Collagen and elastin are thought to dominate the elasticity of the connective tissue including lung parenchyma. The glycosaminoglycans on the proteoglycans may also play a role because osmolarity of interstitial fluid can alter the repulsive forces on the negatively charged glycosaminoglycans, allowing them to collapse or inflate, which can affect the stretching and folding pattern of the fibers. Hence, we hypothesized that the elasticity of lung tissue arises primarily from 1) the topology of the collagen-elastin network and 2) the mechanical interaction between proteoglycans and fibers. We measured the quasi-static, uniaxial stress-strain curves of lung tissue sheets in hypotonic, normal, and hypertonic solutions. We found that the stress-strain curve was sensitive to osmolarity, but this sensitivity decreased after proteoglycan digestion. Images of immunofluorescently labeled collagen networks showed that the fibers follow the alveolar walls that form a hexagonal-like structure. Despite the large heterogeneity, the aspect ratio of the hexagons at 30% uniaxial strain increased linearly with osmolarity. We developed a two-dimensional hexagonal network model of the alveolar structure incorporating the mechanical properties of the collagen-elastin fibers and their interaction with proteoglycans. The model accounted for the stress-strain curves observed under all experimental conditions. The model also predicted how aspect ratio changed with osmolarity and strain, which allowed us to estimate the Young's modulus of a single alveolar wall and a collagen fiber. We therefore identify a novel and important role for the proteoglycans: they stabilize the collagen-elastin network of connective tissues and contribute to lung elasticity and alveolar stability at low to medium lung volumes.

The biomechanical properties of connective tissues play fundamental roles in how mechanical interactions of the body with its environment produce physical forces at the cellular level. It is now recognized that mechanical interactions between cells and the extracellular matrix (ECM) have major regulatory effects on cellular physiology and cell-cycle kinetics that can lead to the reorganization and remodeling of the ECM. The connective tissues are composed of cells and the ECM, which includes water and a variety of biological macromolecules. The macromolecules that are most important in determining the mechanical properties of these tissues are collagen, elastin, and proteoglycans. Among these macromolecules, the most abundant and perhaps most critical for structural integrity is collagen. In this review, we examine how mechanical forces affect the physiological functioning of the lung parenchyma, with special emphasis on the role of collagen. First, we overview the composition of the connective tissue of the lung and their complex structural organization. We then describe how mechanical properties of the parenchyma arise from its composition as well as from the architectural organization of the connective tissue. We argue that, because collagen is the most important load-bearing component of the parenchymal connective tissue, it is also critical in determining the homeostasis and cellular responses to injury. Finally, we overview the interactions between the parenchymal collagen network and cellular remodeling and speculate how mechanotransduction might contribute to disease propagation and the development of small- and large-scale heterogeneities with implications to impaired lung function in emphysema.

Abstract-Angiotensin within the central nervous system appears to be important for the maintenance of hypertension in spontaneously hypertensive rats. This study addresses the hypothesis that blockade of AT 1 receptors in the rostral ventrolateral medulla would decrease blood pressure in spontaneously hypertensive rats and that this tonically active AT 1 -mediated input to the rostral ventrolateral medulla arises from the hypothalamic paraventricular nucleus. Injection of the nonpeptide AT 1 receptor antagonist valsartan bilaterally into the rostral ventrolateral medulla of choralose-anesthetized adult spontaneously hypertensive rats produced a dose-related decrease in mean arterial pressure, with a maximal effect of Ϸ30 mm Hg. Inhibition of the paraventricular nucleus by local injection of muscimol elicited a similar response, which was inhibited by prior injection of valsartan into the rostral ventrolateral medulla. In contrast, in control Wistar-Kyoto rats, neither valsartan injected into the rostral ventrolateral medulla nor muscimol injected into the paraventricular nucleus had a substantial effect on arterial pressure. These data indicate that in spontaneously hypertensive rats but not in Wistar-Kyoto rats, rostral ventrolateral medulla vasomotor neurons are tonically excited by endogenous stimulation of AT 1 receptors, and this input is apparently driven from the hypothalamus. These results suggest that the rostral ventrolateral medulla is one site that the brain renin-angiotensin system acts to maintain elevated blood pressure in spontaneously hypertensive rats. The data supporting of a role of brain Ang II in hypertension in the spontaneously hypertensive rats (SHR) are particularly convincing. Specifically, pharmacological disruption of brain angiotensin signaling decreases AP in SHR. 6 -10 Furthermore, there appear to be alterations in SHR in the amount of angiotensin or its receptors in discrete brain regions. 3,4,11,12 Despite this important role of brain Ang II in hypertension, the site (or sites) within the brain at which Ang II acts in this regard is not fully worked out. Certainly, Ang II can act within the hypothalamus to influence cardiovascular regulation. 13 However, Ang II can also act in the caudal brain stem to increase AP and sympathetic outflow. 14 One region in the caudal brain stem that probably mediates some of the central cardiovascular effects of Ang II is the rostral ventrolateral medulla (RVLM). 15,16 The RVLM appears to be the brain site responsible for the maintenance of basal sympathetic vasomotor activity, and inhibition of RVLM neurons reduces AP to the same extent as total inhibition of sympathetic vasomotor activity. Conversely, stimulation of neurons in the RVLM increases AP. There is evidence that increased activity of the RVLM supports the elevated AP in SHR. [17][18][19] The RVLM also has a high density of angiotensin AT 1 receptors. 20 Furthermore, microinjection of Ang II into the RVLM increases AP and sympathetic nerve activity, [21][22][23][24] and stimulation of A...

We demonstrate the first reported methodology using nanowires that unveils massive numbers of cancer-related urinary microRNAs.

Agonists activating β2-adrenoceptors (β2ARs) on airway smooth muscle (ASM) are the drug of choice for rescue from acute bronchoconstriction in patients with both asthma and chronic obstructive pulmonary disease (COPD). Moreover, the use of long-acting β-agonists combined with inhaled corticosteroids constitutes an important maintenance therapy for these diseases. β-Agonists are effective bronchodilators due primarily to their ability to antagonize ASM contraction. The presumed cellular mechanism of action involves the generation of intracellular cAMP, which in turn can activate the effector molecules cAMP-dependent protein kinase (PKA) and Epac. Other agents such as prostaglandin E2 and phosphodiesterase inhibitors that also increase intracellular cAMP levels in ASM, can also antagonize ASM contraction, and inhibit other ASM functions including proliferation and migration. Therefore, β2ARs and cAMP are key players in combating the pathophysiology of airway narrowing and remodeling. However, limitations of β-agonist therapy due to drug tachyphylaxis related to β2AR desensitization, and recent findings regarding the manner in which β2ARs and cAMP signal, have raised new and interesting questions about these well-studied molecules. In this review we discuss current concepts regarding β2ARs and cAMP in the regulation of ASM cell functions and their therapeutic roles in asthma and COPD.

Abstract-Injection of the excitatory amino acid (EAA) antagonist kynurenic acid (KYN) into the rostral ventrolateral medulla (RVLM) of anesthetized rats has no effect on arterial pressure. However, we recently reported that after inhibition of the caudal ventrolateral medulla, injection of KYN into the RVLM decreased arterial pressure to the same level as produced by complete inhibition of the RVLM. We have suggested that these results reflect tonically active EAA-mediated inputs to the RVLM producing both direct excitation of RVLM vasomotor neurons and indirect inhibition of these neurons. On the basis of this model, we hypothesize that the balance between these EAA-driven direct excitatory and indirect inhibitory influences on the RVLM may be altered in models of experimental hypertension. To begin to test this hypothesis, the effects of injecting KYN into the RVLM of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were compared. In chloralose-anesthetized WKY, bilateral injection of KYN into the RVLM did not alter arterial pressure, whereas similar injections in SHR reduced mean arterial pressure by Ϸ40 mm Hg. After inhibition of the caudal ventrolateral medulla, which similarly increased arterial pressure in both strains, injection of KYN into the RVLM reduced mean arterial pressure to the same level as produced by autonomic blockade. These results suggest that the balance of excitatory and inhibitory influences on RVLM vasomotor neurons driven by tonically active EAA-mediated inputs to the RVLM is disrupted in SHR and may contribute to the hypertension in SHR. Key Words: brain Ⅲ hypertension, experimental Ⅲ glutamate Ⅲ neurotransmitter Ⅲ amino acid Ⅲ rats, inbred SHR T he rostral ventrolateral medulla (RVLM) is critical to the tonic and reflexive regulation of arterial blood pressure (AP). Ongoing activity of RVLM-spinal neurons is responsible for the generation of baseline sympathetic vasomotor tone, and acute inhibition of this region causes a marked decrease in AP, similar to that seen in response to cervical spinal cord transection or inhibition of the autonomic nervous system. 1,2 Previous studies demonstrated that local injection into the RVLM of excitatory amino acid (EAA) receptor antagonists has no effect on resting AP, 3-5 and this has been interpreted as indicating that RVLM neuronal activity at rest is not produced by EAA-mediated inputs to the RVLM. However, we have recently reported that although injection of kynurenic acid (KYN) into the RVLM of anesthetized rats had no effect on baseline AP, after inhibition of the caudal ventrolateral medulla (CVLM), a region that tonically inhibits the RVLM, injection of KYN into the RVLM reduced AP to the same extent as total autonomic blockade. 6 On the basis of these results, it was proposed that tonically active EAAmediated inputs to the RVLM excite RVLM vasomotor neurons and also indirectly inhibit these neurons through excitation of an inhibitory input from the CVLM. 6 Thus, we suggested that blockade of EAA receptors in the RVLM re...

Phenylethanolamine-N-methyltransferase (PNMT)-containing neurons in the rostral ventrolateral medulla (RVLM) are believed to play a role in cardiovascular regulation. To determine whether injection of anti-dopamine beta-hydroxylase (DbetaH)-saporin directly into the RVLM in rats could selectively destroy these cells and thereby provide an approach for evaluating their role in cardiovascular regulation, we studied rats 2 wk after unilateral injection of 21 ng anti-DbetaH-saporin into the RVLM. There was an approximately 90% reduction in the number of PNMT-positive neurons in the RVLM, although the number of non-C1, spinally projecting barosensitive neurons of this area was not altered. The A5 cell group was the only other population of DbetaH-containing cells that was significantly depleted. The depressor response evoked by injection of tyramine into the RVLM was abolished by prior injection of toxin. The pressor response evoked by injection of glutamate into the RVLM was attenuated ipsilateral to the toxin injection but was potentiated contralateral to the toxin injection. Thus anti-DbetaH-saporin can be used to make selective lesions of PNMT-containing cells, allowing for the evaluation of their role in cardiovascular regulation.

Sympathoexcitatory neurons in the rostral ventrolateral medulla (RVLM) play a key role in the tonic maintenance of resting arterial pressure. Removal of tonically active inhibitory inputs to the RVLM provided by the caudal ventrolateral medulla (CVLM) elicits a large increase in arterial pressure. The present study addresses the hypothesis that excitatory amino acids (EAA) provide the excitation of the RVLM responsible for the increase in arterial pressure that occurs after withdrawal of CVLM-mediated inhibition of the RVLM. In rats anesthetized with either alpha-chloralose or urethan, inhibition of the CVLM by local injection of muscimol markedly elevated arterial pressure. Subsequent injection of the EAA receptor antagonist kynurenic acid into the RVLM caused arterial pressure to fall to levels comparable to those that occur-with total autonomic blockade. In contrast, injection of kynurenic acid into the RVLM of control rats had little effect on arterial pressure. These results indicate that the large increase in arterial pressure produced by inhibition of the CVLM is mediated by EAA excitation of RVLM neurons. Furthermore, these data suggest that EAA play a prominent role in the tonic excitation of RVLM neurons, but, in intact rats, inhibition of EAA in the RVLM elicits no change in arterial pressure because of removal of inhibitory as well as excitatory drives of the RVLM.