Abstract Background Most smokers consider that electronic cigarettes are safer than tobacco and are marketed as safe products. Nevertheless, recent reports show the exposure to high levels of electronic cigarette vapors (ECV) activates lung cells and triggers lung inflammation and structural alterations after chronic exposure. In order to assess the potential harmful effect of moderate exposure to ECV, we investigated in mice, its effect on lung and systemic inflammation and on lung structure and function. Methods To reproduce closely the situation frequently encountered in human, we exposed mice during 1h/day during 3 or 6 months with two levels of electronic cigarette power in comparison with mice exposed to cigarette smoke (CS). Lung and systemic inflammation was evaluated by measuring cell recruitment and activation as well as cytokine concentrations. Lung transcriptome, respiratory function and body weight were also measured. Results Our data revealed that chronic exposure to moderate levels of ECV increased specifically lung inflammation including NK cells and T lymphocyte recruitment and the production of CXCL1 and CXCL2 chemokines as well as IL-22 after 3 months, these effects being different from the profile induced by CS. Surprisingly, there is no strong overlap between the impact of the 3 types of emissions on lung transcriptome. Modulation of pro-inflammatory pathways are limited to mice exposed to e-cig set to low power. In contrast, alteration of respiratory function is observed in high-power ECV-exposed mice but not at low power, with a different profile than in CS-exposed mice. Conclusion Subchronic (or mid-term) exposure to ECV might alter the respiratory function independently of the inflammatory response and in a different manner than CS.
Pseudomonas aeruginosa and Candida albicans are two pathogens frequently encountered in the intensive care unit microbial community. We have demonstrated that C. albicans airway exposure protected against P. aeruginosa-induced lung injury. The goal of the present study was to characterize the cellular and molecular mechanisms associated with C. albicans-induced protection. Airway exposure by C. albicans led to the recruitment and activation of natural killer cells, innate lymphoid cells (ILCs), macrophages, and dendritic cells. This recruitment was associated with the secretion of interleukin-22 (IL-22), whose neutralization abolished C. albicans-induced protection. We identified, by flow cytometry, ILCs as the only cellular source of IL-22. Depletion of ILCs by anti-CD90.2 antibodies was associated with a decreased IL-22 secretion and impaired survival after P. aeruginosa challenge. Our results demonstrate that the production of IL-22, mainly by ILCs, is a major and inducible step in protection against P. aeruginosa-induced lung injury. This cytokine may represent a clinical target in Pseudomonas aeruginosa-induced lung injury.
Exposure to coal dust leads to the development of coal worker's pneumoconiosis (CWP), a disease associated with an accumulation of macrophages in the lower respiratory tract. Mechanisms controlling monocyte recruitment are still poorly understood. Since monocyte chemoattractant protein-1 (MCP-1) is recognized as a potent chemotactic factor for blood monocytes, we analysed the presence of MCP-1 in the pulmonary compartment of patients with CWP. Bronchoalveolar lavage fluid (BALF) from 16 nonsmoking control subjects and 27 nonsmoking CWP patients (16 with simple pneumoconiosis (SP) and 11 with progressive massive fibrosis (PMF)) was analysed. Alveolar macrophages (AMs) were purified by adherence and BALF was concentrated tenfold by lyophilization. MCP-1 was measured in BALF and in 3 h AM supernatants using a sandwich enzyme-linked immunosorbent assay (ELISA). The localization of MCP-1 in lung tissue was determined by immunohistochemistry on tissue sections from three patients with CWP and two control subjects. MCP-1 levels were significantly higher in concentrated BALF from patients with SP or PMF (median 370 and 555 pg x mL-1, respectively) than in those from control subjects (median 11 pg x mL-1) (p<0.001). Released MCP-1 in AM supernatants was enhanced in patients with CWP (median 83 pg x mL-1) but compared to controls (median 41 pg x mL-1) this level did not reach significance. Although significantly increased, AM counts in BALF from patients with CWP did not correlate with MCP-1 levels. MCP-1 levels in BALF correlated with MCP-1 levels in AM supernatants (p=0.47; p<0.02). In control lung specimens, MCP-1 was expressed by a few AMs, type II pneumocytes and perivascular smooth muscle cells. CWP sections were characterized by an increased number of AMs and mainly by the presence of fibroblasts (in the myogenic area of fibrotic lesions) and hyperplastic type II pneumocytes, which were strongly immunostained for MCP-1. Our data demonstrate that: 1) patients with coal worker's pneumoconiosis have a marked pulmonary overproduction of monocyte chemoattractant protein-1; and 2) in addition to alveolar macrophages, fibroblasts (probably myofibroblasts) and hyperplastic type II pneumocytes may also be responsible for this increased level of monocyte chemoattractant protein-1 in coal worker's pneumoconiosis.
Tumor necrosis factor a (TNF) and interleukin-1 (IL-1) production by alveolar macrophages (AM) was evaluated in 17 rheumatoid arthritis (RA) patients without interstitial lung disease (ILD, Group 1) and 14 RA patients with clinical ILD (Group 2) in comparison with 10 control subjects. AM after recovery by bronchoalveolar lavage were selected by adherence, and then supernatants were collected after 3 or 24 h of culture. Results showed no modification of IL-1 synthesis in either group of RA patients. Spontaneous TNF production was significantly increased in Group 2 (2.5 ± 0.5 ng/ml) as well as in Group 1 (2.4 ± 0.4 ng/ml) compared with control subjects (0.43 ± 0.1 ng/ml, p < 0.001). In addition, AM from patients untreated or treated exclusively by nonsteroldal antiinflammatory drugs produced similar levels of TNF, whereas those receiving corticosteroids, second-line drugs (such as sulfasalazine, aurothiomalate, and methotrexate), or the combination of both therapy regimens released significantly less TNF. Interestingly, TNF was not different in both groups, but Group 2 had a markedly increased ratio of local immune complex to albumin in bronchoalveolar lavage fluid (0.47 ± 0.12 versus 0.07 ± 0.02 in Group 1; p < 0.002). TNF thus appears an additional component of RA subclinical alveolitis in RA, but its prognostic value and its precise role in lung damage remain to be determined. Development of ILD requires certainly complex interactions of synergistic factors, possibly including local immune complexes detected in BAL fluids.
