Maya Contreras

Hypercapnic acidosis attenuates pulmonary epithelial wound repair by an NF-κB dependent mechanism

Background: Hypercapnic acidosis exerts protective effects in acute lung injury but may also slow cellular repair. These effects may be mediated via inhibition of nuclear factor-κB (NF-κB), a pivotal transcriptional regulator in inflammation and repair. Objectives: To determine the effects of hypercapnic acidosis in pulmonary epithelial wound repair, to elucidate the role of NF-κB and to examine the mechanisms by which these effects are mediated. Methods: Confluent small airway epithelial cell, human bronchial epithelial cell and type II alveolar A549 cell monolayers were subjected to wound injury under conditions of hypercapnic acidosis (pH 7.0, carbon dioxide tension (Pco2) 11 kPa) or normocapnia (pH 7.37, Pco2 5.5 kPa) and the rate of healing determined. Subsequent experiments investigated the role of hypercapnia versus acidosis and elucidated the role of NF-κB and mitogen-activated protein kinases. The roles of cellular mitosis versus migration and of matrix metalloproteinases in mediating these effects were then determined. Results: Hypercapnic acidosis reduced wound closure (mean (SD) 33 (6.3)% vs 64 (5.9)%, p<0.01) and reduced activation of NF-κB compared with normocapnia. Buffering of the acidosis did not alter this inhibitory effect. Prior inhibition of NF-κB activation occluded the effect of hypercapnic acidosis. Inhibition of ERK, JNK and P38 did not modulate wound healing. Hypercapnic acidosis reduced epithelial cell migration but did not alter mitosis, and reduced matrix metalloproteinase-1 while increasing concentrations of tissue inhibitor of metalloproteinase-2. Conclusions: Hypercapnic acidosis inhibits pulmonary epithelial wound healing by reducing cell migration via an NF-κB dependent mechanism that may involve alterations in matrix metalloproteinase activity.

Hypercapnic acidosis attenuates shock and lung injury in early and prolonged systemic sepsis

Objective:To investigate whether acute hypercapnic acidosis—induced by adding CO2 to inspired gas—would protect against severe systemic sepsis-induced lung and systemic organ injury resulting from cecal ligation and puncture. Acute hypercapnic acidosis protects against lung injury after both nonseptic and early pneumonia-induced lung injury. In contrast, prolonged hypercapnia worsens pneumonia-induced lung injury. The effects of hypercapnia and acidosis in the setting of systemic sepsis remain to be determined. Design:Prospective randomized animal study. Setting:University research laboratory. Subjects:Adult male Sprague-Dawley rats. Interventions:In the early systemic sepsis series, post induction of anesthesia and tracheostomy placement, animals were randomized to normocapnia (Fico2 = 0.00, n = 12) or hypercapnic acidosis (Fico2 = 0.05, n = 12). Cecal ligation and puncture were performed and the animals were ventilated for 3 hrs. In the prolonged systemic sepsis series, rats were anesthetized, cecal ligation and puncture were performed, and the animals were allowed to recover. The animals were then randomized to housing under conditions of environmental normocapnia (Fico2 = 0.00, n = 20) or hypercapnia (Fico2 = 0.08, n = 20). After 96 hrs, the animals were reanesthetized, and the severity of lung and hemodynamic injury was assessed. Results:In early systemic sepsis, hypercapnic acidosis attenuated the development and severity of hypotension, and reduced lactate accumulation and the decrement in central venous oxyhemoglobin levels, compared with normocapnia. Hypercapnic acidosis reduced bronchoalveolar lavage neutrophil infiltration, and lung wet/dry weight ratios. In prolonged systemic sepsis, hypercapnic acidosis reduced histologic indices of lung injury. There was no evidence that hypercapnia worsened prolonged systemic sepsis-induced lung injury. Hypercapnic acidosis did not alter lung or systemic bacterial loads in early or prolonged systemic sepsis. Conclusion:Hypercapnic acidosis exerts beneficial effects in early and prolonged cecal ligation and puncture-induced polymicrobial systemic sepsis.

Hypercapnic acidosis attenuates ventilation-induced lung injury by a nuclear factor-κB-dependent mechanism.

Objectives:Hypercapnic acidosis protects against ventilation-induced lung injury. We wished to determine whether the beneficial effects of hypercapnic acidosis in reducing stretch-induced injury were mediated via inhibition of nuclear factor-&kgr;B, a key transcriptional regulator in inflammation, injury, and repair. Design:Prospective randomized animal study. Setting:University research laboratory. Subjects:Adult male Sprague-Dawley rats. Interventions:In separate experimental series, the potential for hypercapnic acidosis to attenuate moderate and severe ventilation-induced lung injury was determined. In each series, following induction of anesthesia and tracheostomy, Sprague-Dawley rats were randomized to (normocapnia; FICO2 0.00) or (hypercapnic acidosis; FICO2 0.05), subjected to high stretch ventilation, and the severity of lung injury and indices of activation of the nuclear factor-&kgr;B pathway were assessed. Subsequent in vitro experiments examined the potential for hypercapnic acidosis to reduce pulmonary epithelial inflammation and injury induced by cyclic mechanical stretch. The role of the nuclear factor-&kgr;B pathway in hypercapnic acidosis–mediated protection from stretch injury was then determined. Measurements and Main Results:Hypercapnic acidosis attenuated moderate and severe ventilation-induced lung injury, as evidenced by improved oxygenation, compliance, and reduced histologic injury compared to normocapnic conditions. Hypercapnic acidosis reduced indices of inflammation such as interleukin-6 and bronchoalveolar lavage neutrophil infiltration. Hypercapnic acidosis reduced the decrement of the nuclear factor-&kgr;B inhibitor I&kgr;B&agr; and reduced the generation of cytokine-induced neutrophil chemoattractant-1. Hypercapnic acidosis reduced cyclic mechanical stretch-induced nuclear factor-&kgr;B activation, reduced interleukin-8 production, and decreased epithelial injury and cell death compared to normocapnia. Conclusions:Hypercapnic acidosis attenuated ventilation-induced lung injury independent of injury severity and decreased mechanical stretch-induced epithelial injury and death, via a nuclear factor-&kgr;B–dependent mechanism.

Hypercapnia and acidosis in sepsis: a double-edged sword?

Acute respiratory distress syndrome is a devastating disease that causes substantial morbidity and mortality. Mechanical ventilation can worsen lung injury, whereas ventilatory strategies that reduce lung stretch, resulting in a “permissive” hypercapnic acidosis (HCA), improve outcome. HCA directly reduces nonsepsis-induced lung injury in preclinical models and, therefore, has therapeutic potential in these patients. These beneficial effects are mediated via inhibition of the host immune response, particularly cytokine signaling, phagocyte function, and the adaptive immune response. Of concern, these immunosuppressive effects of HCA may hinder the host response to microbial infection. Recent studies suggest that HCA is protective in the earlier phases of bacterial pneumonia-induced sepsis but may worsen injury in the setting of prolonged lung sepsis. In contrast, HCA is protective in preclinical models of early and prolonged systemic sepsis. Buffering of the HCA is not beneficial and may worsen pneumonia-induced injury.

Differential Effects of Buffered Hypercapnia versus Hypercapnic Acidosis on Shock and Lung Injury Induced by Systemic Sepsis

Background:Acute hypercapnic acidosis protects against lung injury caused by nonseptic insults and after both pulmonary and systemic sepsis. The authors wished to dissect the contribution of the acidosis versus hypercapnia per se to the effects of hypercapnic acidosis on the hemodynamic profile and severity of lung injury induced by systemic sepsis. Methods:In the hypercapnic acidosis series, adult male Sprague-Dawley rats were randomized to normocapnia or hypercapnic acidosis—produced by adding 5% carbon dioxide to the inspired gas—and cecal ligation and puncture performed. In the buffered hypercapnia series, animals were first randomized to housing under conditions of environmental normocapnia or hypercapnia—produced by exposure to 8% carbon dioxide—to allow renal buffering. After 96 h, cecal ligation and puncture was performed. In both series, the animals were ventilated for 6 h, and the severity of the lung injury and hemodynamic deterioration were assessed. Results:Both hypercapnic acidosis and buffered hypercapnia attenuated the development and severity of hypotension and reduced lactate accumulation compared to normocapnia. Hypercapnic acidosis reduced lung injury and inflammation, decreased mean (± SD) bronchoalveolar lavage protein concentration (232 ± 50 versus 279 ± 27 μg · ml−1) and median neutrophil counts (3,370 versus 9,120 cells · ml−1), and reduced histologic lung injury. In contrast, buffered hypercapnia did not reduce the severity of systemic sepsis induced lung injury. Conclusions:Both hypercapnic acidosis and buffered hypercapnia attenuate the hemodynamic consequences of systemic sepsis. In contrast, hypercapnic acidosis, but not buffered hypercapnia, reduced the severity of sepsis-induced lung injury.

Evolution of the Inflammatory and Fibroproliferative Responses during Resolution and Repair after Ventilator-induced Lung Injury in the Rat

Background: The time course and mechanisms of resolution and repair, and the potential for fibrosis following ventilation-induced lung injury (VILI), are unclear. We sought to examine the pattern of inflammation, injury, repair, and fibrosis following VILI. Methods: Sixty anesthetized rats were subject to high-stretch; low-stretch, or sham ventilation, and randomly allocated to undergo periods of recovery of 6, 24, 48, and 96 h, and 7 and 14 days. Animals were then reanesthetized, and the extent of lung injury, inflammation, and repair determined. Results: No injury was seen following low-stretch or sham ventilation. VILI caused severe lung injury, maximal at 24 h, but largely resolved by 96 h. Arterial oxygen tension decreased from a mean (SD) of 144.8 (4.1) mmHg to 96.2 (10.3) mmHg 6 h after VILI, before gradually recovering to 131.2 (14.3) mmHg at 96 h. VILI induced an early neutrophilic alveolitis and a later lymphocytic alveolitis, followed by a monocyte/macrophage infiltration. Alveolar tumor necrosis factor-&agr;, interleukin-1&bgr;, and transforming growth factor-&bgr;1 concentrations peaked at 6 h and returned to baseline within 24 h, while interleukin-10 remained increased for 48 h. VILI generated a marked but transient fibroproliferative response, which restored normal lung architecture. There was no evidence of fibrosis at 7 and 14 days. Conclusions: High-stretch ventilation caused severe lung injury, activating a transient inflammatory and fibroproliferative repair response, which restored normal lung architecture without evidence of fibrosis.

Clinical Review: Gene-based therapies for ALI/ARDS: where are we now?

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) confer substantial morbidity and mortality, and have no specific therapy. The accessibility of the distal lung epithelium via the airway route, and the relatively transient nature of ALI/ARDS, suggest that the disease may be amenable to gene-based therapies. Ongoing advances in our understanding of the pathophysiology of ALI/ARDS have revealed multiple therapeutic targets for gene-based approaches. Strategies to enhance or restore lung epithelial and/or endothelial cell function, to strengthen lung defense mechanisms against injury, to speed clearance of infection and to enhance the repair process following ALI/ARDS have all demonstrated promise in preclinical models. Despite three decades of gene therapy research, however, the clinical potential for gene-based approaches to lung diseases including ALI/ARDS remains to be realized. Multiple barriers to effective pulmonary gene therapy exist, including the pulmonary architecture, pulmonary defense mechanisms against inhaled particles, the immunogenicity of viral vectors and the poor transfection efficiency of nonviral delivery methods. Deficits remain in our knowledge regarding the optimal molecular targets for gene-based approaches. Encouragingly, recent progress in overcoming these barriers offers hope for the successful translation of gene-based approaches for ALI/ARDS to the clinical setting.

Permissive hypercapnia: what to remember.

Purpose of review Hypercapnia is a central component of diverse respiratory disorders, while ‘permissive hypercapnia’ is frequently used in ventilatory strategies for patients with severe respiratory failure. This review will present data from recent studies relating to hypercapnia, focusing on issues that are of importance to anesthesiologists caring for the surgical and/or critically ill patient. Recent findings Protective ventilatory strategies involving permissive hypercapnia are widely used in patients with severe respiratory failure, particularly in acute respiratory distress syndrome, status asthmaticus, chronic obstructive pulmonary disease and neonatal respiratory failure. The physiologic effects of hypercapnia are increasingly well understood, and important recent insights have emerged regarding the cellular and molecular mechanisms of action of hypercapnia and acidosis. Acute hypercapnic acidosis is protective in multiple models of nonseptic lung injury. These effects are mediated in part through inhibition of the NF-&kgr;B pathway. Hypercapnia-mediated NF-&kgr;B inhibition may also explain several deleterious effects, including delayed epithelial wound healing and decreased bacterial killing, which has been demonstrated to cause worse lung injury in prolonged untreated pneumonia models. Summary The mechanisms of action of hypercapnia and acidosis continue to be elucidated, and this knowledge is central to determining the safety and therapeutic utility of hypercapnia in protective lung ventilatory strategies.

Hypercapnia: Permissive, Therapeutic, or Not at All?

In the past, hypercapnia and its concomitant hypercapnic acidosis, have been considered to be adverse, and were strictly avoided in the critically ill. Support for this approach derived from concerns regarding the link between hypercapnia and/or acidosis and adverse outcome in diverse clinical contexts, including cardiac arrest, sepsis, and neonatal asphyxia [1]. However, accumulating evidence from experimental and clinical studies demonstrates the potential for mechanical ventilation to directly injure the lungs — a phenomenon termed ‘ventilator-induced lung injury (VILI)’ — and has mandated a rethink of our approaches to hypercapnia.