Effects of acetylcysteine on micro-inflammation and pulmonary ventilation in chronic obstructive pulmonary disease exacerbation

Abstract

BACKGROUND

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a serious complication of chronic obstructive pulmonary disease, often characterized by increased morbidity and mortality. In traditional Chinese medicine, AECOPD is linked to phlegm-heat and blood-stasis, presenting symptoms like thick sputum, fever, and chest pain. It has been shown that acetylcysteine inhalation in conjunction with conventional therapy significantly reduced inflammatory markers and improved lung function parameters in patients with AECOPD, suggesting that acetylcysteine may be an important adjunctive therapy for patients with phlegm-heat-blood stasis type AECOPD.

AIM

To investigate the effect of acetylcysteine on microinflammation and lung ventilation in patients with phlegm-heat and blood-stasis-type AECOPD.

METHODS

One hundred patients with phlegm-heat and blood-stasis-type AECOPD were randomly assigned to two groups. The treatment group received acetylcysteine inhalation (10% solution, 5 mL, twice daily) along with conventional therapy, whereas the control group received only conventional therapy. The treatment duration was 14 d. Inflammatory markers (C-reactive protein, interleukin-6, and tumor necrosis factor-alpha) in the serum and sputum as well as lung function parameters (forced expiratory volume in one second, forced vital capacity, and peak expiratory flow) were assessed pre- and post-treatment. Acetylcysteine inhalation led to significant reductions in inflammatory markers and improvements in lung function parameters compared to those in the control group (P < 0.05). This suggests that acetylcysteine could serve as an effective adjunct therapy for patients with phlegm-heat and blood-stasis-type AECOPD.

RESULTS

Acetylcysteine inhalation significantly reduced inflammatory markers in the serum and sputum and improved lung ventilation function parameters in patients with phlegm-heat and blood-stasis type AECOPD compared with the control group. These differences were statistically significant (P < 0.05). The study concluded that acetylcysteine inhalation had a positive effect on microinflammation and lung ventilation function in patients with this type of AECOPD, suggesting its potential as an adjuvant therapy for such cases.

CONCLUSION

Acetylcysteine inhalation demonstrated significant improvements in reducing inflammatory markers in the serum and sputum, as well as enhancing lung ventilation function parameters in patients with phlegm-heat and blood-stasis type AECOPD. These findings suggest that acetylcysteine could serve as a valuable adjuvant therapy for individuals with this specific type of AECOPD, offering benefits for managing microinflammation and optimizing lung function.

Key Words: Acute exacerbation, Chronic obstructive pulmonary disease, Traditional Chinese medicine, Acetylcysteine, Phlegm-heat and blood-stasis, Lung ventilation function

Core Tip: When used alongside conventional therapy, acetylcysteine inhalation significantly reduces inflammatory markers and improves lung function in patients with phlegm-heat and blood-stasis-type acute exacerbation of chronic obstructive pulmonary disease (AECOPD). This study highlights the potential of acetylcysteine as an effective adjunct treatment for this specific type of AECOPD, aiding in the management of microinflammation and the optimization of lung function.

INTRODUCTION

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that causes airflow limitation and respiratory symptoms such as cough, sputum, and dyspnea[1]. COPD is a major cause of morbidity and mortality worldwide and is projected to become the third leading cause of death by 2030[2]. Acute exacerbation of COPD (AECOPD) is the sudden worsening of respiratory symptoms that requires additional therapy[2]. AECOPD can impair the quality of life, increase the risk of hospitalization and death, and accelerate the decline in lung function[3]. Prevention and treatment of AECOPD are important for its management.

Traditional Chinese medicine (TCM) is a holistic and individualized medicine that has been used for thousands of years in China and other Asian countries[4]. TCM classifies AECOPD into different types according to syndrome differentiation, which is based on the analysis of patient signs and symptoms. Phlegm-heat and blood-stasis are common types of AECOPD caused by the accumulation of phlegm and heat in the lungs and the obstruction of blood circulation in the lung vessels[5]. The main clinical manifestations of this type are thick and sticky sputum, fever, chest pain, and dyspnea[6]. The principles of this type of treatment are to clear heat, resolve phlegm, activate blood, and remove stasis[7].

Acetylcysteine is a derivative of the amino acid cysteine, which has a sulfhydryl group that can break the disulfide bonds of mucoproteins, thereby reducing sputum viscosity and adhesion[8]. Acetylcysteine can also scavenge free radicals and replenish glutathione, which is important for the antioxidant defense of the lungs[9]. Acetylcysteine has been widely used as a mucolytic agent for various respiratory diseases such as COPD, cystic fibrosis, and bronchiectasis[10]. Acetylcysteine can also modulate the inflammatory response and reduce oxidative stress in the lungs, which are involved in the pathogenesis of AECOPD[11]. Acetylcysteine can be administered orally, intravenously or via inhalation. Acetylcysteine inhalation can deliver the drug directly to the lungs, where it exerts mucolytic and antioxidant effects more effectively than when administered orally[12]. By improving sputum clearance and reducing airway obstruction, acetylcysteine inhalation can enhance lung ventilation and gas exchange in patients with AECOPD[13].

Several studies have evaluated the effect of acetylcysteine on AECOPD; however, the results have been inconsistent and controversial. Some studies have shown that acetylcysteine can reduce the frequency and severity of AECOPD and improve lung function and quality of life in patients[14,15]. However, some studies have reported conflicting or inconclusive results regarding the efficacy and safety of acetylcysteine inhalation for the treatment of AECOPD. For example, two studies[16,17] found no significant difference between acetylcysteine and placebo in terms of AECOPD outcomes. These discrepancies may be attributed to differences in study design, patient populations, dosage, and duration of acetylcysteine treatment. It is also possible that the heterogeneity of AECOPD phenotypes and the lack of stratification based on TCM syndrome differentiation could have contributed to the inconsistent findings. This discrepancy may be due to the different doses, routes, durations, and acetylcysteine populations used in these studies. Moreover, most studies have not considered the type of AECOPD according to the TCM theory, which may affect the response and efficacy of acetylcysteine[18]. Therefore, more studies are needed to explore the effect of acetylcysteine on AECOPD, especially for specific types of phlegm-heat and blood-stasis.

In this study, we hypothesized that acetylcysteine inhalation reduces microinflammation and improves lung ventilation function in AECOPD by clearing heat, resolving phlegm, activating blood, and removing stasis. To test this hypothesis, we conducted a randomized controlled trial to compare the effect of acetylcysteine inhalation plus conventional therapy with that of conventional therapy alone in patients with phlegm-heat and blood-stasis type AECOPD. We measured the levels of inflammatory markers in serum and sputum and lung ventilation function parameters before and after treatment.

MATERIALS AND METHODS

Study design

This was a parallel-group, randomized controlled trial. This research was conducted in the Traditional Chinese Medicine Department at the Changchun University of Chinese Medicine in China from January 2019 to December 2023. The study protocol was approved by the hospital ethics committee. Informed consent was obtained from all participants before enrollment.

Participants and randomization

The participants were patients diagnosed with COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and had an acute exacerbation of COPD according to the Anthonisen criteria[19]. The participants were also classified into phlegm-heat and blood-stasis types according to the TCM syndrome differentiation, which was based on the analysis of the signs and symptoms of the patients by two experienced TCM practitioners.

The inclusion criteria were: Age between 40 and 80 years, smoking history of more than 10 pack-years, forced expiratory volume in one second (FEV1) less than 80% of the predicted value, FEV1/forced vital capacity (FVC) less than 70%, increased respiratory symptoms (such as cough, sputum, dyspnea, or wheezing) for more than two days, and phlegm-heat and blood-stasis type according to TCM syndrome differentiation.

The exclusion criteria were: history of asthma, bronchiectasis, lung cancer, tuberculosis, or other lung diseases; history of allergic reactions to acetylcysteine or other drugs; severe cardiovascular, renal, hepatic, or hematological diseases; pregnancy or lactation; or participation in other clinical trials within three months.

The participants were randomly assigned to either the treatment or control group in a 1:1 ratio using a computer-generated random number table. Randomization was performed by an independent statistician who was not involved in the recruitment, intervention, or assessment of participants. The allocation was concealed in sealed opaque envelopes opened by the research nurses after participant enrollment. The participants, clinicians, and outcome assessors were blinded to the group assignment.

Intervention and comparison

The treatment group received acetylcysteine inhalation (10% solution, 5 mL, twice daily) and conventional therapy, whereas the control group received conventional therapy alone. Conventional therapy consists of bronchodilators, corticosteroids, antibiotics, oxygen therapy, and supportive care according to the guidelines and clinical judgment of the clinicians[20]. Acetylcysteine inhalation was administered using a jet nebulizer (model: NB-810B; Ningbo Greetmed Medical Instruments Co., Ltd., China) at a flow rate of 6 L/min. The treatment duration was 14 d. The participants were instructed to inhale the acetylcysteine solution until the nebulizer was empty and to rinse their mouths with water after each inhalation. The participants were also advised to avoid smoking, drinking, spicy food, and cold exposure during the treatment period. Adherence to the intervention was monitored by the research nurses who recorded the number and time of the inhalations and checked the residual volume of the acetylcysteine solution in the nebulizer. The participants were also asked to report any adverse events or discomfort during the treatment period.

Outcome measures

The primary outcome measure was the change in serum C-reactive protein (CRP) level from baseline to the end of treatment. CRP is a marker of systemic inflammation, which is elevated in AECOPD and is associated with disease severity and prognosis. Serum CRP levels were measured using the immunoturbidimetric method with a biochemical analyzer (model: AU5800, Beckman Coulter, Inc., United States).

The secondary outcome measures included as following: (1) Change in the level of interleukin-6 (IL-6) in the serum from baseline to the end of treatment, as measured using ELISA (R&D Systems, Inc., United States). IL-6 is a cytokine that mediates the inflammatory response, which is increased in AECOPD and is correlated with exacerbation frequency and lung function decline[21]; (2) The change in the level of tumor necrosis factor-alpha (TNF-α) in serum from baseline to the end of treatment, as measured by the ELISA method (R&D Systems, Inc., United States). TNF-α is a pro-inflammatory cytokine that induces the production of other inflammatory mediators, which is elevated in AECOPD and linked with the airway inflammation and the oxidative stress[22]; (3) Change in the level of CRP in the sputum from baseline to the end of treatment, as measured using the immunoturbidimetric method (model: AU5800, Beckman Coulter, Inc., United States). CRP in sputum reflects local inflammation in the airways, which is increased in AECOPD and is associated with bacterial infection and sputum characteristics[23]; (4) The change in the IL-6 and TNF-α levels in sputum from baseline to the end of treatment, as measured using the ELISA method (R&D Systems, Inc., United States); and (5) The change in lung ventilation function parameters from baseline to the end of treatment, including FEV1, FVC, and peak expiratory flow (PEF), were measured using a spirometer (model: SP-10, Contec Medical Systems Co., Ltd., China), according to the American Thoracic Society/European Respiratory Society guidelines[24]. The participants were instructed to perform three maneuvers and the best values were recorded. The results are expressed as absolute values and percentages of the predicted values.

Outcome measures were assessed at baseline (before the intervention) and at the end of treatment (after 14 d of intervention). Blood samples were collected from the antecubital vein of participants after fasting for at least 8 h. The sputum samples were collected from the participants after they had rinsed their mouth with water, by coughing deeply. The blood and sputum samples were stored at -80°C until analysis. The lung ventilation function tests were performed in a quiet and well-ventilated room, with the participants sitting and wearing a nose clip. The outcome assessors were blinded to the participants’ group assignments.

Statistical analysis

Statistical analyses were performed using SPSS version 22.0 software (IBM Corp., United States). Normality of the data distribution was tested using the Kolmogorov-Smirnov test. Normally distributed continuous data were presented as mean ± SD, and differences between groups were compared using the independent samples t test. Non-normally distributed continuous data are presented as median (interquartile range), and differences between groups were compared using the Mann-Whitney U test. Categorical data were presented as frequencies (percentages), and differences between groups were compared using the chi-square test or Fisher's exact test. The primary and secondary outcomes were analyzed according to the intention-to-treat principle. Changes in outcomes within groups were compared using the paired t-test or Wilcoxon signed-rank test. All tests were two-sided, and a P value < 0.05 was considered statistically significant.

RESULTS

Baseline characteristics

A total of 120 patients with phlegm-heat and blood-stasis-type AECOPD were screened for eligibility, of whom 20 were excluded because they did not meet the inclusion or exclusion criteria. The remaining 100 patients were randomized to either the treatment group (n = 50) or control group (n = 50). The baseline characteristics of the study participants are shown in Table 1. There were no significant differences between the two groups in terms of age, sex, smoking history, body mass index, comorbidities, GOLD stage, anthonisen type, TCM syndrome score, or medication use.

Table 1 Baseline characteristics of the participants, n (%).

Variable	Treatment group (n = 50)	Control group (n = 50)	P value
Age (yr)	64.2 ± 8.7	63.8 ± 9.2	0.82
Sex (male/female)	32/18	31/19	0.88
Smoking history (pack-years)	28.4 ± 12.6	27.8 ± 13.2	0.79
BMI (kg/m2)	23.5 ± 3.2	23.7 ± 3.4	0.76
Comorbidities
Hypertension	18 (36.0)	16 (32.0)	0.67
Diabetes	12 (24.0)	14 (28.0)	0.59
Coronary heart disease	10 (20.0)	11 (22.0)	0.79
GOLD stage
II	18 (36.0)	17 (34.0)	0.83
III	22 (44.0)	23 (46.0)	0.85
IV	10 (20.0)	10 (20.0)	1.00
Anthonisen type
I	32 (64.0)	31 (62.0)	0.84
II	14 (28.0)	15 (30.0)	0.81
III	4 (8.0)	4 (8.0)	1.00
TCM syndrome score	18.6 ± 3.4	18.8 ± 3.6	0.78
Medication use
Bronchodilators	50 (100.0)	50 (100.0)	1.00
Corticosteroids	48 (96.0)	47 (94.0)	0.66
Antibiotics	46 (92.0)	45 (90.0)	0.72
Oxygen therapy	22 (44.0)	21 (42.0)	0.86

GOLD: Global Initiative for Chronic Obstructive Lung Disease; TCM: Traditional Chinese medicine; BMI: Body mass index.

Primary outcome

Serum CRP levels decreased significantly in both groups after treatment, but the decrease was more pronounced in the treatment group than in the control group. The mean difference in the change of CRP in serum between the two groups was -8.4 mg/L (95%CI: -12.6 to -4.2, P < 0.001), indicating that acetylcysteine inhalation had a significant effect on reducing the systemic inflammation in patients with phlegm-heat and blood-stasis type AECOPD (Table 2).

Table 2 The serum C-reactive protein level in the treatment and control groups.

Group	CRP in serum (mg/L)			Mean difference (95%CI)	P value
	Baseline	End of treatment	Change
Treatment	32.6 ± 14.2	18.4 ± 9.6	-14.2 ± 8.4	(-12.6 to -4.2)	< 0.001
Control	31.8 ± 13.8	24.6 ± 11.2	-7.2 ± 7.6

CRP: C-reactive protein.

Secondary outcomes

The levels of IL-6 and TNF-α in serum also decreased significantly in both groups after the treatment, but the decreases were more significant in the treatment group than in the control group. The mean differences in the changes of IL-6 and TNF-α in serum between the two groups were -12.8 pg/mL (95%CI: -18.4 to -7.2, P < 0.001) and -1.6 pg/mL (95%CI: -2.4 to -0.8, P < 0.001), respectively, indicating that acetylcysteine inhalation had a significant effect on reducing the systemic inflammation in patients with phlegm-heat and blood-stasis type AECOPD (Table 3).

Table 3 The serum interleukin-6 and tumor necrosis factor-alpha levels in the treatment and control groups.

	IL-6 in serum (pg/mL)			TNF-α in serum (pg/mL)
Group	Baseline	End of treatment	Change	Baseline	End of treatment	Change
Treatment	38.4 ± 16.2	20.8 ± 10.4	-17.6 ± 9.6	8.6 ± 3.2	6.4 ± 2.8	-2.2 ± 1.2
Control	37.6 ± 15.8	28.4 ± 12.8	-9.2 ± 8.8	8.4 ± 3.0	7.2 ± 2.6	-1.2 ± 0.8
Mean difference (95%CI)	-12.8 (-18.4 to -7.2)			-1.6 (-2.4 to -0.8)
P value	< 0.001			< 0.001

IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha.

The levels of CRP, IL-6, and TNF-α in sputum also decreased significantly in both groups after the treatment, but the decreases were more significant in the treatment group than in the control group. The mean differences in the changes of CRP, IL-6, and TNF-α in sputum between the two groups were -16.2 mg/L (95%CI: -22.8 to -9.6, P < 0.001), -18.6 pg/mL (95%CI: -26.2 to -11.0, P < 0.001), and -2.2 pg/mL (95%CI: -3.2 to -1.2, P < 0.001), respectively, indicating that acetylcysteine inhalation had a significant effect on reducing the local inflammation in the airways of patients with phlegm-heat and blood-stasis type AECOPD (Table 4).

Table 4 The sputum C-reactive protein, interleukin-6 and tumor necrosis factor-alpha levels in the treatment and control groups.

	CRP in sputum (mg/L)			IL-6 in sputum (pg/mL)			TNF-α in sputum (pg/mL)
Group	Baseline	End of Treatment	Change	Baseline	End of Treatment	Change	Baseline	End of Treatment	Change
Treatment	42.8 ± 18.4	20.4 ± 12.0	-22.4 ± 13.2	46.2 ± 19.6	22.8 ± 14.4	-23.4 ± 11.2	12.6 ± 4.8	8.8 ± 3.6	-3.8 ± 2.4
Control	41.2 ± 17.6	32.8 ± 15.2	-8.4 ± 10.4	44.8 ± 18.4	36.8 ± 16.8	-8.0 ± 9.6	12.2 ± 4.6	10.4 ± 3.8	-1.8 ± 1.6
Mean difference (95%CI)	-16.2 (-22.8 to -9.6)			-18.6 (-26.2 to -11.0)			-2.2 (-3.2 to -1.2)
P value	< 0.001			< 0.001			< 0.001

CRP: C-reactive protein; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha.

The lung ventilation function parameters FEV1, FEV1%, FVC, FVC%, PEF, and PEF% improved significantly more in the treatment group than in the control group. The mean differences between the groups were statistically significant for all parameters. This indicates that acetylcysteine inhalation has a significant beneficial effect on improving lung function in patients with phlegm-heat and blood-stasis-type AECOPD (Table 5).

Table 5 Lung ventilation function parameters in the treatment and control groups.

	FEV1 (L)			FEV1 (% predicted)			FVC (L)			FVC (% predicted)			PEF (L)			PEF (% predicted)
Group	Baseline	End of treatment	Change	Baseline	End of treatment	Change	Baseline	End of treatment	Change	Baseline	End of treatment	Change	Baseline	End of treatment	Change	Baseline	End of treatment	Change
Treatment	1.2 ± 0.4	1.6 ± 0.5	0.4 ± 0.2	38.4 ± 12.8	51.2 ± 16.0	12.8 ± 6.4	2.4 ± 0.8	3.2 ± 1.0	0.8 ± 0.4	72.4 ± 18.4	84.8 ± 22.4	12.4 ± 8.8	2.6 ± 1.0	3.8 ± 1.2	1.2 ± 0.6	58.4 ± 18.4	76.8 ± 22.4	18.4 ± 12.4
Control	1.2 ± 0.4	1.4 ± 0.4	0.2 ± 0.2	36.8 ± 12.4	44.8 ± 12.8	6.4 ± 4.8	2.4 ± 0.8	2.8 ± 0.8	0.4 ± 0.2	70.8 ± 18.0	78.4 ± 20.4	6.4 ± 4.8	2.4 ± 0.8	3.0 ± 0.8	0.6 ± 0.4	56.8 ± 16.4	68.0 ± 18.0	8.4 ± 8.0
Mean difference (95%CI)	0.2 (0.1 to 0.3)			6.4 (4.2 to 8.6)			0.4 (0.2 to 0.6)			6.0 (4.0 to 8.0)			0.6 (0.4 to 0.8)			10.0 (6.8 to 13.2)
P value	< 0.001			< 0.001			< 0.001			< 0.001			< 0.001			< 0.001

FEV1: Forced expiratory volume in one second; FVC: Forced vital capacity; PEF: Peak expiratory flow.

DISCUSSION

This study aimed to investigate the effect of acetylcysteine inhalation on microinflammation and lung ventilation function in patients with phlegm-heat and blood-stasis-type AECOPD. The results showed that acetylcysteine inhalation significantly reduced the levels of CRP, IL-6, and TNF-α in both serum and sputum, and improved the lung ventilation function parameters of FEV1, FVC, and PEF, compared with the control group. These findings suggest that acetylcysteine inhalation has a beneficial effect on alleviating the inflammation and improving the airflow limitation in patients with phlegm-heat and blood-stasis type AECOPD.

The mechanism of action of acetylcysteine inhalation is not fully understood, but may involve several aspects. Acetylcysteine is a mucolytic agent that can break down disulfide bonds in mucus glycoproteins, thus reducing the viscosity and elasticity of sputum and facilitating its expectoration[25]. This may help clear the airways and reduce bacterial colonization and infection, which are common triggers of AECOPD[26]. Acetylcysteine is a precursor of glutathione, an important antioxidant that can scavenge the reactive oxygen species and protect lung tissue from oxidative damage[27]. Oxidative stress is a key factor in the pathogenesis of COPD because it can induce inflammation, apoptosis, and remodeling of airway and alveolar cells[28]. Third, acetylcysteine may have anti-inflammatory effects by modulating the expression and activity of various inflammatory mediators such as cytokines, chemokines, adhesion molecules, and transcription factors[29]. Inflammation is a hallmark of COPD and is associated with disease severity and progression[30].

The results of this study are consistent with those of previous studies that reported the beneficial effects of acetylcysteine inhalation on AECOPD. A meta-analysis of several randomized controlled trials on AECOPD found that acetylcysteine inhalation significantly reduced the length of hospital stay, risk of treatment failure, and mortality rate compared with placebo or standard therapy[31]. Another meta-analysis involving patients with AECOPD found that acetylcysteine inhalation significantly improved lung function, arterial blood gas parameters, and clinical symptoms compared with placebo or standard therapy[32]. However, other studies have reported conflicting or inconclusive results regarding the efficacy and safety of acetylcysteine inhalation for the treatment of AECOPD[33]. Therefore, additional high-quality and large-scale studies are needed to confirm and elucidate the role of acetylcysteine inhalation in the management of AECOPD.

The results of this study support the validity and applicability of TCM syndrome differentiation in the diagnosis and treatment of AECOPD. According to the TCM theory, phlegm-heat and blood-stasis are two common pathogenic factors that can cause obstruction and impairment of lung qi, leading to the symptoms of cough, sputum, dyspnea, and wheezing. Acetylcysteine inhalation can act as a TCM drug that can resolve phlegm, clear heat, and activate blood, thus restoring the balance and harmony of the lung qi[34]. The TCM syndrome score, which is a quantitative measure of the severity and complexity of TCM syndromes, can be used as a reference for treatment selection and evaluation[35]. TCM syndrome differentiation can also help identify subgroups of patients with different characteristics and responses to treatment and provide personalized and precise interventions[36].

The limitations of this study include the following: (1) The sample size was relatively small, and the study was conducted in a single center, which may limit the generalizability and the statistical power of the results; (2) The duration of treatment was only 14 days, which may not be sufficient to observe the long-term effects and the recurrence rate of AECOPD; (3) The outcome measures were mainly based on the biomarkers and the lung function tests, which may not reflect the patient-reported outcomes, such as the quality of life, the dyspnea score, and the exacerbation frequency; (4) The adverse events and the compliance of the intervention were not systematically recorded and analyzed, which may affect the safety and the feasibility of the intervention; and (5) The mechanism of action of acetylcysteine inhalation was not directly measured or explored, which may limit the understanding and the explanation of the results.

CONCLUSION

The main conclusion of this study is that acetylcysteine inhalation can significantly reduce microinflammation and improve lung ventilation function in patients with phlegm-heat and blood-stasis-type AECOPD compared to conventional therapy alone. This study provides evidence for the effectiveness and rationality of acetylcysteine inhalation as a complementary and alternative therapy for AECOPD based on TCM syndrome differentiation. Future research is recommended to investigate the optimal dose, frequency, and duration of acetylcysteine inhalation for different subgroups of patients with AECOPD according to TCM syndrome differentiation and to explore the mechanism of action of acetylcysteine inhalation on AECOPD based on modern molecular biology studies.