Cigarette smoke initiates an inflammatory response that has aftermath long after quitting. We segregated former smokers, according to their lung function and their co-founding diseases, in 3 groups: Cancer, Emphysema and COPD. Then we searched for outlier genes in intersections of Venn diagrams where we identified 6 subsets and 23 genes that may be responsible for disease outcome. Genes expressed in the cancer patients with or without emphysema (PPA subset) were BHLH, FPRL2, CD49D, DEADH, NRs4A3, MBLL, GNS, BE675435, ISGF-3, and FLJ23462. Patients with emphysema as co-founding disease, with or without cancer (APP), had only ANXA2 in common. Genes expressed only in non-cancer patients (AAP subset) of COPD group were IL-1A, SOX13, RPP38; TBXA2R, NPEPL1, CFLAR, TFEB, PRKCBP1, IGF1R, DDX11, and KCNAB1. HIV-1Rev was the gene expressed in cancer patients with emphysema (APA subset). Then, we also looked at out-layers genes significantly expressed in all patients (PPP subset with 5066 genes), the down-regulated in Emphysema were MMP9, PLUNC, CEACAM5, and NR4A1 while the up-regulated were F2R, COL15A1, PDE4C, and BGN. We chose genes and checked them at the protein level on immune cells, this showed that neutrophils from Cancer group had increased expression of CD49d, and their total number was also increased in bronchial-alveolar lavage (154%). Macrophages in the lung of patients with emphysema were associated with a significant increase of adhesion molecule CD58 and to significant CD95 decrease, indicating they do not die. Besides, macrophages downregulated MMP9 in the lung compared to blood macrophages. Overall, we find that cancer progression requires a stickier and greater number of neutrophils in the lung while emphysema requires stickier and longevous macrophages to lead matrix destruction, and together with higher expression of SOX13 and RPP38, may promote autoimmunity. We also identified two genes, ANXA2 and HIV1-rev, that may be a pivot between cancer and emphysema outcome of inflammation.

Asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) are all chronic pulmonary diseases, albeit with different etiologies, that are characterized by airflow limitation, chronic inflammation, and abnormal mucus production/rheology. Small synthetic molecule-based therapies are commonly prescribed for all three diseases. However, there has been increased interest in \"biologicals\" to treat these diseases. Biologicals typically constitute protein- or peptide-based therapies and are often more potent than small molecule-based drugs. In this review, we shall describe the pros and cons of several different biological-based therapies for respiratory disease, including dornase alfa, a recombinant DNAase that reduces mucus viscosity and short palate lung and nasal epithelial clone 1 (SPLUNC1)-derived peptides that treat Na(+) hyperabsorption and rebalance CF airway surface liquid homeostasis.

Hepatoid or α-fetoprotein (AFP)-producing adenocarcinomas of stomach growing in a solid pattern are highly aggressive tumors. It is difficult to detect hepatoid differentiation solely based on findings from hematoxylin and eosin stainings, especially in small biopsy specimens. Gastric adenocarcinomas with hepatoid differentiation should be distinguished from solid-type gastric adenocarcinoma because of their different biological behavior. We immunohistochemically analyzed hepatocellular markers (AFP, glypican 3, and Hepatocyte paraffin 1 [HepPar-1]) and possible markers of gastric hepatoid adenocarcinoma (Sal-like protein 4 [SALL4] and palate, lung, and nasal epithelium carcinoma-associated protein [PLUNC]) to detect hepatoid differentiation in 45 gastric hepatoid adenocarcinomas and 47 nonhepatoid solid-type poorly differentiated adenocarcinomas. There were a higher incidence of vascular invasion (P = .0055) and distant metastasis (P = .0458) in hepatoid adenocarcinoma than in nonhepatoid adenocarcinoma. AFP, SALL4, HepPar-1, and glypican 3 were significantly higher in hepatoid adenocarcinoma than in nonhepatoid adenocarcinoma. All 5 markers were positive in both the hepatoid/solid and the tubular component. In hepatoid adenocarcinoma, the frequency of distant metastasis was significantly higher in SALL4-negative cases than in SALL4-positive cases (P = .0381). HepPar-1 was associated with liver metastasis (P = .0452). PLUNC was correlated with lymph node metastasis (P = .0375). There was a significant difference in the survival rate between HepPar-1-positive and HepPar-1-negative groups (P = .0437). The coexpression of PLUNC and SALL4 and the other coexpression of HepPar-1 and PLUNC were associated with poorer prognosis (P = .0181 and P = .0443, respectively). AFP, SALL4, HepPar-1, and glypican 3 are useful for the detection of hepatoid differentiation. A combination of PLUNC, HepPar-1, and SALL4 could be a reliable prognostic indicator in hepatoid adenocarcinoma of the stomach.

The epithelia that line the conducting airways are the lung\'s first point of contact with inhaled pathogens and toxicants. As such, they are known to play an important role in the lung\'s innate defense system, which includes (i) the production of airway surface liquid (ASL) that helps cleanse the airways through the physical removal of pathogens and toxicants on the mucociliary escalator and (ii) the secretion of anti-microbial proteins into the ASL to kill inhaled pathogens. Interestingly, the recently crystallized short palate lung and nasal epithelial clone 1 (SPLUNC1) protein appears to be a multi-functional protein. That is, it not only acts as an anti-microbial agent, but also modulates ASL homeostasis by acting as an endogenous inhibitor of the epithelial Na(+) channel (ENaC). This review will focus on the latter function of SPLUNC1, and will discuss new structural and physiological data regarding SPLUNC1\'s failure to function as a regulator of ASL hydration in CF airways.

The \'transiently expressed in neural precursors\' (TENP) gene product is a member of the bacterial/permeability-increasing (BPI) family of antimicrobial proteins but was first identified as having a role in an early neurological event occurring in post-mitotic cells. However, recent characterisation of the egg white proteome has shown that TENP is an important egg component constituting ~0.1-0.5% of the total protein and suggesting it is expressed in the adult oviduct. In this study we confirmed quantitatively that the expression of TENP is largely confined to the tubular glands of the magnum of the oviduct, where egg white synthesis occurs, with around 10,000 times more expression than in the embryo where TENP was first identified. TENP expression is significantly increased with the administration of oestrogen or progesterone (P<0.001) and is reduced in regressed oviducts (P<0.001) demonstrating gonadal steroid control, typical of an oviduct and egg specific gene. A putative translational start site for TENP has been characterised and the evidence indicates that it is expressed as one predominant transcript. In comparison with the published sequence, insertion and deletion events have been identified causing a partial frame-shift that results in an altered amino acid sequence to that previously documented. TENP is conserved across divergent avian species being found in chicken, turkey, duck and zebra finch and its expression profile confirmed in both chicken and duck. Similarity searches have shown homology with the BPI-like family of innate immune genes, particularly with palate, lung and nasal epithelial clone (PLUNC) members of this family. We therefore believe that at least in adults the role of TENP is as a major component of egg, particularly the white and it is probable that it contributes to its antimicrobial function.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with aberrant host defense responses. However, whether innate immunity is similarly impaired in patients with eosinophilic and those with noneosinophilic CRSwNP remains unclear.
OBJECTIVE: We sought to evaluate the expression and possible modulation of short palate, lung, and nasal epithelium clone 1 (SPLUNC1), an innate immune molecule, in the 2 CRSwNP subsets.
METHODS: Polyp tissue and uncinate processes were collected from 40 patients with CRSwNP, 27 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 22 control subjects. Expression of SPLUNC1; Toll-like receptor (TLR) 2, TLR3, and TLR4; and the proinflammatory cytokines IL-1α, IL-4, IL-13, IL-17A, and IFN-γ was examined in nasal tissues. Additionally, SPLUNC1 expression in response to specific inflammatory stimulation was measured in cultured polyp epithelial cells and A549 cells.
RESULTS: Polyp tissues exhibited significantly decreased expression of SPLUNC1 and other innate immune molecules compared with uncinate process tissues from patients with CRSwNP (P < .05), patients with CRSsNP, and healthy control subjects. Moreover, the eosinophilic CRSwNP subset exhibited significantly decreased SPLUNC1 expression and numbers of submucosal glands, as well as significantly increased IL-4 and IL-13 mRNA levels, compared with the noneosinophilic subset (P < .05). Accordingly, SPLUNC1 expression in polyp epithelial cells was significantly inhibited by IL-4 and IL-13 stimulation in vitro but was significantly upregulated after stimulation with TLR agonists and glucocorticoids (P < .05).
CONCLUSIONS: Differential SPLUNC1 suppression between the eosinophilic and noneosinophilic CRSwNP subsets suggests that they possess distinct pathogenic mechanisms. This finding might benefit the design of appropriate therapeutic interventions targeted to each subset.