Pulmonary adenocarcinoma in a captive ocelot (Leopardus pardalis): morphologic and immunophenotypic characterization - case report

ABSTRACT Pulmonary adenocarcinoma is a malignant epithelial neoplasia that usually arises from conducting airways or alveolar parenchyma. It has rarely been described in wild felids, with no previous reports in ocelots. In domestic cats it is a very aggressive neoplasm with a high metastatic rate that usually evolves to death. This report aimed to describe a pulmonary adenocarcinoma in a captive and senile ocelot (Leopardus pardalis), with a thorough morphologic and immunophenotypically characterization, evidencing the epithelial-mesenchymal transition (EMT) phenomenon in a high metastatic carcinoma, an important feature rarely described in veterinary medicine, even in domestic cats.

Towards a Quantitative Mechanistic Understanding of Localized Pulmonary Tissue Retention—A Combined In Vivo/In Silico Approach Based on Four Model Drugs

Increasing affinity to lung tissue is an important strategy to achieve pulmonary retention and to prolong the duration of effect in the lung. As the lung is a very heterogeneous organ, differences in structure and blood flow may influence local pulmonary disposition. Here, a novel lung preparation technique was employed to investigate regional lung distribution of four drugs (salmeterol, fluticasone propionate, linezolid, and indomethacin) after intravenous administration in rats. A semi-mechanistic model was used to describe the observed drug concentrations in the trachea, bronchi, and the alveolar parenchyma based on tissue specific affinities (Kp) and blood flows. The model-based analysis was able to explain the pulmonary pharmacokinetics (PK) of the two neutral and one basic model drugs, suggesting up to six-fold differences in Kp between trachea and alveolar parenchyma for salmeterol. Applying the same principles, it was not possible to predict the pulmonary PK of indomethacin, indicating that acidic drugs might show different pulmonary PK characteristics. The separate estimates for local Kp, tracheal and bronchial blood flow were reported for the first time. This work highlights the importance of lung physiology- and drug-specific parameters for regional pulmonary tissue retention. Its understanding is key to optimize inhaled drugs for lung diseases.

Distal respiratory tract viral infections in young children trigger a marked increase in alveolar mast cells

Viral infections predispose to the development of childhood asthma, a disease associated with increased lung mast cells (MCs). This study investigated whether viral lower respiratory tract infections (LRTIs) can already evoke a MC response during childhood.Lung tissue from young children who died following LRTIs were processed for immunohistochemical identification of MCs. Children who died from nonrespiratory causes served as controls. MCs were examined in relation to sensitisation in infant mice exposed to allergen during influenza A infection.Increased numbers of MCs were observed in the alveolar parenchyma of children infected with LRTIs (median (range) 12.5 (0–78) MCs per mm2) compared to controls (0.63 (0–4) MCs per mm2, p=0.0005). The alveolar MC expansion was associated with a higher proportion of CD34+ tryptase+ progenitors (controls: 0% (0–1%); LRTIs: 0.9% (0–3%) CD34+ MCs (p=0.01)) and an increased expression of the vascular cell adhesion molecule (VCAM)-1 (controls: 0.2 (0.07–0.3); LRTIs: 0.3 (0.02–2) VCAM-1 per mm2 (p=0.04)). Similarly, infant mice infected with H1N1 alone or together with house dust mite (HDM) developed an increase in alveolar MCs (saline: 0.4 (0.3–0.5); HDM: 0.6 (0.4–0.9); H1N1: 1.4 (0.4–2.0); HDM+H1N1: 2.2 (1.2–4.4) MCs per mm2 (p<0.0001)). Alveolar MCs continued to increase and remained significantly higher into adulthood when exposed to H1N1+HDM (day 36: 2.2 (1.2–4.4); day 57: 4.6 (1.6–15) MCs per mm2 (p=0.01)) but not when infected with H1N1 alone.Our data demonstrate that distal viral infections in young children evoke a rapid accumulation of alveolar MCs. Apart from revealing a novel immune response to distal infections, our data may have important implications for the link between viral infections during early childhood and subsequent asthma development.

Alveolar T-helper type-2 immunity in atopic asthma is associated with poor clinical control

Many patients with asthma remain symptomatic despite treatment with conventional ICSs. The present study shows a link between poor asthma control and a Th2-skewed immunity in the alveolar parenchyma, a region not reached by conventional ICSs.

Depletion of pulmonary EC-SOD after exposure to hyperoxia

Extracellular superoxide dismutase (EC-SOD) is highly expressed in lung tissue. EC-SOD contains a heparin-binding domain that is sensitive to proteolysis. This heparin-binding domain is important in allowing EC-SOD to exist in relatively high concentrations in specific regions of the extracellular matrix and on cell surfaces. EC-SOD has been shown to protect the lung against hyperoxia in transgenic and knockout studies. This study tests the hypothesis that proteolytic clearance of EC-SOD from the lung during hyperoxia contributes to the oxidant-antioxidant imbalance that is associated with this injury. Exposure to 100% oxygen for 72 h resulted in a significant decrease in EC-SOD levels in the lungs and bronchoalveolar lavage fluid of mice. This correlated with a significant depletion of EC-SOD from the alveolar parenchyma as determined by immunofluorescence and immunohistochemistry. EC-SOD mRNA was unaffected by hyperoxia; however, there was an increase in the ratio of proteolyzed to uncut EC-SOD after hyperoxia, which suggests that hyperoxia depletes EC-SOD from the alveolar parenchyma by cutting the heparin-binding domain. This may enhance hyperoxic pulmonary injury by altering the oxidant-antioxidant balance in alveolar spaces.

Dihedral angles of septal “bend” structures in lung parenchyma

Butler, J. P., E. H. Oldmixon, and F. G. Hoppin, Jr.Dihedral angles of septal “bend” structures in lung parenchyma. J. Appl. Physiol. 81: 1800–1806, 1996.—Alveolar parenchyma comprises two interacting tensile systems: the cable system (a network of linear condensations of connective tissue) and the membrane system (a network of quasiplanar alveolar septa). Inferences can be drawn about the mechanics of this structure from its configuration. We reported earlier (E. H. Oldmixon, J. P. Butler, and F. G. Hoppin, Jr. J. Appl. Physiol. 64: 299–307, 1988) that the angles between alveolar septa at the common three-way junctions (J) are nearly uniform, indicating that septal tensions are also nearly uniform. We now report on the interseptal angles at the next most common class of septal junction (B), a structure where two septa meet along a segment of the cable system. We find, first, that the distributions of interseptal angles at B junctions have means >120°, are narrow, and have few, if any, angles <120°. The findings of uniform 120° angles at J junctions and a cutoff below 120° at B junctions are also characteristic of soap films supported on a frame, which follows the physical principle of surface area minimization. We suggest that this principle may be operative in parenchymal development and remodeling.

Lengths and topology of alveolar septal borders

To clarify the mechanics of alveolar parenchyma, we undertook a stereological and topological study in perfusion-fixed canine lungs of the borders of alveolar septa. We defined the principal borders as those along which one septum 1) joins two others (J), 2) joins one other at a distinct angle (B), or 3) joins no other structure (E). E and B borders are invariably reinforced with heavy connective tissue cables; J borders are not. Relative net lengths, determined from the number of traces per section area, were J, 45%; E, 19%; and B, 25%. These were remarkably constant over 10 canine lobes (5 animals, 4 volumes). Parenchyma, then, departs from the simple models that comprise only Js and Es. Bs are important; their net length exceeds that of Es. With lobe deflation, E shortened somewhat more than required to maintain geometric similarity, suggesting that the alveolar duct contracted disproportionately. A three-dimensional reconstruction was made from serial sections, and individual border segments were followed through the reconstruction. Typical lengths of individual J, B, and E borders were nearly equal. To characterize how the network of borders were interconnected, we counted the nodes at which they meet by class, e.g., EBE for the meeting of one B, two Es. The most common are JJJJ, 26%; EEEJ, 10%; EBJ, 24%; EBE, 8%; BBJJ, 12%. If parenchyma were constructed only from free-standing entrance rings and septal junctions, only JJJJ and EEEJ would be anticipated. The presence of EBJ, EBE, and BBJJ underscores parenchymal complexity. Only 7% of septa examined were bordered entirely by Js. Connective tissue cables were not confined to the alveolar duct's lumen but often extended to the primary septa at the periphery of the ductal unit. They rarely linked adjacent alveolar ducts; only 1 in 200 cable segments crossed from one duct to another. These observations support the concept that the parenchyma is an elastic network, characterized in part by a serial mechanical linkage from connective tissue cable to septal membrane to cable again.