Effects of N-acetylcysteine in Meconium-Induced Acute Lung Injury



Fig. 1
Experimental paradigm. A treatment administration, PA post-administration, Mec meconium, NAC N-acetylcysteine, SAL physiological saline, i.i. intratracheal, i.v. intravenous



All animals were oxygen-ventilated for additional 5 h after the treatment. Cardiorespiratory parameters were recorded at 0.5, 1, 2, 3, 4, and 5 h to investigate early effects of the treatment. At the end of experiments, animals were sacrificed by an overdose of anesthetics.



2.2 Measurement and Evaluation of Cardiopulmonary Parameters


Tracheal airflow and VT were measured by a heated Fleisch head connected to a pneumotachograph. Airway pressure was registered via a pneumatic catheter placed in the tracheal tube and connected to an electromanometer. Cdyn was calculated as a ratio between VT (adjusted per kg body weight) and airway pressure gradient (PIP-PEEP). Systolic (SBP) and diastolic (DBP) blood pressures were measured via a catheter in the femoral artery connected to an electromanometer, and the mean arterial blood pressure (MABP) was calculated as MABP = DBP + 1/3(SBP − DBP).

Heart rate (HR) was obtained from ECG recorded by subcutaneous electrodes. HRV was evaluated using a computer system (VariaPulse TF3, Sima Media, Czech Republic). Parameters of time analysis, mean duration of R-R interval (RR) and mean squared successive difference (MSSD), and parameters of spectral analysis, i.e., spectral powers in low frequency (LF: 0.05–0.15 Hz) and high frequency (HF: 0.15–2.0 Hz) bands were analyzed. From the mentioned parameters, MSSD and HF have been established as markers of parasympathetic (vagal) activity, while LF band represents the activity of both branches of the autonomic cardiac control and that of baroreceptors (Thayer et al. 2011).


2.3 Biochemical Analysis of Blood Plasma


Quantification of total antioxidant status (TAS) in the blood plasma at the end of experiment was carried out using ABTS (2,2′-azino-di-[3-ethylbenzothiazoline sulphonate]) radical formation kinetics (Randox TAS kit, Randox laboratories Ltd., UK) and expressed in mmol/L. A concentration of thiobarbituric-acid reactive substances (TBARS) was determined from the absorbance at 532 nm and expressed in nmol/mg protein. A concentration of aldosterone was measured by Aldosterone ELISA kit (BioVendor, Czech Republic) and was expressed in pg/mL.


2.4 Statistical Analysis


Data were expressed as means ± SE. Normality of data distribution was assessed by the Kolmogorov-Smirnov test. Since the distribution of some HRV variables (spectral powers) was extremely skewed, a logarithmic transformation of these data was used to improve normality before a statistical analysis was performed. Then, between-group differences were analyzed by one-way ANOVA with a post-hoc LSD test. Within-group differences were evaluated by Wilcoxon test. Strength of association between biochemical and cardiovascular markers were expressed by Pearson’s correlation coefficient (r) and Bonferroni probability (p). A value of p < 0.05 was considered statistically significant.



3 Results


Body weight and initial values of all cardiopulmonary parameters were comparable between the groups before the intratracheal instillation of meconium or saline.


3.1 Cardiovascular Parameters


Before administration of treatment, no significant between-group differences were found. During 5 min of treatment (two intervals of 2.5 min, A1 and A2), a significant increase in MABP was found in Mec + NAC group vs. both sham-treated control groups (Sal + Sal and Mec + Sal). The increase in MABP was accompanied by elevation in HRV parameters, i.e., a significant increase in MSSD and insignificant one in both LF and HF spectral powers, whereas no changes were observed in the mean heart rate (Table 1).


Table 1
Cardiovascular parameters in saline-instilled sham-treated animals (Sal + Sal group), in meconium-instilled sham-treated animals (Mec + Sal group), and in meconium-instilled NAC-treated animals (Mec + NAC group) before treatment, during 5 min of treatment administration (intervals A1 and A2, each of 2.5 min), and immediately post-treatment administration (intervals PA1 and PA2, each of 2.5 min)




































































































































 
Before
A1
A2
PA1
PA2

MABP (kPa)

Sal + Sal
8.2 ± 0.8
7.8 ± 0.8
8.5 ± 0.9
8.8 ± 0.9
9.0 ± 1.0

Mec + Sal
8.5 ± 0.7
8.2 ± 0.7
8.3 ± 0.7
8.4 ± 0.7
8.3 ± 0.7

Mec + NAC
9.9 ± 0.7
11.9 ± 0.5cf

12.1 ± 0.6be

12.3 ± 0.8be

12.0 ± 0.8bd

HR (bpm)

Sal + Sal
211 ± 11
212 ± 12
215 ± 10
213 ± 9
210 ± 8

Mec + Sal
213 ± 14
217 ± 14
216 ± 14
207 ± 10
208 ± 10

Mec + NAC
212 ± 10
217 ± 7
216 ± 13
215 ± 10
213 ± 14

MSSD (ms2)

Sal + Sal
1.9 ± 0.4
1.6 ± 0.5
1.7 ± 0.5
1.7 ± 0.5
1.6 ± 0.4

Mec + Sal
2.4 ± 0.5
3.3 ± 0.7
3.8 ± 0.8
3.7 ± 0.7
2.9 ± 0.7

Mec + NAC
1.7 ± 0.3
9.9 ± 5.7
20.2 ± 12.7
10.1 ± 3.6d

7.1 ± 2.7

logLF

Sal + Sal
−1.1 ± 0.6
−0.4 ± 0.4
−0.2 ± 0.3
−0.4 ± 0.6
−0.8 ± 0.6

Mec + Sal
−1.9 ± 0.6
0.0 ± 0.5
−1.1 ± 0.6
−0.3 ± 0.6
−0.2 ± 0.4

Mec + NAC
−1.4 ± 0.8
0.0 ± 1.2
0.7 ± 1.3
1.2 ± 0.9
0.7 ± 0.8

logHF

Sal + Sal
0.5 ± 0.1
0.4 ± 0.2
0.5 ± 0.2
0.6 ± 0.1
0.6 ± 0.1

Mec + Sal
0.7 ± 0.1
0.3 ± 0.1
0.3 ± 0.2
0.9 ± 0.4
0.4 ± 0.3

Mec + NAC
0.3 ± 0.4
0.9 ± 0.8
1.6 ± 1.0
1.8 ± 0.8
1.3 ± 0.8


See Methods for the explanation of cardiac acronyms. For between-group comparisons: Mec + NAC vs. Mec + Sal: bp < 0.01, cp < 0.001; Mec + NAC vs. Sal + Sal: dp < 0.05, ep < 0.01, fp < 0.001

Along the further course of experiment, most of the changes in the treated group gradually adjusted to the values comparable with the sham-treated groups. However, parameters of HRV, particularly MSSD, remained higher till the end of experiment (Table 2).


Table 2
Cardiovascular parameters in saline-instilled sham-treated animals (Sal + Sal group), in meconium-instilled sham-treated animals (Mec + Sal group), and in meconium-instilled N-acetylcysteine-treated animals (Mec + NAC group) before and after intratracheal meconium/saline (Before/After M/S) instillation and during 5 h after treatment administration































































 
Before M/S
After M/S
30 min
1 h
2 h
3 h
4 h
5 h

MABP (kPa)

Sal + Sal
9.6 ± 0.7
9.5 ± 0.7
9.6 ± 0.9
8.4 ± 0.8
10.0 ± 0.6
9.8 ± 0.3
10.0 ± 0.8
10.3 ± 0.8

Mec + Sal
9.0 ± 0.2
8.7 ± 0.7
8.6 ± 0.4
8.6 ± 0.4
9.3 ± 0.6
8.6 ± 0.4
9.1 ± 0.3
9.0 ± 0.4

Mec + NAC
9.5 ± 0.5
10.3 ± 0.3
10.7 ± 0.8
10.3 ± 0.7
10.4 ± 0.6a

10.0 ± 0.9
10.1 ± 1.0
9.9 ± 0.9

HR (bpm)

Sal + Sal
206 ± 14
208 ± 10
213 ± 9
221 ± 5
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Jul 10, 2016 | Posted by in RESPIRATORY | Comments Off on Effects of N-acetylcysteine in Meconium-Induced Acute Lung Injury

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