Nasal cytokine responses to natural colds in asthmatic children.

BACKGROUND: The mechanisms by which viruses induce asthma exacerbations are not well understood. OBJECTIVE: We characterized fluctuations in nasal aspirate cytokines during naturally occurring respiratory viral infections in children with asthma. METHODS: Sixteen children underwent home collections of nasal aspirates when they were without cold symptoms and again during self-reported respiratory illnesses. The presence of viral infection was ascertained by multiplex PCR. Cytokines were measured using multiplex immune assay. mRNA expression for selected markers of viral infection was measured using RT-PCR. A cumulative respiratory symptom score was calculated for each day of measurement. Generalized estimated equations were used to evaluate associations between viral infection and marker elevation, and between marker elevation and symptom score. RESULTS: The 16 patients completed a total of 37 weeks of assessment (15 'well' weeks; 22 self-assessed 'sick' weeks). Viral infections were detected in 3 of the 'well' weeks and 17 of the 'sick' weeks (10 rhinovirus, three coronavirus, two influenza A, two influenza B, two respiratory syncytial virus, one parainfluenza). Compared to virus-negative well weeks, nasal aspirate IFN-γ, CXCL8/IL-8, CXCL10/IP-10, CCL5/RANTES, CCL11/eotaxin-1, CCL2/MCP-1, CCL4/MIP-1ß, CCL7/MCP-3, and CCL20/MIP3α protein levels increased during virus-positive sick weeks. Only a subset of cytokines (IFN-γ, CXCL8, CCL2, CCL4, CCL5, and CCL20) correlated with self-reported respiratory tract symptoms. While many aspirates were dilute and showed no mRNA signal, viral infection significantly increased the number of samples that were positive for IFN-λ1, IFN-λ2/3, TLR3, RIG-I, and IRF7 mRNA. CONCLUSIONS AND CLINICAL RELEVANCE: We conclude that in children with asthma, naturally occurring viral infections apparently induce a robust innate immune response including expression of specific chemokines, IFNs, and IFN-responsive genes.

Extracellular signal-regulated kinase 7 (ERK7), a novel ERK with a C-terminal domain that regulates its activity, its cellular localization, and cell growth.

Mitogen-activated protein (MAP) kinases play distinct roles in a variety of cellular signaling pathways and are regulated through multiple mechanisms. In this study, a novel 61-kDa member of the MAP kinase family, termed extracellular signal-regulated kinase 7 (ERK7), has been cloned and characterized. Although it has the signature TEY activation motif of ERK1 and ERK2, ERK7 is not activated by extracellular stimuli that typically activate ERK1 and ERK2 or by common activators of c-Jun N-terminal kinase (JNK) and p38 kinase. Instead, ERK7 has appreciable constitutive activity in serum-starved cells that is dependent on the presence of its C-terminal domain. Interestingly, the C-terminal tail, not the kinase domain, of ERK7 regulates its nuclear localization and inhibition of growth. Taken together, these results elucidate a novel type of MAP kinase whereby interactions via its C-terminal tail, rather than extracellular signal-mediated activation cascades, regulate its activity, localization, and function.

Src tyrosine kinase mediates stimulation of Raf-1 and mitogen-activated protein kinase by the tumor promoter thapsigargin.

Thapsigargin is a non-phorbol ester-type tumor promoter that elevates the intracellular Ca2+ (Ca(i)2+) levels by blocking the microsomal Ca2+ ATPase. At present, the consequence of this Ca(i)2+ increase and the nature of the tumorigenicity of thapsigargin still remain to be elucidated. Previously, we demonstrated that thapsigargin activates the mitogen-activated protein (MAP) kinase via Ca(i)2+ but independently of protein kinase C or Ca2+ influx. Here, we show that thapsigargin also rapidly stimulates the Src tyrosine kinase. Transfection of a v-Src gene into a hippocampal cell line (H19-7) renders a constitutive activation of MAP kinase, whereas transfection of a kinase-deficient Src mutant blocks the activation by thapsigargin, suggesting that Src is required for the thapsigargin-induced MAP kinase activation. Cotransfection of a dominant-inhibitory Raf-1 and the v-Src genes into H19-7 cells results in an inhibition of the otherwise constitutively elevated MAP kinase activity, suggesting that Raf-1 is required for the Src-dependent activation of MAP kinase. Similarly, in the LA-90 cells, expression of a temperature-sensitive allele of v-Src constitutively activates Raf-1 and MAP kinase, whereas expression of a dominant-inhibitory Raf-1 mutant abolishes the MAP kinase activation induced by either v-Src or thapsigargin treatment. Together, these results suggest that thapsigargin stimulates MAP kinase signaling via Src and Raf-1. The activation of this Src-MAP kinase pathway suggests a biochemical mechanism for the tumorigenic nature of thapsigargin.

Mitogen-activated signaling and cell cycle regulation in airway smooth muscle.

Increased airway smooth muscle mass has been demonstrated in patients with bronchopulmonary dysplasia and asthma. These data highlight the need for a precise understanding of the events involved in airway smooth muscle mitogenesis. To that end, investigators have developed cell culture systems adopting tracheal and bronchial myocytes from different species. A growing body of literature suggests that common signal transduction pathways regulate airway smooth muscle cell cycle entry across species lines. This review summarizes what is known about mitogen-activated signal transduction in airway smooth muscle cells. The extracellular signal regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI 3-kinase) pathways appear to be major positive regulators of airway smooth muscle proliferation. It is also conceivable that growth factor stimulation of airway smooth muscle simultaneously elicits signaling through negative regulatory pathways such as the p38 mitogen-activated protein (MAP) kinase pathway, perhaps as a safeguard against excessive growth.

Effects of series compliance on twitches superimposed on voluntary contractions.

The activation of skeletal muscle during voluntary isometric contraction has been assessed by measuring the increase in force caused by a superimposed maximal shock to the motor nerve (the twitch-interpolation technique). When the muscle is held isometric, the increase in force with stimulation (superimposed twitch force) decreases with increasing voluntary force, and a line fit through the data can be extrapolated to maximal voluntary force at the zero twitch force axis. In a previous paper we questioned the applicability of this technique in situations where a high series compliance allows the muscle to shorten during the superimposed twitch. To explore effects of series compliance, we measured force of the adductor pollicis during voluntary isometric contractions with noncompliant and compliant loading devices. With the compliant loading device, superimposed twitch force was systematically less than with the noncompliant device, and the plot of superimposed twitch force vs. voluntary force was often concave upward, preventing easy extrapolation to maximal voluntary force. These findings are consistent with force-velocity characteristics of muscle and suggest that twitch-interpolation data must be interpreted with caution when the muscle is not held isometric during the superimposed twitch.

Relative strengths of the chest wall muscles.

We hypothesized that during maximal respiratory efforts involving the simultaneous activation of two or more chest wall muscles (or muscle groups), differences in muscle strength require that the activity of the stronger muscle be submaximal to prevent changes in thoracoabdominal configuration. Furthermore we predicted that maximal respiratory pressures are limited by the strength of the weaker muscle involved. To test these hypotheses, we measured the pleural pressure, abdominal pressure (Pab), and transdiaphragmatic pressure (Pdi) generated during maximal inspiratory, open-glottis and closed-glottis expulsive, and combined inspiratory and expulsive maneuvers in four adults. We then determined the activation of the diaphragm and abdominal muscles during selected maximal respiratory maneuvers, using electromyography and phrenic nerve stimulation. In all subjects, the Pdi generated during maximal inspiratory efforts was significantly lower than the Pdi generated during open-glottis expulsive or combined efforts, suggesting that rib cage, not diaphragm, strength limits maximal inspiratory pressure. Similarly, at high lung volumes, the Pab generated during closed-glottis expulsive efforts was significantly greater than that generated during open-glottis efforts, suggesting that the latter pressure is limited by diaphragm, not abdominal muscle, strength. As predicted, diaphragm activation was submaximal during maximal inspiratory efforts, and abdominal muscle activation was submaximal during open-glottis expulsive efforts at midlung volume. Additionally, assisting the inspiratory muscles of the rib cage with negative body-surface pressure significantly increased maximal inspiratory pressure, whereas loading the rib cage muscles with rib cage compression decreased maximal inspiratory pressure. We conclude that activation of the chest wall muscles during static respiratory efforts is determined by the relative strengths and mechanical advantage of the muscles involved.

Preferential fatigue of the rib cage muscles during inspiratory resistive loaded ventilation.

Because the inspiratory rib cage muscles are recruited during inspiratory resistive loaded breathing, we hypothesized that such loading would preferentially fatigue the rib cage muscles. We measured the pressure developed by the inspiratory rib cage muscles during maximal static inspiratory maneuvers (Pinsp) and the pressure developed by the diaphragm during maximal static open-glottis expulsive maneuvers (Pdimax) in four human subjects, both before and after fatigue induced by an inspiratory resistive loaded breathing task. Tasks consisted of maintaining a target esophageal pressure, breathing frequency, and duty cycle for 3-5 min, after which the subjects maintained the highest esophageal pressure possible for an additional 5 min. After loading, Pinsp decreased in all subjects [control, -128 +/- 14 (SD) cmH2O; with fatigue, -102 +/- 18 cmH2O; P less than 0.001, paired t test]. Pdimax was unchanged (control, -192 +/- 23 cmH2O; fatigue, -195 +/- 27 cmH2O). These data suggest that 1) inability to sustain the target during loading resulted from fatigue of the inspiratory rib cage muscles, not diaphragm, and 2) simultaneous measurement of Pinsp and Pdimax may be useful in partitioning muscle fatigue into rib cage and diaphragmatic components.

Effect of pentoxiphylline on oxygen transport during hypothermia.

At least two investigators have demonstrated a reduction in O2 extraction during induced hypothermia (Cain and Bradley, J. Appl. Physiol. 55: 1713-1717, 1983; Schumacker et al., J. Appl. Physiol. 63: 1246-1252, 1987). We hypothesized that administration of pentoxiphylline (PTX), a theobromine that lowers blood viscosity and has vasodilator effects, would increase O2 extraction during hypothermia. To test this hypothesis, we studied O2 transport in anesthetized, paralyzed, mechanically ventilated beagles exposed to hypoxic hypoxia during either 1) normothermia (38 degrees C), 2) hypothermia (30 degrees C), or 3) hypothermia + PTX (30 degrees C and PTX, 20 mg.kg-1.h-1). Measurements included arterial and mixed venous PO2, hemoglobin concentration and saturation, cardiac output, systemic vascular resistance (SVR), blood viscosity, and O2 consumption (VO2). Critical levels of O2 delivery (DO2, the product of arterial O2 content and cardiac output) were determined by a system of linear regression. Hypothermia significantly decreased base line cardiac output (-35%), DO2 (-37%), and VO2 (-45%), while increasing SVR and blood viscosity. Addition of PTX increased cardiac output (35%) and VO2 (14%), and returned SVR and blood viscosity to normothermic levels. Hypothermia alone failed to significantly reduce the critical level of DO2, but addition of PTX did [normothermia, 11.4 +/- 4.2 (SD) ml.kg-1.min-1; hypothermia, 9.3 +/- 3.6; hypothermia + PTX, 6.6 +/- 1.3; P less than 0.05, analysis of variance]. The O2 extraction ratio (VO2/DO2) at the critical level of DO2 was decreased during hypothermia alone (normothermia, 0.60 +/- 0.13; hypothermia, 0.42 +/- 0.16; hypothermia + PTX, 0.62 +/- 0.19; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Chest wall motion of infants during spinal anesthesia.

To test the extent to which diaphragmatic contraction moves the rib cage in awake supine infants during quiet breathing, we studied chest wall motion in seven prematurely born infants before and during spinal anesthesia for inguinal hernia repair. Infants were studied at or around term (postconceptional age 43 +/- 8 wk). Spinal anesthesia produced a sensory block at the T2-T4 level, with concomitant motor block at a slightly lower level. This resulted in the loss of most intercostal muscle activity, whereas diaphragmatic function was preserved. Rib cage and abdominal displacements were measured with respiratory inductance plethysmography before and during spinal anesthesia. During the anesthetic, outward inspiratory rib cage motion decreased in six infants (P less than 0.02, paired t test); four of these developed paradoxical inward movement of the rib cage during inspiration. One infant, the most immature in the group, had inward movement of the rib cage both before and during the anesthetic. Abdominal displacements increased during spinal anesthesia in six of seven infants (P less than 0.05), suggesting an increase in diaphragmatic motion. We conclude that, in the group of infants studied, outward rib cage movement during awake tidal breathing requires active, coordinated intercostal muscle activity that is suppressed by spinal anesthesia.

Effect of fatigue on maximal inspiratory pressure-flow capacity.

The inspiratory muscles can be fatigued by repetitive contractions characterized by high force (inspiratory resistive loads) or high velocities of shortening (hyperpnea). The effects of fatigue induced by inspiratory resistive loaded breathing (pressure tasks) or by eucapnic hyperpnea (flow tasks) on maximal inspiratory pressure-flow capacity and rib cage and diaphragm strength were examined in five healthy adult subjects. Tasks consisted of sustaining an assigned breathing frequency, duty cycle, and either a "pressure-time product" of esophageal pressure (for the pressure tasks) or peak inspiratory flow rate (for the flow tasks). Esophageal pressure was measured during maximal inspiratory efforts against a closed glottis (Pesmax), maximal transdiaphragmatic pressure was measured during open-glottis expulsive maneuvers (Pdimax), and maximal inspiratory flow (VImax) was measured during maximal inspiratory efforts with no added external resistance before and after fatiguing pressure and flow tasks. The reduction in Pesmax) with pressure fatigue (-25 +/- 7%) was significantly greater than the change in Pesmax with flow fatigue (-8 +/- 8%, P less than 0.01). In contrast, the reductions in Pdimax (-11 +/- 8%) and VImax (-16 +/- 3%) with flow fatigue were greater than the changes in Pdimax (-0.6 +/- 4%, P less than 0.05) or VImax (-3 +/- 4%, P less than 0.05) with pressure fatigue. We conclude that respiratory muscle performance is dependent not only on the presence of fatigue but whether fatigue was induced by pressure tasks or flow tasks. The specific impairment of Pesmax and not of Pdimax or flow with pressure fatigue may reflect selective fatigue of the rib cage muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Exposure of immature rats to hyperoxia increases tracheal smooth muscle stress generation in vitro.

Recently, we demonstrated that chronic exposure to hyperoxia causes in vivo airway muscarinic receptor hyperresponsiveness in the developing rat [Am. J. Physiol. 262 (Lung Cell. Mol. Physiol. 6): L263-L269, 1992]. To test whether airway cholinergic hyperresponsiveness might result from intrinsic alterations in smooth muscle contractility, we measured the effect of in vivo hyperoxia on the contractile force elicited by acetylcholine (ACh) of isometrically mounted tracheal rings in vitro. Tracheal rings were obtained from 3-wk-old rats exposed to air or to > 95% O2 for 8 days. Muscarinic responses were determined by measuring the force elicited by exposure to increasing concentrations of ACh. Responses were normalized to the morphometrically determined tracheal smooth muscle cross-sectional area in a plane perpendicular to the axis of force generation. In vivo O2 exposure significantly increased maximal ACh-induced stress generation (response to 10(-3) M ACh: air, 15.92 +/- 1.37 g/mm2; O2, 21.78 +/- 1.52 g/mm2; P = 0.010). The ACh-induced stress generation of cylinders from hyperoxic rats was substantially reduced by both epithelial removal and treatment with the cyclooxygenase inhibitor indomethacin. We conclude that in vivo hyperoxic exposure increases tracheal smooth muscle contractile function in vitro and that epithelium-derived prostaglandin(s) contributes to the observed increase in maximal contractile responsiveness.

Concentration-dependent effects of cocaine on monoamine-induced constriction of cannulated, pressurized cerebral arteries from fetal sheep.

Drugs, such as cocaine, which may alter monoamine neurotransmitter responsiveness, could adversely affect the regulation of cerebral vasculature. Cocaine exhibits at least two mechanisms that may alter vascular responsiveness: synaptic uptake inhibition, which may augment response to stimulation, and Na+ channel inhibition, which may attenuate response. To help elicit the concentration-dependent effects of cocaine, the effects of cocaine on monoamine neurotransmitter responsiveness were studied in vitro on fetal sheep cerebral arteries (120 days gestation). The changes in diameter of segments of cannulated, pressurized fetal sheep cerebral artery were measured with a videomicroscaler system. Cumulative concentration-response curves (10(-10) to 10(-4)M) were generated for two monoamines, norepinephrine and serotonin, alone and in the presence of cocaine (10(-5) or 10(-4)M). Cocaine caused concentration-dependent alteration of response. At 10(-4)M, cocaine attenuated mean maximal norepinephrine-induced vasoconstriction 46.2% (P < 0.05). At 10(-5)M, cocaine increased sensitivity to norepinephrine (log EC50 decreased -6.63 +/- 0.09 to -7.11 +/- 0.03) and to serotonin (log EC50 decreased -7.24 +/- 0.04 to -7.81 +/- 0.09) (P < 0.05). The higher concentration of cocaine (10(-4)M) did not significantly decrease log EC50 norepinephrine. Cocaine (10(-4)M) also attenuated the response to single doses of norepinephrine (10(-6)M) and serotonin (10(-6)M) by 26.5% and 40.0%, respectively (P < or = 0.05). It is concluded that cocaine has concentration-dependent effects on vasoconstriction of the fetal sheep cerebral artery in vitro. This cocaine-induced alteration of cerebral vascular responsiveness to monoamines may be important in the regulation of fetal cerebral blood flow.

Respiratory insufficiency in newborns with abdominal wall defects.

Respiratory failure in newborns with abdominal wall defects has been attributed to increased intra-abdominal pressure and elevation of the diaphragm after closure. Despite surgical techniques designed to minimize intra-abdominal pressure, we have observed prolonged respiratory insufficiency in several such infants. We reviewed the charts of 108 infants from 1975 to 1982 who had abdominal wall defects: 53 with gastroschisis, 29 with small omphaloceles, 22 with liver-containing or giant omphaloceles (GO), and four with cloacal exstrophy. Nine infants with GO (41%) had prolonged respiratory insufficiency and five died. Infants with GO required longer periods of oxygenation and ventilation (P less than .001, ANOVA) than infants with other abdominal wall defects. Clinical observation suggested that infants with GO have a small, narrow thorax. We obtained detailed measurements from the chest radiographs of infants in all groups. After correction for birth weight, babies with GO had smaller chest widths (P less than .001) and lung areas (P less than .05) than infants with other abdominal wall defects. At autopsy, one newborn with GO was found to have severe pulmonary hypoplasia. Prolonged respiratory insufficiency in infants with GO may be explained by pulmonary hypoplasia and/or by a narrow chest deformity which limits lung expansion.

Airway remodeling: potential contributions of subepithelial fibrosis and airway smooth muscle hypertrophy/hyperplasia to airway narrowing in asthma.

Recently, much attention has been focused on the airway structural changes accompanying chronic, severe asthma, and the potential ramifications of these changes for airway function and medical management. Airway remodeling may exaggerate airway narrowing by: (i) thickening of the airway wall internal to the smooth muscle, thereby increasing the luminal obstruction generated by a given degree of smooth muscle shortening; (ii) increasing the amount of smooth muscle, thereby increasing shortening; and/or (iii) reducing the load on the smooth muscle, either by increasing the compliance of the airway wall or by reducing airway-parenchymal interdependence. The possibility also exists that airway remodeling represents a protective mechanism against excessive airway narrowing. The major airway structural changes occurring in asthma are subepithelial protein deposition and increased airway smooth muscle mass (hypertrophy, hyperplasia, or both). Several investigators have found correlations between the magnitudes of subepithelial thickening and smooth muscle hypertrophy/hyperplasia and the severity of airways disease, though interpretation has been made difficult by study differences in patient population, treatment, indices of disease severity, and morphometric technique. Taken together, these data suggest that increases in airway remodeling may contribute significantly to the airflow obstruction observed in patients with asthma. However, data proving a causal relationship between airway remodeling and asthma severity remain elusive.

Action of the inspiratory muscles of the rib cage during breathing in newborns.

To determine whether the rib cage muscles actively contribute to tidal volume change in infancy, we measured tidal volume (VT), using a pneumotachograph, respiratory gastric pressure swings (Pga), using a liquid-filled gastric catheter, and rib cage and abdominal volume, using respiratory inductive plethysmography in 15 newborns, both before and during 2% CO2-induced hyperventilation. Active rib cage expansion produced by phasic contraction of the inspiratory muscles of the rib cage should reduce respiratory abdominal pressure fluctuations by moving the anterior abdominal wall outward and cephalad, thereby having an expanding influence on the abdominal cavity. During quiet sleep (n = 13), CO2-induced hyperventilation was associated with significant increases in VT, Pga, rib cage volume (Vrc), and abdominal volume (Vab). Increments in Pga were small relative to VT, as shown by an increase in the slope of the VT versus Pga respiratory loop (VT/Pga) in all subjects (p less than 0.001, paired t test). CO2 breathing was associated with an increase in the contribution of the rib cage compartment to total volume change (Vrc/Vrc + Vab) in all infants studied (p less than 0.001, paired t test), and the total volume response to hyperventilation was more strongly related to changes in rib cage volume (slope = 0.62, r = 0.90) than to abdominal volume (slope = 0.31, r = 0.60). During REM sleep (n = 6), mean VT/Pga did not change significantly, and the rib cage contribution to tidal breathing decreased in three of six infants.(ABSTRACT TRUNCATED AT 250 WORDS)

p38 MAP kinase negatively regulates cyclin D1 expression in airway smooth muscle cells.

We have demonstrated that platelet-derived growth factor (PDGF) stimulates p38 mitogen-activated protein (MAP) kinase activation in bovine tracheal myocytes, suggesting that p38 is involved in growth regulation. We therefore examined whether p38 regulates expression of cyclin D1, a G(1) cyclin required for cell cycle traversal. The chemical p38 inhibitors SB-202190 and SB-203580 each increased basal and PDGF-induced cyclin D1 promoter activity and protein abundance. Overexpression of a dominant negative allele of MAP kinase kinase-3 (MKK3), an upstream activator of p38alpha, had similar effects. Conversely, active MKK3 and MKK6, both of which increase p38alpha activity, each decreased transcription from the cyclin D1 promoter. Together, these data demonstrate that p38 negatively regulates cyclin D1 expression. We tested whether p38 regulates cyclin D1 expression via inhibition of extracellular signal-regulated kinase (ERK) activation. Chemical inhibitors of p38 induced modest ERK phosphorylation and activation. However, dominant negative MKK3 was insufficient to activate ERK, and active MKK3 and MKK6 did not attenuate platelet-derived growth factor-mediated ERK activation. These data are consistent with the notion that p38alpha negatively regulates cyclin D1 expression via an ERK-independent pathway.

Cdc42, but not RhoA, regulates cyclin D1 expression in bovine tracheal myocytes.

We previously demonstrated that Rac1 increased cyclin D1 promoter activity in an extracellular signal-regulated kinase (ERK)-independent, antioxidant-sensitive manner. Here, we examined the regulation of cyclin D1 expression by Cdc42 and RhoA. Overexpression of active Cdc42, but not of RhoA, induced transcription from the cyclin D1 promoter. Furthermore, dominant negative Cdc42, but not RhoA, attenuated platelet-derived growth factor-mediated activation of the cyclin D1 promoter. Overexpression of active Cdc42 increased cyclin D1 protein abundance in COS cells. Cdc42-induced cyclin D1 promoter activation was independent of ERK as evidenced by insensitivity to PD-98059, an inhibitor of mitogen-activated protein kinase/ERK kinase (MEK). Furthermore, Cdc42 was neither sufficient nor required for activation of ERK. Similar to Rac1-induced cyclin D1 expression, pretreatment with the antioxidants catalase and ebselen inhibited Cdc42-mediated transcription from the cyclin D1 promoter. Finally, like Rac1, active Cdc42 induced transactivation of the cyclin D1 promoter cAMP response element binding protein/activating transcription factor-2 binding site. Together, these data suggest that in airway smooth muscle cells, Cdc42 and Rac1 share a common signaling pathway to cyclin D1 promoter activation.

Mitogen-activated signaling in cultured airway smooth muscle cells.

Airway hyperresponsiveness and excess smooth muscle mass coexist in patients with asthma and bronchopulmonary dysplasia. This increase in airway smooth muscle mass, which in part relates to smooth muscle proliferation, may increase bronchoconstrictor-induced airway narrowing, even in the absence of excessive force generation. Thus, there is need for a precise understanding of the events involved in airway smooth muscle mitogenesis. This review examines the inflammatory substances and growth factors that induce airway smooth muscle proliferation, and the signaling pathways that may be involved in the transduction of these extracellular signals to the cell nucleus. Also discussed are various antimitogenic substances and potential mechanisms underlying the inhibition of cell proliferation. Central to the discussion are the extracellular signal regulated kinases (ERKs), serine/threonine kinases of the mitogen-activated protein kinase (MAP kinase) superfamily, which upon activation, translocate from the cytoplasm to the nucleus after mitogenic stimulation. Insight gained from studies of cultured airway smooth muscle growth and mitogen-activated signaling may shed light on parallel mechanisms that may operate in asthma and in bronchopulmonary dysplasia, and may lead to therapeutic interventions against airway remodeling.