Pathogen persistence in the respiratory tract is an important preoccupation, and of particular relevance to infectious diseases such as tuberculosis. The equilibrium between elimination of pathogens and the magnitude of the host response is a sword of Damocles for susceptible patients. The alveolar macrophage is the first sentinel of the respiratory tree and constitutes the dominant immune cell in the steady state. This immune cell is a key player in the balance between defense against pathogens and tolerance toward innocuous stimuli. This review focuses on the role of alveolar macrophages in limiting lung tissue damage from potentially innocuous stimuli and from infections, processes that are relevant to appropriate tolerance of potential causes of lung disease. Notably, the different anti-inflammatory strategies employed by alveolar macrophages and lung tissue damage control are explored. These two properties, in addition to macrophage manipulation by pathogens, are discussed to explain how alveolar macrophages may drive pathogen persistence in the airways.

Perfluoropentane (PFP)-based oxygen-loaded nanobubbles (OLNBs) were previously proposed as adjuvant therapeutic tools for pathologies of different etiology sharing hypoxia as a common feature, including cancer, infection, and autoimmunity. Here we introduce a new platform of oxygen nanocarriers, based on 2H,3H-decafluoropentane (DFP) as core fluorocarbon. These new nanocarriers have been named oxygen-loaded nanodroplets (OLNDs) since DFP is liquid at body temperature, unlike gaseous PFP. Dextran-shelled OLNDs, available either in liquid or gel formulations, display spherical morphology, ~600 nm diameters, anionic charge, good oxygen carrying capacity, and no toxic effects on human keratinocytes after cell internalization. In vitro OLNDs result more effective in releasing oxygen to hypoxic environments than former OLNBs, as demonstrated by analysis through oxymetry. In vivo, OLNDs effectively enhance oxy-hemoglobin levels, as emerged from investigation by photoacoustic imaging. Interestingly, ultrasound (US) treatment further improves transdermal oxygen release from OLNDs. Taken together, these data suggest that US-activated, DFP-based OLNDs might be innovative, suitable and cost-effective devices to topically treat hypoxia-associated pathologies of the cutaneous tissues.

Nanoparticles (NPs) are materials with overall dimensions in the nanoscale range. They have unique physicochemical properties, and have emerged as important players in current research in modern medicine. In the last few decades, several types of NPs and microparticles have been synthesized and proposed for use as contrast agents for diagnostics and imaging and for drug delivery; for example, in cancer therapy. Yet specific targeting that will improve their delivery still represents an unsolved challenge. The mechanism by which NPs enter the cell has important implications not only for their fate but also for their impact on biological systems. Several papers in the literature discuss the potential risks related to NP exposure, and more recently the concept that even sublethal doses of NPs may elicit a cell response has been proposed. In this review, we intend to present an overall view of cell mechanisms that may be perturbed by cell-NP interaction. Published data, in fact, emphasize that NPs should no longer be viewed only as simple carriers for biomedical applications, but that they can also play an active role in mediating biological effects.

Under the action of near-infrared radiation, shape anisotropic gold nanoparticles emit two-photon luminescence and release heat. Accordingly, they have been proposed for imaging, photothermal therapies and thermo-controlled drug delivery. In all these applications particular care must be given to control the nanoparticle − cell interaction and the thermal efficiency of the nanoparticles, while minimizing their intrinsic cytotoxicity. We present here the characterization of the cell interaction of newly developed branched gold nanostars, obtained by laurylsulfobetaine-driven seed-growth synthesis. The study provides information on the size distribution, the shape anisotropy, the cellular uptake and cytotoxicity of the gold nanostars as well as their intracellular dynamic behavior by means of two-photon luminescence imaging, fluorescence correlation spectroscopy and particle tracking. The results show that the gold nanostars are internalized as well as the widely used gold nanorods and are less toxic under prolonged treatments. At the same time they display remarkable twophoton luminescence and large extinction under polarized light in the near-infrared region of the spectrum, 800−950 nm. Gold nanostars appear then a valuable alternative to other elongated or in-homogeneous nanoparticles for cell imaging.

When citing, please refer to the published version. MMP-9 and increases TIMP-1 without affecting TIMP-2 secretion, whereas in human 60 keratinocytes it reduces MMP-2, MMP-9, and TIMP-2, without affecting TIMP-1 release. 61Provided that the phenotype of the cellular environment is better understood, chronic wounds 62 might be targeted by new oxygenating compounds such as chitosan-or dextran-shelled and 63 2H,3H-decafluoropentane-cored oxygen-loaded nanodroplets (OLNs). Here, we investigated 64 the effects of hypoxia and dextran-shelled OLNs on the pro-angiogenic phenotype and 65 behavior of human dermal microvascular endothelium (HMEC-1 cell line), another cell 66 population playing key roles during wound healing. Normoxic HMEC-1 constitutively 67 released MMP-2, TIMP-1 and TIMP-2 proteins, but not MMP-9. Hypoxia enhanced MMP-2 68 and reduced TIMP-1 secretion, without affecting TIMP-2 levels, and compromised cell 69 ability to migrate and invade the extracellular matrix. When taken up by HMEC-1, nontoxic 70OLNs abrogated the effects of hypoxia, restoring normoxic MMP/TIMP levels and 71 promoting cell migration, matrix invasion, and formation of microvessels. These effects were 72 specifically dependent on time-sustained oxygen diffusion from OLN core, since they were 73 not achieved by oxygen-free nanodroplets or oxygen-saturated solution. Collectively, these 74 data provide new information on the effects of hypoxia on dermal endothelium and support 75 the hypothesis that OLNs might be used as effective adjuvant tools to promote chronic wound 76 healing processes. 77 78Keywords: oxygen; nanodroplet; matrix metalloproteinase (MMP); tissue inhibitor of 79 metalloproteinase (TIMP); human microvascular endothelial cell (HMEC); skin. 80 5 Introduction 81 82After injury, skin integrity must be restored promptly to reestablish the homeostatic 83 mechanisms, minimize fluid loss, and prevent infection [Greaves et al., 2013]. This is 84 achieved through wound healing, a complex biological process where multiple pathways are 85 simultaneously activated to induce tissue repair and regeneration. Traditionally, acute wound 86 healing is defined as a complex multi-step and multi-cellular process, distinguished in four 87 phases involving different cell types: i) hemostasis, involving platelets; ii) inflammation, 88 involving neutrophils, monocytes, and macrophages; iii) proliferation, involving 89 keratinocytes, endothelial cells, and fibroblasts; and iv) matrix remodeling, involving 90 keratinocytes, myofibroblasts, and endothelial cells. [Diegelmann et al., 2004]. In particular, 91 during the third and fourth phases, the endothelium plays a pivotal role, since wound 92 microvasculature is rebuilt through angiogenesis to restore the supply of oxygen, blood 93 constituents and nutrients to the regenerating tissue, helping to promote fibroplasia and 94 prevent sustained tissue hypoxia [Eming et al., 2014]. Notably, oxygen represents a key 95 regulator of normal wound healing since it is required for collagen deposition, 96 epith...