Reduced Airway Responsiveness Research Articles

The role of adenosine as a novel bronchoprovocant in asthma.

There is evidence that bronchial hyperresponsiveness to inhaled adenosine may be a better marker of airway allergic inflammation than bronchial hyperresponsiveness to other spasmogens. Here the authors review the most recent development in this area of rapidly evolving clinical research, focusing on the putative role of adenosine as a useful bronchoprovocant in asthma. New studies have provided evidence that hyperresponsiveness to AMP strongly correlates with sputum, blood/bronchial tissue eosinophilia and exhaled nitric oxide, whereas hyperresponsiveness to methacholine is related to changes in forced expiratory volume in 1 s, thus reflecting changes in airway caliber and functional state. Other recent studies have emphasized that the state of atopy is critically important in the bronchial response to inhaled AMP. The early finding that in people with asthma treatment with inhaled glucocorticosteroids significantly reduces airway responsiveness to AMP, as compared with other spasmogens such as methacholine or bradykinin, has been confirmed by recent reports which have also outlined that this is an early phenomenon. Taken together these studies evidence that hyperresponsiveness to inhaled adenosine may be a better marker of airway allergic inflammation than hyperresponsiveness to other spasmogens. This peculiar property of adenosine suggests that bronchial provocation with inhaled adenosine could provide a reliable noninvasive tool for monitoring asthma activity/progression, and assessing the response to antiinflammatory treatments.

Repeated Exposure to Isoprene Oxidation Products Causes Enhanced Respiratory Tract Effects in Multiple Murine Strains

Ozone reacts with terpenes, common hydrocarbons in cleaning and consumer products as well as the ambient environment, to form particle- and gas-phase products; these have been shown to cause sensory irritation and airflow limitation in mice during single exposures. Isoprene, a hemiterpene emitted from both plants and animals as a bioeffluent, induces the largest effects. This study evaluated the effects of repeated exposures to isoprene oxidation products (OPs) on airway irritation, airflow limitation, and airway responsiveness. A secondary objective was to evaluate a genetic influence by examining multiple murine strains. Six strains (A/J, AKR/J, BALB/c, Swiss Webster, C57Bl/6, and C3H/HeN; total n = 35) were exposed to isoprene oxidation products (1080 ± 155 ppb isoprene + 3227 ± 157 ppb ozone at admixing) for 3 h/day for 4 consecutive days. Respiratory parameters were monitored on days 1 and 4 via head-out plethysmography, and airway responsiveness to aerosolized methacholine was evaluated 24 h before the first exposure and immediately after the fourth exposure. Sensory irritation was observed during exposure, as evidenced by a reduction in respiratory frequency (f). A reduction in peak expiratory flow normalized for tidal volume (PEF/VT) also occurred, indicating an airflow limitation effect. Marked enhancement of the effects on f and PEF/VT was observed with repeated exposures, suggesting a cumulative effect. Frequency was reduced from 46.0 ± 2.3% of baseline during exposure 1 to 34.2 ± 2.1% during exposure 4 (p = .00002; pooled values for all strains). Similarly, PEF/VT decreased from 75.6 ± 3.9% of baseline during exposure 1 to 53.1 ± 3.7% during exposure 4 (p < .00001). A significant reduction in airway responsiveness was observed following repeated exposures in most strains. Interstrain differences in responses were noted, indicating a genetic component. These findings have important implications for indoor environments, where isoprene concentrations can be high in buildings with high occupant densities. The findings are also relevant to outdoor environments, where isoprene emissions from vegetation lead to the formation of isoprene OPs, which may partition onto existing particulate matter (PM) in the atmosphere to contribute to secondary organic aerosol. Further, the genetic variability observed in the mouse strains examined suggests that interindividual differences in response may also exist in human populations, which may help to explain the high variability in symptom reporting in indoor environments.

Fluticasone Propionate via the Diskhaler or Hydrofluoroalkane-134a Metered-Dose Inhaler on Methacholine-Induced Airway Hyperresponsiveness

s: To compare the effect of 4 weeks of treatment with fluticasone propionate (FP), 100 micro g bid, delivered either via the Diskhaler (GlaxoSmithKline; Middlesex, UK) or a hydrofluoroalkane (HFA)-134a pressurized metered-dose inhaler (pMDI) on airway responsiveness. A single-center, randomized, double-blind, double-dummy, placebo-controlled crossover study. Outpatients. Patients with mild asthma who had not received corticosteroids for 4 weeks prior to the study. FP, 100 micro g bid, via the Diskhaler, HFA-134a pMDI, or placebo for periods of 4 weeks. The primary efficacy variable was the provocative dose of methacholine causing a 20% fall in FEV(1) (PD(20)) at the end of each 4-week treatment period. The FP formulations were defined as equivalent if the treatment difference was within +/- 1 doubling dose of methacholine. Forty-seven patients were included in the per-protocol population. The baseline PD(20) geometric mean was 0.21 mg, which increased to 0.55 mg with FP via the HFA-134a pMDI and to 0.68 mg with FP via the Diskhaler. The treatment difference between adjusted means was - 0.16 doubling doses (95% confidence interval, - 0.62 to 0.31 doubling doses; p = 0.503). Both significantly decreased airway responsiveness compared to placebo (p < 0.001), and also significantly increased lung function with no difference between the two active groups. FP was well tolerated with few adverse events and no effect on serum cortisol levels. FP delivered via the HFA-134a pMDI is equivalent to FP via the Diskhaler in reducing airway responsiveness.

Beyond our pages

Beyond our pages

CONSEQUENCES OF LONG-TERM INFLAMMATION: The Natural History of Asthma

Although asthma is classically defined as reversible airflow obstruction, and often remits in younger subjects with milder disease, the natural history of asthma is that various degrees of airflow obstruction may persist and, in the long-term, asthma may become moderately to fully irreversible. Severe, irreversible airflow obstruction may develop despite apparently appropriate therapy and in the absence of other risk factors, such as smoking and environmental insults. All studies of subjects with persisting asthma show increased decline in lung function compared with normal subjects. Persistent abnormal physiology is reflected both in reduced airflow rates and in increased airway responsiveness. The cellular and molecular mechanisms of airway remodeling are described elsewhere in this issue. Questions not yet clearly answered are the reasons for these persistent abnormalities in some asthmatics, and which subjects are most at risk. Factors that adversely impact the outcome as adults identified relatively consistently among many longitudinal studies of the natural history of asthma include: Female gender. Environmental tobacco smoke exposure in childhood. Personal tobacco smoking in adolescence and adulthood. Age of onset of symptoms. Severity of childhood asthma. Duration of asthma. Severity of lung function abnormality in childhood. Bronchodilator reversibility. Degree of airway hyperresponsiveness. Delay in initiating anti-inflammatory therapy. Remission among adult asthmatics is uncommon, but is associated with better initial lung function, young age, male gender, and lesser degrees of airway responsiveness. The role of atopy remains controversial. Conversely, risk factors for death from asthma include older age, smoking, atopy, impaired lung function, and moderate to high reversibility. Treatment can improve lung function, reduce airway responsiveness, and improve quality of life. The overall effect of treatment on the natural history of the disease is not yet clear, despite significant short-term improvements from effective anti-inflammatory therapy.

Reduction of allergic airway responses in P-selectin-deficient mice.

P-selectin is an adhesion receptor that has been shown to be important in the recruitment of eosinophils and lymphocytes in a variety of inflammatory conditions. Because cellular recruitment is thought to be a critical event in allergen-induced changes in airway responsiveness, we reasoned that P-selectin-deficient mice would exhibit reduced airway responsiveness and cellular trafficking noted in wild-type (+/+) mice. Both (+/+) and P-selectin-deficient (-/-) mice sensitized and challenged with ovalbumin (OVA/OVA) exhibited the same capacity to produce increased titers of total and OVA-specific immunoglobulin E. Airway responsiveness to methacholine was significantly greater in the (+/+) (OVA/OVA) animals than it was in the respective (-/-) (OVA/OVA) group or control groups (P = 0.0016). Bronchoalveolar lavage fluid from (-/-) (OVA/OVA) mice contained significantly fewer eosinophils and lymphocytes compared with the (+/+) (OVA/OVA) mice (P < 0.05). These results suggest that the predominant role of P-selectin in OVA-induced airway hyperresponsiveness is to promote the airway inflammatory response to allergen inhalation.

Inhaled lysine acetylsalicylate (L-ASA) attenuates the bronchoconstrictor response to adenosine 5'-monophosphate (AMP) in asthmatic subjects

When administered by inhalation, adenosine 5'-monophosphate (AMP) provokes dose-related bronchoconstriction in asthmatic subjects by a mechanism believed to involve mast cell mediator release. However, little is known of the change in airway responsiveness to AMP after cyclo-oxygenase blockade. The aim of this study was to investigate the effect of the potent cyclo-oxygenase inhibitor, lysine acetylsalicylate (L-ASA) administered by inhalation, on AMP-induced bronchoconstriction in a group of nine asthmatic subjects. The subjects studied attended the laboratory on six separate occasions to receive nebulized L-ASA (solution of 90 mg.ml-1) or matched placebo (glycine solution, 30 mg.ml-1) 15 min prior to bronchoprovocation tests with AMP, histamine and methacholine in a randomized, double-blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and agonist responsiveness was expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). Administration of both L-ASA and glycine solution caused a small but significant acute fall in FEV1 from baseline, which returned to normal within 15 min. When compared to placebo, inhaled L-ASA reduced the airway responsiveness to AMP in all the subjects studied, the geometric mean (range) values for PC20 AMP increasing significantly from 36.3 (7.9-250.5) to 101.8 (27.2-1300) mg.ml-1 after placebo and L-ASA, respectively. Moreover, nebulized L-ASA induced a small but significant reduction in airway responsiveness to histamine, the geometric mean (range) PC20 values for histamine increasing from 2.77 (1.05-5.49) to 4.36 (1.69-11.24) mg.ml-1 after placebo and L-ASA, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhaled loop diuretics and basal airway responsiveness in man: evidence of a role for cyclo-oxygenase products

Inhaled frusemide protects asthmatic airways against a wide variety of bronchoconstrictor stimuli by unknown mechanisms. To investigate whether inhaled loop diuretics modulate baseline bronchial responsiveness, a randomized, double-blind, placebo-controlled study was conducted to test the ability of frusemide (40 mg) and bumetanide (2 mg) to displace concentration-response curves with methacholine in 14 healthy volunteers. In addition, separate randomized, double-blind studies were carried out to evaluate the effects of oral flurbiprofen, a potent cyclo-oxygenase inhibitor, on the protective action of frusemide against methacholine-induced bronchoconstriction. Inhaled loop diuretics significantly increased the provocative concentration of methacholine causing a 15% decrease in forced expiratory volume in one second (PC15FEV1) from the geometric mean (range) value of 58.6 (9.2-233) mg.ml-1 after placebo administration, to 129 (13.8-505) and to 106 (6.6-510) mg.ml-1 after administration of frusemide and bumetanide, respectively. Similar results were obtained when data from partial flow-volume curves were used for analysis. In the eight subjects studied, pretreatment with oral placebo and inhaled frusemide reduced airway responsiveness to methacholine, with a geometric mean (range) PC15FEV1 value of 116 (25.4-405) mg.ml-1, and premedication with oral flurbiprofen abolished this protective effect, the geometric mean (range) PC15FEV1 methacholine being reduced to a value of 50.3 (16.6-189) mg.ml-1. In addition, oral flurbiprofen alone failed to alter airway responsiveness to methacholine. In view of these findings, it is suggested that bronchoprotective prostaglandins may mediate the effects of loop diuretics against methacholine-induced bronchoconstriction in man.

Alpha 4 integrin-induced cytokine production and eosinophil function.

The eosinophil α4 integrin receptor is likely to play an important role in eosinophil adhesion as well as signal transduction. In vitro studies have shown that triggering eosinophil α4 integrin induces GM-CSF and IL-3 release by eosinophils [5]. In vivo studies have shown that the eosinophil α4 integrin acts not only as a firm adhesion receptor, but also as a rolling receptor [68]. Preliminary studies of α4 models of asthma suggest that neutralizing antibodies to α4 inhibit eosinophil migration into the airway in some [52], but not all [1] models of asthma. Neutralizing antibodies to α4 improve airway function in some animal models of asthma in which eosinophil migration is only partially inhibited [1]. This suggests that the α4 antibodies may not only be inhibiting recruitment, but also activation of eosinophils. For example, in a sheep model of allergen-induced asthma, the anti-α4 integrin antibody HP 1/2 blocked late-phase airway changes and post-challenge airway hyperresponsiveness, but did not consistently alter the composition of leukocytes (including eosinophils) recovered by bronchoalveolar lavage is [1]. Because the anti-α-4 integrin antibody was also effective in reducing airway responsiveness following airway (as opposed to intravenous) administration, it may have functioned by inhibiting integrin-mediated cellular activation as opposed to inhibiting integrin-mediated adhesion. It is likely that several adhesion receptors other than VLA-4 are important to the pathogenesis of allergic inflammation. For example, in animal models of asthma, neutralizing antibodies to the adhesion molecules E-selectin [33] and ICAM [79] significantly reduce the airway inflammatory response. Therefore, future studies will determine the clinical utility of targeting α-4 integrin receptors in diseases associated with eosinophilic inflammation.

Different effects of inhaled amiloride and frusemide on airway responsiveness to dry air challenge in asthmatic subjects

Amiloride, a Na+ channel blocker, and frusemide, an inhibitor of the Na+/K+/2Cl- co-transporter on the basolateral surface of airway epithelial cells, have the potential to affect water transport across the airway epithelium. As isocapnic hyperventilation challenge (ISH) with dry air may provoke airway narrowing in asthmatic subjects by dehydrating the airways, inhaled amiloride and frusemide may reduce airway responsiveness by effecting airway hydration. Fifteen asthmatic subjects (6 females, 9 males), who had a fall in forced expiratory volume in one second (FEV1) of 20% after ISH, inhaled amiloride (11 mg), or its vehicle, from a Fisoneb ultrasonic nebulizer, within 10 min before ISH. On a separate day, eight of these subjects inhaled frusemide (38 mg), from the same Fisoneb, 10 min before ISH. After breathing, 30 l at resting ventilation, subjects breathed at 30% of their maximum voluntary ventilation (MVV i.e. predicted FEV1x35), then at 60% MVV, and finally at MVV for 3 or 4 min. FEV1 was measured 1, 3, 5, 7 and 9 min after each period, or until it was stable. Airway sensitivity was expressed as the ventilation (l-min-1) which provoked a 10, 15, 20 or 30% fall in FEV1, (PVE10, PVE15, PVE20 and PVE30, respectively). There was no significant difference in the PVE10,15,20,30 between the vehicle and amiloride treatment day; however, in the 8 subjects who inhaled frusemide, frusemide caused a significant increase in the PVE20 when compared to amiloride. In conclusion, inhaled amiloride failed to protect against ISH, whereas frusemide was effective at reducing airway responsiveness. Further studies are needed to explain the mechanism of action of frusemide.

The role of intercellular adhesion molecule-1 in chronic airway inflammation.

We have examined the role of intercellular adhesion molecule-1 (ICAM-1) in chronic airway inflammation and airway hyperresponsiveness in a primate model of asthma. Airway cellular composition was assessed by bronchoalveolar lavage (BAL) and airway responsiveness was measured as the bronchoconstrictor response to inhaled methacholine. In animals with chronic airway inflammation (increased BAL eosinophils) and sustained airway hyperresponsiveness, a 7 day dosing scheme with a murine anti-human ICAM-1 monoclonal antibody (R6.5, 2 mg/kg/day; i.v.) did not reduce the existing airway inflammation or airway hyperresponsiveness. In contrast, a similar dosing scheme with dexamethasone (0.2 mg/kg/day, i.m.) was found to significantly reduce both the airway eosinophilia and hyperresponsiveness. However, one week after cessation of dexamethasone treatment, the airway inflammation and hyperresponsiveness returned to pre-treatment levels. In further experiments where animals were first treated with dexamethasone (7 days) followed by a 7 day treatment with R6.5, the reoccurrence of airway inflammation and subsequent increase in airway responsiveness was prevented. We conclude that the efficacy of ICAM-1 is primarily associated with inhibition of the influx of inflammatory cells into the airways and subsequent reduction in airway responsiveness. These data suggest that in lungs with pre-existing inflammation the modulation of ICAM-1 following treatment with glucocorticoids may be a novel and more selective long-term treatment for control of the chronic airway inflammation and hyperresponsiveness associated with bronchial asthma.

Differential effect of glucocorticoids on pulmonary responses and eosinophils

The persistent airway hyperresponsivenes oof Basenji-Greyhound (BG) dogs to 10% citric acid (CA) is abolished by chronic administration of methylprednisolone (MP) and is accompanied by the disappearance of eosinophils from the bronchoalveolar lavage (BAL) fluid. To determine whether the disappearance of eosinophils from BAL fluid was temporally related to the loss of airway responsiveness to CA, we investigated the time course of the reduction in airway responsiveness to CA and correlated it with changes in cell profiles in BAL fluid in a group of BG dogs treated with MP for 1 to 7 days. Six dogs in separate studies were pretreated with MP (2 mg/kg/day) subcutaneously for either 1, 3 or 7 days. Each dog served as its own control for each set of studies. Under thiopental anesthesia, lung resistance (R l) was calculated from transpulmonary pressure and flow measurements prior to and 5 minutes following the completion of a 10% CA aerosol. BAL was performed on a separate occasion with the animals pretreated with MP for either 1, 7, 10 or 14 days. Baseline R l was not significantly different in each control annd treatment group. The pulmonary response to CA challenge was diminished following 1, 3 and 7 days of MP pretreatment. Although eosinophils disappeared from the peripheral blood following 1 day of MP treatment, eosinophils in BAL did not begin decreasing until 10 days of MP pretreatment. This temporal dissociation between CA hyperresponsiveness and eosinophils in the BAL fluid suggests that epithelial damage by toxic products of eosinophils in the airway lumen does not play a direct role in citric acid induced airway hyperresponsiveness in BG dogs.

Azelastine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential.

Azelastine is an antiallergic agent which demonstrates histamine H1-receptor antagonist activity and also inhibits histamine release from mast cells following antigen and non-antigen stimuli. Azelastine antagonises histamine- and leukotriene-induced bronchospasm in animal studies and reduces airway responsiveness to inhaled antigen or distilled water, and exercise challenge. In comparative studies, orally administered azelastine in doses up to 4 mg/day consistently relieved symptoms in patients with seasonal or perennial rhinitis - comparable to inhaled sodium cromoglycate (cromolyn sodium) 80 mg/day, oral chlorpheniramine (chlorphenamine) and oral terfenadine 120 mg/day. In addition, azelastine administered as an intranasal spray was as effective as oral terfenadine 120 mg/day and intranasal budesonide 0.4 mg/day in alleviating symptoms of rhinitis. Azelastine is also a potent antiasthmatic agent which produces significant and long lasting bronchodilation in patients with bronchial asthma. The drug is superior to placebo and comparable to oral ketotifen 2 mg/day and sustained release theophylline 700 mg/day when administered as a twice daily oral 4 mg dose. Azelastine is generally well tolerated: the most common adverse effects are altered taste perception and drowsiness. Adverse effects are mild and transient and result in withdrawal of treatment in less than 2% of patients. In a comparative study oral azelastine 2 or 4 mg/day produced no more sedation than terfenadine 120 mg/day. Thus, barring unexpected findings with wider clinical use, azelastine offers an effective and well tolerated choice of treatment for patients with allergic rhinitis and/or bronchial asthma, which may be particularly beneficial in patients in whom inhaled drug treatment is contraindicated.

The effect of oral prostaglandin E 1 on airway responsiveness in asthmatic subjects

Prostaglandin E 1 (PGE 1) is a bronchodilator in humans, but the effect of this prostaglandin on airway responsiveness in asthmatic subjects is not known. The purpose of this study was to examine the effect of oral PGE, treatment on airway responsiveness to inhaled histamine and methacholine in asthmatic subjects. The subjects had inhalation tests performed on separate study days over a period of 2 weeks. PGE 1 (200 μg 4 times daily) or placebo was taken in a double-blind fashion for 4 consecutive days. Each week, after three days of treatment, a histamine or methacholine inhalation test was performed on one day, followed by an inhalation test with the alternative agonist the following day. Baseline forced expired volume in 1 s (FEVI) values were similar before each inhalation test on each study day (P=0.81). However, both histamine and methacholine airway responsiveness decreased following PGE 1 treatment. The mean provocative concentration of histamine causing a 20% fall in FEVI (PC 20 histamine) on the placebo day was 1.47 mg/ml (%SD 3.05) and was 2.35 mg/ml (%SD 2.72) (p < 0.005) during PGE, treatment period. Similarly the PC 20 methacholine was 1.84 mg/ml (%SD 2.30) on the placebo day and was 2.53 mg/ml (%SD 2.06) during PGE, treatment period (p=0.025). This study demonstrates that oral PGEI, administered in doses which did not change airway caliber, can reduce airway responsiveness in mild asthmatics.

Histamine bronchoconstriction reduces airway responsiveness in asthmatic subjects.

Tachyphylaxis occurs to repeated challenges with inhaled histamine but not with inhaled acetylcholine in asthmatic subjects. This study was undertaken to determine whether prior histamine bronchoconstriction reduces airway responsiveness to inhaled acetylcholine in mild asthmatic subjects demonstrating histamine tachyphylaxis. All subjects developed histamine tachyphylaxis with repeated histamine challenge. The mean histamine PC20 increased from 3.74 to 5.92 mg/ml (p less than 0.005) when the histamine challenges were separated by 1 h. Prior acetylcholine bronchoconstriction did not reduce airway responsiveness to subsequent inhalation of either acetylcholine or histamine in these subjects. However, histamine inhalation did reduce airway responsiveness to acetylcholine in all subjects. The mean acetylcholine PC20 following acetylcholine inhalation was 3.37 mg/ml (%SD 2.17) and this increased to 7.76 mg/ml (%SD 1.80) after histamine inhalation (p less than 0.0005). Thus, this study demonstrates that prior histamine, but not acetylcholine, bronchoconstriction can partially protect against bronchoconstriction caused by both histamine and acetylcholine. Therefore, reduced airway responsiveness caused by histamine bronchoconstriction is specific for histamine and is not due to bronchoconstriction per se. However, the reduced airway responsiveness following histamine bronchoconstriction, is nonspecific.

The Effect of Theophylline and β2 Agonists on Airway Reactivity

Increased airway responsiveness occurs in asthma, chronic bronchitis, cystic fibrosis, and other diseases. Theophylline and β2 agonists commonly are used as maintenance therapy for symptoms associated with the increased responsiveness. Both drugs can reduce airway responsiveness to a variety of provocational stimuli. With currently used dosing regimens, theophylline appears to produce relatively constant levels of effect on airway responsiveness and clinical efficacy around the clock, while inhaled β2 agonists appear to have insufficient effects at the end of longer dosing intervals. Improved dosing strategies for β2 agonists may improve the efficacy of these agents in the future.

The effect of theophylline and beta 2 agonists on airway reactivity

Increased airway responsiveness occurs in asthma, chronic bronchitis, cystic fibrosis, and other diseases. Theophylline and beta 2 agonists commonly are used as maintenance therapy for symptoms associated with the increased responsiveness. Both drugs can reduce airway responsiveness to a variety of provocational stimuli. With currently used dosing regimens, theophylline appears to produce relatively constant levels of effect on airway responsiveness and clinical efficacy around the clock, while inhaled beta 2 agonists appear to have insufficient effects at the end of longer dosing intervals. Improved dosing strategies for beta 2 agonists may improve the efficacy of these agents in the future.

Mediators, airway responsiveness, and asthma

There appears to be a close interrelationship among airway responsiveness to mediators and to natural stimuli, the presence and severity of asthma, and endogenous mediator release in the airways. Histamine and methacholine have been most commonly used to measure airway responsiveness. Airway responsiveness to the two drugs is increased in patients with current symptoms of asthma, and the degree of increase relates closely to the degree of variable airflow obstruction and the therapy to control symptoms. The degree of airway responsiveness to histamine also correlates closely with the degree of responsiveness to methacholine and less closely with responsiveness to PGF 2α and to natural stimuli such as exercise and allergens. The less close correlations with responsiveness to exercise and allergens is probably because of variations in the ease and type of endogenous mediator release in the airways by these stimuli. Endogenous mediator release from a number of stimuli including allergens and ozone causes inflammation in the airways, asthma, and airway hyperresponsiveness. These various interrelationships indicate that the treatment of asthma should be directed to reduce airway responsiveness, prevent mediator release, and prevent or reverse inflammation.