Table 1.
In vivo studies demonstrating effects of NAC in animal models of cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), bronchial asthma, idiopathic pulmonary fibrosis (IPF), and lung silicosis.
| Animal Model | Species | NAC Dose/Way of Delivery | Major Findings | Study |
|---|---|---|---|---|
| Model of CF | WT and βENaC-overexpressing mice | NAC (15 μL, 50 mg/kg), i.t. instillation in WT mice; NAC (200 mM, nasal nebulizations) in βENaC-overexpressing mice | WT mice: no reduction in Muc5b, rapid NAC clearance, ↑ total cells and neutrophils in BALF, epithelial injury; βENaC-overexpressing mice: no reduction in AW mucus obstruction | [99] |
| Cigarette smoke (CS)-induced model of COPD | Sprague Dawley rats | NAC (800 mg/kg, once a day, i.g.), from 30 days of CS exposure | ↓ lung damage, emphysema, and alveolar septal cell apoptosis by partial reversing of ↓ VEGF | [118] |
| Ozone-induced model of COPD | C57/BL6 mice | NAC (100 mg/kg, i.p.) before each exposure (preventive) or after completion of exposure (therapeutic), for 6 weeks | Preventive NAC: ↓ BALF macrophages, ↓ AW smooth muscle mass. Therapeutic NAC: reversed AW hyperresponsiveness, ↓ AW smooth muscle mass and apoptotic cells | [119] |
| Cigarette smoke (CS)-induced model of COPD | Rats | NAC (800 mg/kg, once a day, i.g.), from 2 days before the model establishment | ↓ inflammation, enhanced lung functions, ↓ fibrotic changes | [120] |
| OVA-induced model of asthma | Norway rats | NAC (3 mM/kg, once a day, p.o.), pretreatment daily from 7 days before challenge | ↓ AW hyperresponsiveness, ↓ lipid peroxidation, ↓ oxidized GSH, ↓ TNFα, iNOS, ICAM-1, and MUC5AC | [138] |
| OVA-induced model of asthma | Balb/c mice | NAC (320 mg/kg, i.p.), 30 min before and 12 h after each challenge | ↓ AW hyperresponsiveness, ↓ neutrophils and eosinophils in BALF, ↓ IL-13 and IL-5 | [139] |
| OVA-induced model of asthma | Balb/cJ mice | NAC (15 mg/100 g body weight, i.n.), 45 min before three i.n. challenges | ↓ AW inflammation, ↓ mitochondrial damage, ↓ goblet cell hyperplasia, ↓ eosinophil extracellular traps, ↓ oxidative stress in lungs | [140] |
| OVA-induced model of asthma | Balb/c mice | NAC (100 mg/kg), inhalation 1 h after each challenge for 6 days | ↓ AW hyperresponsiveness, ↓ AW inflammation, ↓ claudin 18 | [141] |
| Obesity-associated model of asthma | C57BL/6 J mice | NAC (200 mg/kg, i.g.) | ↓ inflammation and oxidative stress, ↓ IKK-β and NF-κB-P65, ↑ IκB-α, ↓ MDA | [142] |
| Chemical-induced model of asthma | Balb/c mice | NAC (100 mg/kg, i.p.), after each challenge | ↓ AW hyperresponsiveness, ↓ AW inflammation, ↓ goblet cell metaplasia, ↓ inflammatory cell counts in BALF, ↓ IL-4 and IL-5, ↓ oxidative stress | [143] |
| Bleomycin-induced model of IPF | Sprague Dawley rats | NAC (3 mM/kg, p.o.), daily from 1 week prior to i.t. bleomycin instillation and for 14 d postinstillation | ↓ collagen and ↓ inflammatory cells in the lungs, ↑ total GSH and taurine in BALF, no effect on lung edema formation | [72] |
| Bleomycin-induced model of IPF | Sprague Dawley rats | NAC (3 mM/kg, p.o.), daily from 1 week prior to i.t. bleomycin instillation and for 14 d postinstillation | ↓ collagen and fibrotic area in the lungs, ↓ MUC5ac expression, ↓ TNFα and MPO, ↓ mucus hypersecretion | [73] |
| Bleomycin-induced model of IPF | Sprague Dawley rats | NAC (3 mM/kg, p.o.), daily from 1 week prior to i.t. bleomycin instillation and for 14 d postinstillation | ↓ hydroxyproline, ↓ depletion of GSH peroxidase, prevention of ↑ in MPO, NO, and MDA | [161] |
| Bleomycin-induced model of IPF | Sprague Dawley rats | NAC (490 mg/kg/day, p.o.), daily from bleomycin instillation | ↓ lysyl oxidase activity, ↑ GSH, ↓ lung fibrosis, ↓ TGF-β1 and α-SMA expression | [75] |
| Bleomycin-induced model of IPF | Sprague Dawley rats | NAC (300 mg/kg/day, i.p.), daily from 1 week prior to i.t. bleomycin instillation and for 15 d postinstillation | ↑ GSH/GSSG ratio, ↓ NO, ↓ lipid hydroperoxides, ↓ lung weight, ↓ hydroxyproline, ↓ inflammatory cytokines, MPO, and LDH, ↓ deposition of collagen | [74] |
| Bleomycin-induced model of IPF | CF1 mice | NAC (20 mg/kg/day, i.p.), from day 0 of bleomycin instillation, for 60 days | ↓ lung injury, ↓ LDH, neutrophils, total cell counts, and protein in BALF | [162] |
| Bleomycin-induced model of IPF | Wistar rats | NAC (250 mg/kg/day, i.g.), from day 0 of bleomycin instillation, for 31 days | ↓ lung inflammation and fibrosis, ↓ MDA, ↑ SOD | [163] |
| Bleomycin-induced model of IPF | Wistar rats | NAC (4 mg/kg, 3 times/day, i.g.), from 1 day after bleomycin instillation, for 45 days | ↓ lung inflammation and fibrosis, ↓ TGF-β1, TNFα and PDGF expressions, ↑ caveolin-1 | [164] |
| Model of silicosis | Wistar rats | NAC (500 mg/kg/day, p.o.), for 7 days before and up to 28 days after silica instillation | ↓ fibrosis score, ↓ hydroxyproline, MDA, TNFα, IL-8, and hsCRP | [76] |
| Model of silicosis | Sprague Dawley rats | NAC (600 mg/kg/day, by gavage), from day 0 of silica instillation, for 28 days | ↓ ROS, ↓ changes in mitochondrial transmembrane potential, ↓ fibrotic changes, ↓ markers of apoptosis | [77] |
| Model of silicosis | C57BL/6J mice | NAC (1.73 mg/20 g, 3.46 mg/20 g, or 5.19 mg/20 g, by gavage), from day 0 of silica instillation, observation for 5 months | ↓ lung injury, fibrosis, and inflammation, ↓ MDA, ↑ GSH peroxidase, SOD, total antioxidant activity, and E-cadherin, ↓ oxidizing enzymes, vimentin, and cytochrome C | [191] |
Abbreviations: AW: airway, BALF: bronchoalveolar lavage fluid, CF: cystic fibrosis, COPD: chronic obstructive pulmonary disease, GSH: glutathione, GSSG: oxidized glutathione, hsCRP: high-sensitivity C-reactive protein, ICAM-1: intercellular adhesion molecule-1, i.g.: intragastric administration, IκB-α: inhibitor kappa B-α, IKK-β: inhibitor kappa B kinase-β, IL: interleukin, i.n.: intranasal administration, iNOS: inducible nitric oxide synthase, i.p.: intraperitoneal administration, IPF: idiopathic pulmonary fibrosis, LDH: lactate dehydrogenase, MDA: malondialdehyde, MPO: myeloperoxidase, MUC5ac: mucin MUC5ac, NAC: N-acetylcysteine, NF-κB-P65: nuclear factor-κB-P65, NO: nitric oxide, PDGF: platelet-derived growth factor, p.o.: oral administration, ROS: reactive oxygen species, α-SMA: alpha-smooth muscle actin, SOD: superoxide dismutase, TGF-β1: transforming growth factor beta 1, TNFα: tumor necrosis factor alpha, VEGF: vascular endothelial growth factor, WT: wild-type mice, ↑: increased, ↓: decreased.