(2) on chemotaxis of human fetal lung fibroblasts (HFL-1). Using the blind well chamber technique, we found that the PGI(2) analog carbaprostacyclin (10(-6) M) inhibited HFL-1 chemotaxis to human plasma fibronectin (20 microg/ml) 58.0 +/- 13.2% (P < 0.05) and to platelet-derived growth factor (PDGF)-BB (10 ng/ml) 48.7 +/- 4.6% (P < 0.05). Checkerboard analysis demonstrated that carbaprostacyclin inhibits both directed and undirected migration. The inhibitory effect of the carbaprostacyclin was concentration dependent and blocked by the cAMP-dependent protein kinase (PKA) inhibitor KT-5720, suggesting that a cAMP-PKA pathway may be involved in the process. Two other PGI(2) analogs, ciprostene and dehydro-15-cyclohexyl carbaprostacyclin (both 10(-6) M), significantly inhibited fibroblast migration to fibronectin. In summary, PGI(2) appears to inhibit fibroblast chemotaxis to fibronectin and PDGF-BB. Such an effect may contribute to the regulation of fibroblasts in wound healing and could contribute to the pathogenesis of diseases characterized by abnormal tissue repair remodeling.

PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels.

Therapies that mitigate the fibrotic process may be able to slow progressive loss of function in many lung diseases. Because cyclic adenosine monophosphate is known to regulate fibroblasts, the current study was designed to evaluate the activity of selective phosphodiesterase (PDE) inhibitors on two in vitro fibroblast responses: chemotaxis and contraction of three-dimensional collagen gels. Selective PDE4 inhibitors, rolipram and cilomilast, each inhibited the chemotaxis of human fetal lung fibroblasts (HFL-1) toward fibronectin in the blindwell assay system (control: 100% versus cilomilast [10 microM]: 40.5 +/- 7.3% versus rolipram: [10 microM] 32.1 +/- 2.7% cells/5 high-power fields; P < 0.05, both comparisons). These PDE4 inhibitors also inhibited contraction of three-dimensional collagen gels (control: 100% versus cilomilast: 167.7 +/- 6.9% versus rolipram: 129.9 +/- 1.9% of initial size; P < 0.05, both comparisons). Amrinone, a PDE3 inhibitor, and zaprinast, a PDE5 inhibitor, had no effect in either system. Prostaglandin E(2) (PGE(2)) inhibited both chemotaxis and gel contraction, and the PDE4 inhibitors shifted the PGE(2) concentration-dependence curve to the left in both systems. The inhibition of endogenous PGE(2) production by indomethacin diminished the effects of the PDE4 inhibitors in both chemotaxis and gel contraction, consistent with the concept that the PDE4 inhibitory effects on fibroblasts are related to the presence of cyclic adenosine monophosphate in the cells. In summary, these in vitro results suggest that PDE4 inhibitors may be able to suppress fibroblast activity and, thus, have the potential to block the development of progressive fibrosis.