Microvascular maturation of the septal capillary layers takes place in parallel to alveolarization in human lungs.

Primary and secondary septa formed during lung development contain a double-layered capillary network. To improve gas-exchange the capillary network is remodeled into a single-layered one, a process that is called microvascular maturation (MVM). It takes place during classical and continued alveolarization. Classical alveolarization is defined as a formation of new septa from immature septa and continued alveolarization as a formation from mature septa. Until now, MVM was never quantitatively evaluated in human lungs. To correlate alveolarization and MVM, and to determine the transition point from classical to continued alveolarization, the degree of MVM was stereologically estimated. In 12 human lungs (0.1-15 years) the alveolar surface area of immature and mature septa was estimated stereologically by intersection counting. A MVM-quotient (RMVM) was defined as the mature alveolar surface area over total alveolar surface area. The MVM-quotient increased logarithmically over age and showed a bi-phasic increase similar to alveolarization. It did not reach 100% maturity in these samples. A linear correlation between the MVM-quotient and the logarithm of the number of alveoli was observed. We conclude that MVM increased logarithmically and biphasically in parallel to alveolarization until alveolarization ceased. However, at 2-3 years of age three quarters of the alveolar microvasculature are mature. This result may explain a previous postulate that MVM is finished at this age. We hypothesize that as long as alveolarization takes place, MVM will take place in parallel. We propose that the transition from classical to continued alveolarization takes place between the ages of 1-3 years in humans

The Basement Membrane Zone in Asthma: The Supracellular Anchoring Network.

Thickening of the basement membrane zone (BMZ) is a characteristic feature of airway remodeling in the lungs of asthmatics. However the significance of a thickened BMZ in the pathology of the asthmatic airway is not known. In this review we show that the columnar epithelium is linked to the reticular BMZ through the supracellular anchoring network. We discuss the evidence that changes in the width of the BMZ in control airways are part of a supracellular anchoring mechanism for increasing the strength of attachment between the airway epithelium and the extracellular matrix (ECM). We then review the effects of asthma on this anchoring mechanism. We conclude that both thickening of the BMZ and sloughing of columnar epithelium (creola bodies) in asthma represent abnormalities in the supracellular anchoring network attaching the airway epithelium to the ECM. Future research directed toward studying the regulation and development of the supracellular anchoring network may help better understand sloughing of columnar epithelium and the significance of reticular BMZ thickening in the asthmatic airway

Pulmonary vagal reflexes and breathing pattern are not altered in elastase-induced emphysema in rats

The role of nonmyelinated and myelinated vagal afferents in pulmonary reflexes and breathing pattern was examined in elastase-treated emphysemic rats. Fourteen to 17 days after intratracheal instillation of 1 IU/gm of porcine pancreatic elastase or 0.5 mL of saline, elastase-treated rats had a decreased alveolar surface area to volume of parenchyma (Sv) (42.44 ± 1.7 vs. 31.51 ± 1.1 mm /mm ), increased quasistatic compliance (QSC) (1.05 ± 0.06 vs. 1.25 ± 0.09 mL/cm H O), functional residual capacity (FRC) (4.31 ± 0.10 vs. 5.88 ± 0.37 mL), residual volume (RV) (3.02 ± 0.14 vs. 4.27 ± 0.31 mL), and total lung capacity (TLC) (14,04 ± 0.28 vs. 15.58 ± 0.54 mL). There were no changes in the strength of the pulmonary chemoreflex, the strength of the Hering-Breuer inflation reflex, or breathing pattern before or after vagal perineural capsaicin treatment (VPCT) or vagotomy. There were, however, significant negative correlations between Sv and TLC, FRC and RV, and a near significant (p \u3c .09) negative correlation between Sv and QSC, but no significant correlations between Sv and indices of either the pulmonary chemoreflex or Hering-Breuer inflation reflex. The results indicate that pulmonary vagal nonmyelinated and myelinated reflex activity and breathing pattern are not affected by elastase-induced emphysema in rats. 2 3

Contribution of vagal afferents to breathing pattern in rats with lung fibrosis

In anesthestized male Wistar rats with bleomycin-induced lung fibrosis we examined the influence of lung vagal non-myelinated and myelinated afferents in setting breathing pattern. Fourteen days after intratracheal instillation of bleomycin, lung compliance, total lung capacity (TLC) and inspiratory capacity were reduced while functional residual capacity and residual volume were increased. Baseline tidal volume (V(T)) was decreased and frequency (fR) increased in the bleomycin treated rats compared with controls. Selective vagal C-fiber blockade did not affect fR or V(T) in any group. Vagotomy resulted in an increase in V(T) and decrease in fR in both groups with the percent increase in V(T)/TLC and decrease in fR being significantly greater in the bleomycin rats compared with controls. Vagotomy also attenuated the significantly elevated P(CO2) in the bleomycin treated rats suggesting that bleomycin-induced alterations in breathing pattern contribute to blood gas abnormalities. We conclude that vagal myelinated afferents contribute to the rapid shallow breathing in bleomycin treated rats

Organized lymphatic tissue (BALT) in lungs of rhesus monkeys after air pollutant exposure

The presence of bronchus-associated lymphoid tissue (BALT) and its size in humans largely depends upon age. It is detected in 35% of children less than 2 years of age, but absent in the healthy adult lung. Environmental gases or allergens may have an effect on the number of BALT. Lungs of rhesus macaque monkeys were screened by histology for the presence, size, and location of BALT after exposure to filtered air for 2, 6, 12, or 36 months or 12 and 36 months to ozone or 2, 12, or 36 months of house dust mite or a combination of ozone and house dust mite for 12 months. In the lungs of monkeys housed in filtered air for 2 months, no BALT was identified. After 6, 12, or 36 months, the number of BALT showed a significantly increased correlation with age in monkeys housed in filtered air. After 2 months of episodic house dust mite (HDM) exposure, no BALT was found. Monkeys exposed to HDM or HDM + ozone did not show a significant increase in BALT compared to monkeys housed in filtered air. However, monkeys exposed to ozone alone did show significant increases in BALT compared to all other groups. In particular, there were frequent accumulations of lymphocytes in the periarterial space of ozone exposed animals. In conclusion, BALT in rhesus monkeys housed under filtered air conditions is age-dependent. BALT significantly increased in monkeys exposed to ozone in comparison with monkeys exposed to HDM

Persistence of serotonergic enhancement of airway response in a model of childhood asthma.

The persistence of airway hyperresponsiveness (AHR) and serotonergic enhancement of airway smooth muscle (ASM) contraction induced by ozone (O3) plus allergen has not been evaluated. If this mechanism persists after a prolonged recovery, it would indicate that early-life exposure to O3 plus allergen induces functional changes predisposing allergic individuals to asthma-related symptoms throughout life, even in the absence of environmental insult. A persistent serotonergic mechanism in asthma exacerbations may offer a novel therapeutic target, widening treatment options for patients with asthma. The objective of this study was to determine if previously documented AHR and serotonin-enhanced ASM contraction in allergic monkeys exposed to O3 plus house dust mite allergen (HDMA) persist after prolonged recovery. Infant rhesus monkeys sensitized to HDMA were exposed to filtered air (FA) (n = 6) or HDMA plus O3 (n = 6) for 5 months. Monkeys were then housed in a FA environment for 30 months. At 3 years, airway responsiveness was assessed. Airway rings were then harvested, and ASM contraction was evaluated using electrical field stimulation with and without exogenous serotonin and serotonin-subtype receptor antagonists. Animals exposed to O3 plus HDMA exhibited persistent AHR. Serotonin exacerbated the ASM contraction in the exposure group but not in the FA group. Serotonin subtype receptors 2, 3, and 4 appear to drive the response. Our study shows that AHR and serotonin-dependent exacerbation of cholinergic-mediated ASM contraction induced by early-life exposure to O3 plus allergen persist for at least 2.5 years and may contribute to a persistent asthma phenotype

Behavioral inhibition in rhesus monkeys (Macaca mulatta) is related to the airways response, but not immune measures, commonly associated with asthma.

Behavioral inhibition reflects a disposition to react warily to novel situations, and has been associated with atopic diseases such as asthma. Retrospective work established the relationship between behavioral inhibition in rhesus monkeys (Macaca mulatta) and airway hyperresponsiveness, but not atopy, and the suggestion was made that behavioral inhibition might index components of asthma that are not immune-related. In the present study, we prospectively examined the relationship between behavioral inhibition and airway hyperresponsiveness, and whether hormonal and immune measures often associated with asthma were associated with behavioral inhibition and/or airway hyperresponsiveness. In a sample of 49 yearling rhesus monkeys (mean=1.25 years, n=24 behaviorally inhibited animals), we measured in vitro cytokine levels (IL-4, IL-10, IL-12, IFN-γ) in response to stimulation, as well as peripheral blood cell percentages, cortisol levels, and percentage of regulatory T-cells (CD3+CD4+CD25+FOXP3+). Airway reactivity was assessed using an inhaled methacholine challenge. Bronchoalveolar lavage was performed and the proportion of immune cells was determined. Behaviorally inhibited monkeys had airway hyperresponsiveness as indicated by the methacholine challenge (p=0.031), confirming our earlier retrospective result. Airway hyperresponsiveness was also associated with lower lymphocyte percentages in lavage fluid and marginally lower plasma cortisol concentrations. However, none of the tested measures was significantly related to both behavioral inhibition and airway hyperresponsiveness, and so could not mediate their relationship. Airway hyperresponsiveness is common to atopic and non-atopic asthma and behavioral inhibition has been related to altered autonomic activity in other studies. Our results suggest that behavioral inhibition might index an autonomically mediated reactive airway phenotype, and that a variety of stimuli (including inflammation within lung tissue that is not specifically associated with behavioral inhibition) may trigger the airways response