Elevated Urine Hyaluronan Concentrations Are Associated with an Unfavorable Respiratory Outcome in Preterm Neonates at 40 Weeks Postmenstrual Age.

INTRODUCTION: Hyaluronan (HA) is a major component of the extracellular matrix. Increased pulmonary HA concentrations are associated with several respiratory disorders and is a pathophysiological feature of lung disease. We investigated whether elevated urine HA is a biomarker of an unfavorable 40-week respiratory outcome in preterm infants. METHODS: Infants comprised a cohort of preterm neonates <31 weeks gestational age (GA) from the Prematurity-Related Ventilatory Control (Pre-Vent) multicenter study. HA was quantified in urine obtained at 1 week and 1 month of age. Respiratory status at 40 weeks post-menstrual age (PMA) was classified as unfavorable [either (1) deceased at or before 40 weeks PMA, (2) an inpatient on respiratory medication, O2 or other respiratory support at 40 weeks, or (3) discharged prior to 40 weeks on medications/O2/other respiratory support], or favorable (alive and previously discharged, or inpatient and off respiratory medications, off O2, and off other respiratory support at 40 weeks PMA). The association between urine HA and the unfavorable 40 week PMA outcome was examined using a multivariate logistic generalized estimation equation model. RESULTS: Infants with higher HA at 1 week (but not 1 month) showed increased odds of unfavorable respiratory outcome at 40 weeks PMA (OR [95% CI] = 1.87 per 0.01 mg [1.27, 2.73]). DISCUSSION AND CONCLUSION: Neonatal urine screening for HA could identify infants at risk for death or need for respiratory support at term-corrected age (40 weeks PMA). The relationship between elevated HA at 1 week and an unfavorable 40 week outcome was stronger in infants with lower GA.

Sexual dimorphic vulnerability of respiratory control in a neonatal rodent model of fetal alcohol spectrum disorder.

Fetal alcohol spectrum disorder (FASD) has been linked to numerous poor neurological outcomes as well as impairments in respiratory neural control. Females are known to metabolize ethanol (EtOH) differently than males suggesting a sexual dimorphic sensitivity to EtOH exposure. We used a rodent model of FASD to investigate whether EtOH disrupts respiratory neural control. Rat pups received a single intraperitoneal injection of 2 different doses (0.8 mg/g or 4.4 mg/g) of EtOH. Whole-body plethysmography was used ∼24 h later to assess ventilatory responses to acute hypoxia (HVR) and hypercapnia (HCVR). Females treated with 4.4 mg/g of EtOH exhibited an attenuated HVR and HCVR, but there was no effect on males, and no effect of 0.8 mg/g on either sex. There was unexpected mortality of unknown causes, especially in females, that occurred 2-3 days after EtOH administration. These data suggest that important ventilatory defense responses in females are impaired following developmental EtOH exposure, and this may be associated with increased risk of later death.

Calcium-sensing receptor and CPAP-induced neonatal airway hyperreactivity in mice.

BACKGROUND: Continuous positive airway pressure (CPAP) in preterm infants is initially beneficial, but animal models suggest longer term detrimental airway effects towards asthma. We used a neonatal CPAP mouse model and human fetal airway smooth muscle (ASM) to investigate the role of extracellular calcium-sensing receptor (CaSR) in these effects. METHODS: Newborn wild type and smooth muscle-specific CaSR-/- mice were given CPAP for 7 days via a custom device (mimicking CPAP in premature infants), and recovered in normoxia for another 14 days (representing infants at 3-4 years). Airway reactivity was tested using lung slices, and airway CaSR quantified. Role of CaSR was tested using NPS2143 (inhibitor) or siRNA in WT mice. Fetal ASM cells stretched cyclically with/without static stretch mimicking breathing and CPAP were analyzed for intracellular Ca2+ ([Ca2+]i) responses, role of CaSR, and signaling cascades. RESULTS: CPAP increased airway reactivity in WT but not CaSR-/- mice, increasing ASM CaSR. NPS2143 or CaSR siRNA reversed CPAP effects in WT mice. CPAP increased fetal ASM [Ca2+]I, blocked by NPS2143, and increased ERK1/2 and RhoA suggesting two mechanisms by which stretch increases CaSR. CONCLUSIONS: These data implicate CaSR in CPAP effects on airway function with implications for wheezing in former preterm infants. IMPACT: Neonatal CPAP increases airway reactivity to bronchoconstrictor agonist. CPAP increases smooth muscle expression of the extracellular calcium-sensing receptor (CaSR). Inhibition or absence of CaSR blunts CPAP effects on contractility. These data suggest a causal/contributory role for CaSR in stretch effects on the developing airway. These data may impact clinical recognition of the ways that CPAP may contribute to wheezing disorders of former preterm infants.

Cardiorespiratory anomalies and increased brainstem microglia in a rat model of neonatal opioid withdrawal syndrome.

Infants born with neonatal opioid withdrawal syndrome (NOWS) can display abnormal cardiorespiratory patterns including tachypnea, tachycardia, and impaired ventilatory responses to hypoxia (HVR) and hypercapnia (HCVR). Chronic morphine exposure is associated with increased midbrain microglial expression. Using a rat model of pre- and post-natal morphine exposure, we assessed cardiorespiratory features of NOWS (resting tachycardia and tachypnea) including the attenuated HVR and HCVR and whether they are associated with increased brainstem microglia expression. Pregnant rats (dams) received twice-daily subcutaneous injections of morphine (5 mg/kg) during the third (last) week of pregnancy to simulate 3rd trimester in utero opioid exposure. Offspring then received once-daily subcutaneous injections of morphine (0.5 mg/kg) until postnatal (P) day P10 days of age to simulate postnatal morphine therapy. Cardiorespiratory responses were assessed 24 h later (P11 days) following spontaneous withdrawal. Compared to saline-treated pups, morphine-exposed offspring exhibited tachycardia and tachypnea as well as an attenuated HVR and HCVR. Microglial cell counts were increased in the nucleus tractus solitarius (nTS), dorsal motor nucleus of the vagus (DMNV) and nucleus ambiguous (NAamb), but not the retrapezoid nucleus (RTN) or the non-cardiorespriatory region, the cuneate nucleus (CN). These data suggest that the cardiorespiratory features and autonomic dysregulation in NOWS infants may be associated with altered microglial function in specific brainstem cardiorespiratory control regions.

CPAP-induced airway hyper-reactivity in mice is modulated by hyaluronan synthase-3.

BACKGROUND: Continuous positive airway pressure (CPAP) is a primary mode of respiratory support for preterm infants. Animal studies have shown long-term detrimental effects on lung/airway development, particularly airway (AW) hyper-reactivity, as an unfortunate consequence of neonatal CPAP. Since the hyaluronan (HA) synthesizing enzyme hyaluronan synthase-3 (HAS3) is involved in various adult pulmonary disorders, the present study used a neonatal mouse model to investigate the role of HAS3 in CPAP-induced AW hyper-reactivity. METHODS: Male and female neonatal mice were fitted with a custom-made mask for delivery of daily CPAP 3 h/day for 7 days. At postnatal day 21 (2 weeks after CPAP ended), airway (AW) hyper-reactivity and HAS3 expression were assessed with and without in vitro HAS3 siRNA treatment. RESULTS: MRIs of 3-day-old mice confirmed that CPAP increased lung volume with incrementing inflation pressures. CPAP increased AW reactivity in both male and female mice, which was associated with increased airway smooth muscle and epithelial HAS3 immunoreactivity. CPAP did not affect HA accumulation, but HAS3 siRNA reversed CPAP-induced AW hyper-reactivity and reduced HAS3 expression. CONCLUSIONS: These data in mice implicate a role for HAS3 in long-term effects of CPAP in the developing airway in the context of preterm birth and CPAP therapy. IMPACT: Neonatal CPAP increases airway smooth muscle and epithelial HAS3 expression in mice. CPAP-induced airway hyper-reactivity is modulated by HAS3. These data enhance our understanding of the role mechanical forces play on lung development. These data are a significance step toward understanding CPAP effects on developing airway. These data may impact clinical recognition of the ways that CPAP may contribute to wheezing disorders of former preterm infants.

Prenatal Maternal Lipopolysaccharide and Mild Newborn Hyperoxia Increase Intrapulmonary Airway but Not Vessel Reactivity in a Mouse Model.

Maternal infection is a risk for preterm delivery. Preterm newborns often require supplemental oxygen to treat neonatal respiratory distress. Newborn hyperoxia exposure is associated with airway and vascular hyperreactivity, while the complications of maternal infection are variable. In a mouse model of prenatal maternal intraperitoneal lipopolysaccharide (LPS, embryonic day 18) with subsequent newborn hyperoxia (40% oxygen × 7 days) precision-cut living lung slices were used to measure intrapulmonary airway and vascular reactivity at 21 days of age. Hyperoxia increased airway reactivity to methacholine compared to room air controls. Prenatal maternal LPS did not alter airway reactivity in room air. Combined maternal LPS and hyperoxia exposures increased airway reactivity vs. controls, although maximal responses were diminished compared to hyperoxia alone. Vessel reactivity to serotonin did not significantly differ in hyperoxia or room air; however, prenatal maternal LPS appeared to attenuate vessel reactivity in room air. Following room air recovery, LPS with hyperoxia lungs displayed upregulated inflammatory and fibrosis genes compared to room air saline controls (TNFαR1, iNOS, and TGFß). In this model, mild newborn hyperoxia increases airway but not vessel reactivity. Prenatal maternal LPS did not further increase hyperoxic airway reactivity. However, inflammatory genes remain upregulated weeks after recovery from maternal LPS and newborn hyperoxia exposures.

CPAP protects against hyperoxia-induced increase in airway reactivity in neonatal mice.

BACKGROUND: Oxygen and continuous positive airway pressure (CPAP) are primary modes of respiratory support for preterm infants. Animal models, however, have demonstrated adverse unintended effects of hyperoxia and CPAP on lung development. We investigate the effects of combined neonatal hyperoxia and CPAP exposure on airway function and morphology in mice. METHODS: Newborn mice were exposed to hyperoxia (40% O2) 24 h/day for 7 consecutive days with or without daily (3 h/day) concomitant CPAP. Two weeks after CPAP and/or hyperoxia treatment ended, lungs were assessed for airway (AW) hyperreactivity and morphology. RESULTS: CPAP and hyperoxia exposure alone increased airway reactivity compared to untreated control mice. CPAP-induced airway hyperreactivity was associated with epithelial and smooth muscle proliferation. In contrast, combined CPAP and hyperoxia treatment no longer resulted in increased airway reactivity, which was associated with normalization of smooth muscle and epithelial proliferation to values similar to untreated mice. CONCLUSIONS: Our data suggest that the combination of CPAP and hyperoxia decreases the adverse consequences on airway remodeling of either intervention alone. The complex interaction between mechanical stretch (via CPAP) and hyperoxia exposure on development of immature airways has implications for the pathophysiology of airway disease in former preterm infants receiving non-invasive respiratory support. IMPACT: CPAP and mild hyperoxia exposure alone increase airway reactivity in the neonatal mouse model. In contrast, combined CPAP and hyperoxia no longer induce airway hyperreactivity. Combined CPAP and hyperoxia normalize smooth muscle and epithelial proliferation to control values. Interaction between CPAP-induced stretch and mild hyperoxia exposure on immature airways has important implications for airway pathophysiology in former preterm infants.

Depth Transitions of the Frontal Branch of the Facial Nerve: Implications in SMAS rhytidectomy.

BACKGROUND: Anatomy of the frontal branch of the facial nerve relative to the zygomatic arch and the superficial musculoaponeurotic system (SMAS) has been well described. The variability centers on the location where the frontal branch traverses from a deeper to more superficial plane in the SMAS. The goal of this study is to examine the depth transition of the frontal branch of the facial nerve relative to the zygomatic arch with hopes of pinpointing a caution zone for dissection to avoid nerve injury. METHODS: The frontal branch of the facial nerve was dissected in 36 hemifacial fresh cadaver specimens. Pitanguy's line, the zygomatic arch, and temporal crest were marked. Measurements were taken from the zygomatic arch to the location where the frontal branch pierced the temporoparietal fascia. Locations of the superficial temporal artery (STA), the frontal branch cross relative to the lateral orbital rim and frontalis muscle were also measured. RESULTS: In 94.4% (n = 36) of the specimens, the frontal branch was found to transition to an intra-SMAS plane approximately 9.6 mm above the zygomatic arch. In all specimens, the frontal branch transitioned to an intra-SMAS plane approximately 12.2 mm posterior to Pitanguy's line. CONCLUSIONS: This study describes a surgical "caution zone" centered on a point 9.6 mm above the arch and 12.2 mm posterior to Pitanguy's line, and related to the anterior branch of the STA. We hope this anatomical detail will help to decrease the likelihood of intraoperative injury to the frontal branch of the facial nerve.

Mapping the genicular arteries to provide a caution zone during knee surgery.

INTRODUCTION: Reports from the current literature show a lack of detail with depictions of the genicular arteries (GA). The intricate anatomy and infrequency of operating in the posterior knee may lead to surgeons being unfamiliar with the anatomy. The goal of this cadaveric study was to quantitatively map the arteries and create a caution zone that can be utilized when preparing and performing surgical procedures involving the knee. MATERIALS AND METHODS: The left knees of 46 cadavers were used. The distance of the GAs were from the joint line (JL) (+, superior to JL; -, inferior to JL) was measured in two locations: popliteal artery (PA) branch point and medial/lateral knee. The angle the artery traveled between these two points in the posterior knee was measured. A caution map was created. RESULTS: The superolateral GA branched from PA at +47.3 mm and traveled superiorly at 57.7° to +52.2 mm at the lateral knee. The superomedial GA branched from PA at +55.2 mm and traveled superiorly at 66.8° to +57.3 mm at the medial knee. The inferolateral GA branched from PA at -0.6 mm. It traveled superiorly at 74.1° or inferiorly at 62.1° to -1.0 mm at the lateral knee. The inferomedial GA branched from the PA at +9.9 mm. It traveled inferiorly at 21.2° to -33 mm at the medial knee. CONCLUSION: The GAs have a predictable pattern of location in the knee. There is a mismatch between medical textbooks and reality regarding arterial depictions. Knowledge regarding where the arteries are located may help reduce vascular complications in patients in the future.

Side Variations of Anterior Cruciate Ligament Coronal Angles: Implications for ACL Reconstruction.

Current literature has shown a biomechanical advantage of recreating the native coronal obliquity of the anterior cruciate ligament (ACL) during grating procedures; however, the majority of studies on ACL morphological variation have been performed unilaterally. This cadaveric study aimed to evaluate sided ACL coronal angle of inclination variation including trend analysis with sex, age, height, and femoral condyle width. The ACLs of 57 embalmed cadaveric specimens were evaluated bilaterally for a total of 114 ACLs. The knees were flexed to 110°. A 0.70-mm wire measured coronal angulation through the lateral tibial plateau and the medial ACL border. An image taken of the wire allowed digital measurement with the ImageJ software. IBM SPSS was utilized for statistical analysis. Bilateral measurements demonstrated a difference in an individual's sided ACL angulation (P < 0.001). Right-sided angulation was greater in 61.4% (35/57). In cadavers with greater right-side angulation, right ACLs averaged 66.2° versus left ACLs averaged 60.9° (P < 0.001). Cadavers with greater left-sided ACL angles demonstrated average left ACLs measuring 65.5° versus right ACLs measuring 60.6° (P < 0.001). Right-sided angles were greater in 69.7% of females. Understanding the anatomy of the ACL's native coronal angle and variations between a patient's knees is imperative during reconstruction surgery to aid in anatomic tunnel placement for improved knee motion and rotational knee kinematics following surgery. A statistically significant difference exists between an individual's right and left ACL coronal angles of inclination. Clin. Anat. 32:1102-1106, 2019. © 2019 Wiley Periodicals, Inc.

Acute lung injury in neonatal rats causes postsynaptic depression in nucleus tractus solitarii second-order neurons.

Acute Lung Injury (ALI) alters pulmonary reflex responses, in part due to changes in modulation within the lung and airway neuronal control networks. We hypothesized that synaptic efficacy of nucleus tractus solitarii (nTS) neurons, receiving input from lung, airway, and other viscerosensory afferent fibers, would decrease following ALI. Sprague Dawley neonatal rats (postnatal days 9-11) were given intratracheal installations of saline or bleomycin (a well-characterized model that reproduces the pattern of ALI) and then, one week later, in vitro slices were prepared for whole-cell and perforated whole-cell patch-clamp experiments (postnatal days 16-21). In preparations from ALI rats, 2nd-order nTS neurons had significantly decreased amplitudes of both spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs), compared to saline controls. Rise and decay times of sEPSCs were slower in whole-cell recordings from ALI animals. Similarly, the amplitude of tractus solitarii evoked EPSCs (TS-eEPSCs) were significantly lower in 2nd-order nTS neurons from ALI rats. Overall these results suggest the presence of postsynaptic depression at TS-nTS synapses receiving lung, airway, and other viscerosensory afferent tractus solitarii input after bleomycin-induced ALI.

Effect of preoperative immunonutrition on complications after salvage surgery in head and neck cancer.

BACKGROUND: Patients undergoing salvage surgery for recurrent head and neck squamous cell carcinoma are at high risk of postoperative complications due to the adverse effects of radiotherapy on wound healing. Malnutrition is an additional risk factor and we tested the hypothesis that preoperative administration of immunonutrition would decrease complications in this high risk population. METHODS: This single armed study with historical control included consecutive patients undergoing salvage surgery for recurrent head and neck squamous cell carcinoma. We compared outcomes before and after implementation of preoperative immunonutrition and adjusted the regression analysis for gender, age, body mass index, Nutritional Risk Screening (NRS 2002), tobacco and alcohol consumption, tumor localization, tumor stage, and type of surgery. The primary endpoint was overall complications from surgery within a follow-up of 30 days. RESULTS: Ninety-six patients were included (intervention group: 51, control group: 45). Use of preoperative immunonutrition was associated with a significant reduction in overall complications (35% vs. 58%, fully-adjusted odds ratio 0.30 (95%CI 0.10-0.91, p = 0.034). Length of hospital stay was also significantly reduced (17 days vs. 6 days, p = < 0.001). No differences in mortality and hospital readmission were found. These results remained robust in multivariate analysis. CONCLUSIONS: In patients undergoing salvage surgery for recurrent head and neck squamous cell carcinoma, preoperative immunonutrition exhibited favorable effects on the complication rate and consequently reduced the length of hospital stay. By improving both tissue regeneration and immune response, immunonutrition may help to improve surgical outcomes in this high-risk population.

Effect of preoperative immunonutrition on postoperative short-term outcomes of patients with head and neck squamous cell carcinoma.

BACKGROUND: Patients with head and neck squamous cell carcinoma (HNSCC) often acquire an impaired nutritional status resulting in compromised outcomes. Perioperative immunonutrition may have a positive effect on outcomes after elective surgery. METHODS: Short-term outcomes before and after implementation of preoperative immunonutrition were retrospectively assessed. Regression models adjusted for outcome predictors were used to compare the length of stay (LOS) in the hospital, local infections, and general complications. RESULTS: Four hundred eleven patients were included (control group = 209 and the intervention group = 202). With immunonutrition, hospital LOS was significantly lower (median 6 vs 8 days; adjusted mean difference of -5.65 days; P < .001) and local infections were significantly reduced (7.4% vs 15.3%; adjusted odds ratio [OR] 0.30; P = .006). Subgroup analysis showed more pronounced effects in patients with previous radiotherapy and extensive surgery. CONCLUSION: Patients receiving preoperative immunonutrition had a shorter hospital LOS and a lower rate for wound infections and local complications. These effects remained robust after a multivariate adjustment.

Long-term effects of recurrent intermittent hypoxia and hyperoxia on respiratory system mechanics in neonatal mice.

BACKGROUND: Premature infants are at increased risk for wheezing disorders. Clinically, these neonates experience recurrent episodes of apnea and desaturation often treated by increasing the fraction of inspired oxygen (FIO2). We developed a novel paradigm of neonatal intermittent hypoxia with subsequent hyperoxia overshoots (CIHO/E) and hypothesized that CIHO/E elicits long-term changes on pulmonary mechanics in mice. METHODS: Neonatal C57BL/6 mice received CIHO/E, which consisted of 10% O2 (1 min) followed by a transient exposure to 50% FIO2, on 10-min repeating cycles 24 h/d from birth to P7. Baseline respiratory mechanics, methacholine challenge, RT-PCR for pro and antioxidants, radial alveolar counts, and airway smooth muscle actin were assessed at P21 after 2-wk room air recovery. Control groups were mice exposed to normoxia, chronic intermittent hyperoxia (CIHE), and chronic intermittent hypoxia (CIHO). RESULTS: CIHO/E and CIHE increased airway resistance at higher doses of methacholine and decreased baseline compliance compared with normoxia mice. Lung mRNA for NOX2 was increased by CIHO/E. Radial alveolar counts and airway smooth muscle actin was not different between groups. CONCLUSION: Neonatal intermittent hypoxia/hyperoxia exposure results in long-term changes in respiratory mechanics. We speculate that recurrent desaturation with hyperoxia overshoot may increase oxidative stress and contribute to wheezing in former preterm infants.

A critical postnatal period of heightened vulnerability to lipopolysaccharide.

Evidence of respiratory abnormalities and vulnerability to infection during a critical period of development have been implicated in Sudden Infant Death Syndrome (SIDS). Here we investigated whether the acute hypoxic ventilatory response (HVR) exhibits a heightened vulnerability to the endotoxin lipopolysaccharide (LPS) during a critical period of development. The acute HVR was measured 2h after an i.p. injection of saline or LPS (0.1mg/kg) at various postnatal (P) ages (P5, P10, or P20days). LPS attenuated the early (1-2min) and late (4-6min) phase of the acute HVR in P10 but not P5 or P20 rats. The P10 age group exhibited the largest increase in brainstem TNFα and iNOS mRNA expression following LPS. LPS also caused a higher mortality rate in P10 rats (48%) compared to P5 (12%) and P20 (0%) age groups. After stratifying LPS treated P10 rats into survivors vs non-survivors, only the latter exhibited an attenuated HVR (specifically the early phase). Thus, the heightened vulnerability to endotoxin exposure during this critical period of development is characterized by a depression of the ventilatory response to acute hypoxia in association with an increased incidence of mortality. These data share similarities with some of the circumstances surrounding a SIDS scenario, including evidence of infection, increased brainstem cytokine expression, a disturbance in respiratory control, and a peak incidence of mortality during a critical period of development.

Increased airway reactivity in a neonatal mouse model of continuous positive airway pressure.

BACKGROUND: Continuous positive airway pressure (CPAP) is a primary form of respiratory support used in the intensive care of preterm infants, but its long-term effects on airway (AW) function are unknown. METHODS: We developed a neonatal mouse model of CPAP treatment to determine whether it modifies later AW reactivity. Unanesthetized spontaneously breathing mice were fitted with a mask to deliver CPAP (6 cmH2O, 3 h/day) for 7 consecutive days starting at postnatal day 1. AW reactivity to methacholine was assessed using the in vitro living lung slice preparation. RESULTS: One week of CPAP increased AW responsiveness to methacholine in male, but not female mice, compared to untreated control animals. The AW hyper-reactivity of male mice persisted for 2 wk (at P21) after CPAP treatment ended. Four days of CPAP, however, did not significantly increase AW reactivity. Females also exhibited AW hyper-reactivity at P21, suggesting a delayed response to early (7 d) CPAP treatment. The effects of 7 d of CPAP on hyper-reactivity to methacholine were unique to smaller AWs whereas larger ones were relatively unaffected. CONCLUSION: These data may be important to our understanding of the potential long-term consequences of neonatal CPAP therapy used in the intensive care of preterm infants.

Airway Hyperreactivity Is Delayed after Mild Neonatal Hyperoxic Exposure.

BACKGROUND: Wheezing disorders are prominent in former preterm infants beyond the neonatal period. OBJECTIVES: We used a neonatal mouse model to investigate the time course of airway hyperreactivity in response to mild (40% oxygen) or severe (70% oxygen) neonatal hyperoxia. METHODS: After hyperoxic exposure during the first week of postnatal life, we measured changes in airway reactivity using the in vitro living lung slice preparation at the end of exposure [postnatal day 8 (P8)] and 2 weeks later (P21). This was accompanied by measures of smooth muscle actin, myosin light chain (MLC) and alveolar morphology. RESULTS: Neither mild nor severe hyperoxia exposure affected airway reactivity to methacholine at P8 compared to normoxic controls. In contrast, airway reactivity was enhanced at P21 in mice exposed to mild (but not severe) hyperoxia, 2 weeks after exposure ended. This was associated with increased airway α-smooth muscle actin expression at P21 after 40% oxygen exposure without a significant increase in MLC. Alveolar morphology via radial alveolar counts was comparably diminished by both 40 and 70% oxygen at both P8 and P21. CONCLUSIONS: These data demonstrate that early mild hyperoxia exposure causes a delayed augmentation of airway reactivity, suggesting a long-term alteration in the trajectory of airway smooth muscle development and consistent with resultant symptomatology.

Intrapulmonary lipopolysaccharide exposure upregulates cytokine expression in the neonatal brainstem.

UNLABELLED: Perinatal inflammation and neonatal sepsis trigger lung and brain injury. We hypothesized that endotoxin exposure in the immature lung upregulates proinflammatory cytokine expression in the brainstem and impairs respiratory control. Lipopolysaccharide (LPS) or saline was administered intratracheally to vagal intact or denervated rat pups. LPS increased brainstem IL-1ß and vagotomy blunted this response. There was an attenuated ventilatory response to hypoxia and increased brainstem IL-1ß expression after LPS. CONCLUSION: Intratracheal endotoxin exposure in rat pups is associated with upregulation of IL-1ß in the brainstem that is vagally mediated and associated with an impaired hypoxic ventilatory response.

Airway inflammation and central respiratory control: results from in vivo and in vitro neonatal rat.

In infants, respiratory infection elicits tachypnea. To begin to evaluate the role of brainstem cytokine expression in modulation of breathing pattern changes, we compared the pattern generated after endotracheal instillation of lipopolysaccharide (LPS) in in vivo rat pups to local pro-inflammatory cytokine injection in the nucleus tractus solitarius (nTS) in an in vitro en bloc brainstem spinal cord preparation. We hypothesized that both challenges would elicit similar changes in patterning of respiration. In anesthetized, spontaneously breathing rat pups, lipopolysaccharide (LPS) or saline was instilled in the airway of urethane-anesthetized rats (postnatal days 10-11). We recorded diaphragm EMG over the subsequent 2h and saw a 20-30% decrease in interburst interval (Te) at 20-80min post-injection in LPS-instilled animals with no significant change in Ti. In contrast, IL-1ß injections into the nTS of en bloc in vitro brainstem-spinal cord preparations from 0 to 5 day-old pups maintained Ti and caused an increase in Te as early as 20min later, decreasing frequency for 80-120min after injection. Our results suggest that the neonatal respiratory response to the cytokine IL-1ß mediated inflammatory response depends on the site of the inflammatory stimulus and that the direct effect of IL-1ß in the nTS is to slow rather than increase rate.