**4. Toxicity of nanoparticles to the lung**

Epidemiological studies have confirmed a positive correlation between levels of particulate pollution and increased morbidity and mortality rates among general populations (Gwinn & Vallyathan, 2006; Stone et al., 2007).

The adverse health effects seem to be dominated by pulmonary symptoms. For instance, many reports have addressed that occupational exposure of inhaled rigid nanoparticles (NPs) can lead to respiratory diseases such as pneumoconiosis (pulmonary fibrosis) and bronchitis (Byrne & Baugh, 2008; Lkhasuren et al., 2007).

Increasing inhalation of ambient ultrafine particles has been linked with exacerbation of respiratory symptoms and mortality among COPD sufferers (Xia et al., 2009). It has also been documented that NPs can instigate oxidative stress and cellular toxicity in various types of cells (Huang et al., 2009).

It was also reported that chronic exposure to NPs can potentially predispose humans to lung inflammation and increase the risk of COPD.

A concentration range of NPs within the level found in ambience and in nanotechnology industries (Klaine et al., 2008) can promote mucin aggregation.

The second safety aspect of deep lung deposition is the interaction of nanoparticles with the alveolar environment. The alveolar space is covered with a thin surfactant film. This film has important physiological functions e.g. to accelerate gas exchange and to lower the surface tension in the alveolar space. Compromising these functions by inhalable nanoparticles might cause life threatening consequences. Therefore, the compatibility of a delivery system with the alveolar environment must be considered (Azarmi et al., 2008).

For these reasons vesicular nanocarriers, composed of lung surfactants and/or synthetic amphiphiles, provide an efficient delivery system for the treatment of pulmonary disorders due to their biocompatibility, biodegradability and non-toxic nature (Taylor & Newton, 2004).

whether the local inflammation is sufficient to induce systemic effects, or whether a second

Over the years it was evidenced that mucus hypersecretion is an important manifestation of COPD. In the classical phenotype of chronic bronchitis, mucus hypersecretion is the key presenting symptom that appears independent of airflow obstruction. A more recent work demonstrated that obstruction of the small airways by inflammatory exudates containing mucus is predictive of early death after volume reduction surgery in patients with advanced COPD (Hogg et al., 2007). It was suggested that such occlusion enhanced the probability of infection in the lower respiratory tract. In addition, several epidemiological studies showed an association between mucus hypersecretion and outcomes in patients with COPD. Mucus hypersecretion is not an innocent disorder. However, despite these observations, until now few studies have focused on the effects of mucolytic drugs in patients with COPD, even though some of these mucolytic drugs also appear to have antioxidant properties (Dekhuijzen, 2004; Rahman et al., 1997; Rahman &

Histopathological findings from surgical specimens clearly show that increased goblet cell numbers and increased MUC5AC and MUC5B production and secretion are found in the lumen of small airways in COPD patients (Caramori et al., 2004). These findings are inversely associated with pre-surgical Forced Expiratory Volume in the 1st second (FEV1). Thus, patients with higher FEV1 have less goblet cell metaplasia than patients with lower FEV1, suggesting that the presence of mucin-producing cells in the airways is related to increased airflow obstruction. The presence of a prominent goblet cell phenotype also negatively correlates with FEV1 improvement following lung volume reduction surgery (Kim et al., 2005). Collectively, these results show that mucus secretion may be significant enough to result in physiologically and clinically measurable mechanical obstruction of small airways, and it may significantly impact disease pathogenesis and prognosis. The main cause of COPD in humans is cigarette smoking. In mice, chronic cigarette smoke exposure causes strain dependent mucous metaplasia. Cigarette smoke itself has also been shown to promote mucin synthesis directly in vitro by activation of the EGFR cascade (Shao et al., 2004). Inhalation, of one of the many potential toxicants present in cigarette smoke, acrolein (acrylic aldehyde), induces mucous metaplasia and MUC5AC production in animals. Acrolein also induces MUC5AC production in human airway epithelial cell lines, and it is found at significantly elevated levels in the induced sputum and exhaled breath

It has been suggested that mucus can also serve as a suitable medium for adherence and growth of some bacterial pathogens, such as non-typeable H. influenzae. Gram positive and gram negative bacteria products up-regulate MUC5AC and MUC2 gene expression and mucin secretion in human respiratory epithelial cell lines in vitro, and the same effect can be seen in some animal models in vivo. Viral infections are also closely associated with COPD exacerbations in humans (Wedzicha & Donaldson, 2003; Beckham et al., 2005). Surgical specimens from smokers with COPD show increased goblet cell numbers in the epithelium of peripheral airways compared to non-smokers. This is accompanied by increased macrophages and CD8 positive T-lymphocytes, both of which are indicative of viral. Roles for IL-6 and virus-induced mucin overproduction have been suggested. In vivo, IL-6 production is enhanced during the early phase of bacterial or viral-induced inflammation.

pathogenetic event is required (Evans & Koo, 2009; Huertas & Palange 2011).

Kilty 2006; Decramer & Janssens, 2010).

condensates of COPD patients, (Deshmukh et al., 2008).
