Pulmonary Immunotoxicology Download Pdf =LINK=

Pulmonary Immunotoxicology Download Pdf =LINK=

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Overall, these data indicate that in utero As exposure reduces infant thymic size and function, likely through inhibiting breast milk trophic factors and/or inducing apoptosis and oxidative stress. These effects may contribute to infant immune deficiency evidenced by increased RTI prevalence. Lack of data supporting a relationship between early-life As exposure and non-pulmonary infections suggests that the developing lung is specifically targeted by As. Furthermore, given increasing evidence of As-associated adverse immune-related outcomes, it is likely that immune disruption resulting from early-life As exposure will have long-term detrimental consequences well into adulthood, as seen in increased prevalence of bronchiectasis and lung, kidney and bladder cancers.

Studies reviewed here show that As significantly impacts both innate and adaptive immune defenses. Likely mechanisms involve altered expression of key immune regulators, induced apoptosis, oxidative stress and inflammation in circulating PBMC, impaired lymphocyte activation and macrophage function, and altered cellular and humoral immunity (Table 1). Specific examples of concordance between epidemiological and experimental data are i) reduced expression of MHC class II molecules, CD69, IL-1β and TNF-α; ii) altered expression of airway adhesion- and migration-related genes/proteins; iii) decreased stimulated lymphocyte proliferation and IL-2 secretion; iv) impaired macrophage adhesion, phagocytosis and stimulated ROS production involving altered Rho A-ROCK signaling; v) induced apoptosis of PBMC; and vi) decreased stimulated ROS production by PBMC (Table 1). These effects can result in immunosuppression, as evidenced by reduced microbial clearance in animals and increased prevalence of opportunistic infections in humans, particularly RTI. Furthermore, epidemiological data suggest marked susceptibility of the lung to perturbation by As, especially during prenatal and childhood development, which results in unprecedented rates of chronic lung diseases, notably lung cancer and bronchiectasis. Experimental data suggest that such pulmonary effects could involve disrupted PAM function and airway remodeling resulting in impaired clearance of pulmonary pathogens. The pleiotropic effects of As on the immune system, including specific examples of compromised immune surveillance such as decreased rejection of MHC mismatched allografts and reduced migration of PBMC, neutrophils and DC to sites of infection in various animal models (Table 2), lend biological plausibility to increased rates of infection, cancers and other immune-related illnesses observed in As-exposed human populations, and are illustrated in Figure 1.

It must also be borne in mind that airborne microplastics may also have an impact on the digestive tract and the immune system. It is known that among airborne particles, the smallest particles (i.e. the inhalable fraction) are absorbed via the pulmonary epithelium [70, 71]. They reach the systemic circulation and exert an immune effect on the so called gut-lung axis [72]. A proportion of the larger particles (the extrathoracic fraction) is transported to the gastrointestinal tract by mucociliary clearance, where it undergoes the fate of ingested particles. Hence, depending of the particle size, both ingested and inhaled plastics are able to interact with intestinal tissues, reach the bloodstream and (potentially) dysregulate the immune response.

Respiratory disease is a leading cause of death, closely following heart disease, stroke and cancer according to the World Health Organization [1]. Despite large investment in research and development of treatments, incidence rates for major respiratory diseases, excluding cancer, such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, asthma and acute lung injury have remained constant or have increased over the last decade [2,3,4].

Although there are no in vivo models that encompass all aspects of the clinical disease pathology of COPD, some notable successes have been documented in animal models of cigarette smoke exposure, elastase-induced emphysema and LPS challenge [69]. Exposure of either guinea pigs or mice to cigarette smoke produces certain characteristics of human COPD, such as emphysema, small airway remodeling, and pulmonary hypertension [69, 70]. However, this model mimics only mild emphysema and usually takes months to develop [69]. Delivery of elastase to the lung rapidly induces emphysematic phenotype in mice, for which disease severity can be controlled by elastase dose, route of administration and duration [69, 71]. The physiological relevance of elastase and LPS models is questionable due to observed differences in mechanism [64, 69, 72].

PCLS have been successfully used to study the early onset of lung fibrosis in IPF. By exposure to TGF-β1 and cadmium chloride, PCLS from human or rat have shown relevant pathohistological changes observed in early lung fibrosis, including upregulation of important pro-fibrotic genes, increased thickness of alveolar septa, and aberrant activation of pulmonary cells [38, 85, 86]. More recently, Alsafadi et al. established an ex vivo human PCLS model of early fibrosis, which requires exposure of PCLS to a combination of profibrotic growth factors and signaling molecules (TGF-β1, TNF-α, platelet-derived growth factor-AB, and lysophosphatidic acid), paving a way to study early-stage IPF pathomechanisms and evaluate novel therapies [29]. In addition, evaluation of novel therapies for IPF treatment using PCLS is currently underway. Caffeine, which inhibits TGF-β-induced increases of profibrotic gene expression, significantly reduces fibrosis in PCLS from bleomycin-treated mice [36]. Moreover, targeting PI3K signaling has been also shown to be a promising anti-fibrotic treatment strategy using IPF patient-derived PCLS [34].

With regards to safety of inhaled therapeutics, key functional aspects and damage are assessed using well-validated pathological readouts on standardized safety studies intended for safety pharmacology assessments [110]. However, less well-defined is the impact on adverse impact on the immune system in the lung, particularly in response to the targeting of anti-inflammatory pathways and immune cell function with inherent risk to host defense. For many years the study of immunotoxicology in the lung has relied on the investigation of ex vivo lung tissues and fluids for cytokine release, basic histopathology to assess immune infiltrates and immune cell phenotyping by flow cytometry on BAL samples or lung tissue digests/disaggregations. Similarly, assessment of host defense in the presence of immunomodulatory drug candidates using preclinical models of lung viral and bacterial infection has been the mainstay of testing for increased infection risk. For this purpose, the type of study will comprise the species and pathogen of relevance to the disease under treatment and a druggable pathway of interest. However, these models are intensive, complex, cumbersome and expensive to undertake, with potential issues of translatability to the targeted human diseased population. The evolution of complex in vitro culture systems might provide a way forward for assessing adverse impact on host defense in a diseased population at an early point in the immunomodulatory drug development timeline. For example, ALI epithelial cultures supplemented with immune cells, and PCLS derived from diseased human lungs, where an immune resident cell component is present, could bridge the translation from preclinical testing to the patient population.

Figure 1. A putative AOP for pulmonary deposition and retention of nanosized foreign matter leading to lung cancer, including anchored in silico and in vitro methods. (A) A putative AOP developed based on information and knowledge about the process-generated and engineered nanoparticles diesel exhaust, carbon black, and TiO2. Suggested relevant existing KEs in the AOP-Wiki, that could serve for informing development of the proposed AOP, are mentioned within parentheses. (B) The AOP supports integrated application of in silico- and in vitro-based standard OECD tests with new approach methodologies (NAMs), including models/approaches for prediction of deposited dose, detection of ROS generation, inflammation, DNA damage, mutations, and cell transformation. Examples of specific assays are provided at the bottom. MIE, molecular initiating event; KE, key event; AO, adverse outcome; AOP, adverse outcome pathway; IC-PMS, inductively coupled plasma mass spectrometry; AAS, atomic absorption spectroscopy; TEM, transmission electron microscopy; ROS, reactive oxygen species; DCFH-DA, 2'-7'dichlorofluorescin diacetate; GSH, glutathione; ELISA, enzyme-linked immunosorbent assay; HT, high-throughput; FPG, formamidopyrimidine DNA glycosylase; OECD, Organization for Economic Co-operation and Development; HPRT, hypoxanthine phosphorybosyl transferase; TK, thymidine kinase; FE1-MML, FE1-MutaMouse lung epithelial cells.

We further evaluated the level of Reactive Oxygen Species (ROS) to know whether Bi2Se3 NPs could induce oxidative stress in the lungs. A time dependent increase in ROS level (Fig. 4j) was observed for day 14 (~7.5 fold), 30 (~17.3 fold) and 90 (~18.6 folds) than the control group; the level, however declined on day 180 to ~12.5 folds. Significant increase in LDH and total protein could imply damage to membrane integrity leading to neutrophil infiltration50, characterized by respiratory burst and substantiate through increased ROS production51. Previous published reports also confirm NP-mediated pulmonary toxicity pertaining to increased cell death, LDH, ALP and total protein activity in BALF20,52,53.

This volume, third in a series on biologic markers, focuses on the human immune system and its response to environmental toxicants. The authoring committee provides direction for continuing development of biologic markers, with strategies for applying markers to immunotoxicology in humans and recommended outlines for clinical and field studies. 2b1af7f3a8