The pulmonary system

Lungs

Lungs exchange O2 and CO2 between the blood and air, and participate in regulation of the pH in the body.

In adult human males, the average weights of the right and left lungs are 445 and 395 g, respectively (Molina & DiMaio, 2012), and the lungs together weight approximately 840 grams. Similar lung weights have been measured by Whimster (1971) and Whimster & MacFarlane (1974). Most of the mass of lungs is due to blood (Brudin et al., 1987). Lungs contain ∼150 mL arterial, 100 mL capillary, and 200 mL venous blood (Thiriet, 2014).

Gas exchange

Air comes to the lungs via trachea, which is divided into bronchi, and further into smaller bronchioles (diameter 0.5-1 mm), ending up in alveoli (diameter 0.2-0.3 mm), where the gases are exchanged. Bronchioles are supported by smooth muscle which can contract or relax as needed. Alveolus is composed of epithelial tissue, formed by type I (squamous) and type II (cuboidal or great) alveolar cells, and macrophages. Squamous cells enable the gas exchange via diffusion, and cuboidal cells secrete surfactant into the lumen to lower the surface tension of water. Alveolus contains collagen and elastic fibres, allowing alveoli to stretch and spring back during inhalation/exhalation cycle. Alveoli are surrounded by dense mesh of blood capillaries. The support for capillaries is weak, causing those to collapse if intraluminal pressure is low or alveolar pressure is increased.

Aquaporins facilitate the transport of O2, CO2, and other gases across cell membranes.

Oxygen transport

At rest, lungs provide about 1 L O2 per min to the tissues via the vascular system, of which only about 1/4 is used. O2 is poorly soluble in water, and therefore about 98% of oxygen is transported as bound to haemoglobin in red blood cells.

Regional hematocrit, as measured using [11C]CO and [methyl-11C]albumin PET, is 0.90 ± 0.01 in the lungs and 0.94 ± 0.02 in thoracic wall in healthy subjects, but lower (0.81-0.86) in patients with pneumonia, anaemia, or pancreatitis (Brudin et al., 1986).

Carbon dioxide transport

CO2 is soluble in water, and about 7% of it in the blood is directly dissolved in the water, 70% is dissolved in water as bicarbonate ion, HCO3-, and the rest is bound to haemoglobin in red blood cells. Carbonic anhydrase (CA) enzymes catalyse the reaction

and transport of HCO3- across membranes is facilitated by anion exchangers.

Circulation

The lungs have two circulations, pulmonary and bronchial circulation.

Pulmonary circulation is part of the vascular system. Pulmonary circulation receives all of the cardiac output; all venous blood is pumped from the right side of the heart via pulmonary arteries to the lungs for the gas exchange before returning via pulmonary veins into the left side of the heart.

Pulmonary capillaries have diameters between 2 and 13 µm, enabling effective exchange of molecules between blood and extravascular volume. Red blood cells are small and highly deformable and can transit rapidly, while more rigid and large white blood cells travel slowly (Doerschuk et al., 1993). Rigid particles with a diameter >10 µm may be permanently trapped in the lung capillaries.

Endothelial walls are normally tight, but inflammation leads to increased permeability.

Bronchial circulation provides oxygenated blood to the walls of pulmonary arteries and veins, bronchi and bronchioles, nerves, lymph nodes, and visceral pleura. It is part of the systemic circulation, but can also contribute to the gas exchange when pulmonary circulation is compromised. On the other hand, pulmonary circulation participates in supplying bronchi and bronchioles with blood flow. Bronchial blood flow is low, only 1-5% of pulmonary circulation. Bronchial arteries are less than 1.5 mm in diameter.

Bronchial smooth muscle cells contain NMDA receptors (subtype of iGluRs in glutamatergic system), regulating smooth muscle contraction.

Immune cells in the lung tissue and airway mucosa mainly enter via the bronchial circulation.

PET imaging of the lungs

Precise attenuation correction of the pulmonary regions from CT is difficult because of the breathing during the relatively long PET scan, while the CT scan used for calculating attenuation correction may record only part of the respiratory cycle. Simulation has suggested that the error can be up to 25% (Holman et al., 2016). Traditional PET transmission scan takes markedly longer time than CT, providing a time-averaged density distribution over several respiratory cycles that matches better with the PET acquisition. Movement artefacts can partially be solved with respiratory gating.

If long axis field of view PET scanner is not available, full lung PET imaging would require scans at more than one bed positions, providing only static images that cannot be analysed using kinetic methods, but steady-state technique must be used instead.

Air and blood in lungs

Tracer concentration in lungs is influenced by volume fractions of air (VA) and blood (VB), which have to be accounted for in quantitative analysis. Concentration in the volume of interest, as measured with PET, (CPET(t)), is the volume fraction weighted sum of concentrations in the air (CA(t)), blood (CB(t)), and lung parenchyma (tissue, CT(t)):

With most tracers we can assume that CA=0, and thus

Lung density (tissue fraction, 1-VA) can be assessed from PET transmission scan or CT (Rhodes et al., 1981; Schuster et al., 1986a and 1986b; Lambrou et al., 2011; Holman et al., 2015; Matsunaga et al., 2017). Regional lung tissue fraction is calculated from equation

where HUR is the mean Hounsfield Unit inside the lung region, HUA is the HU of air (-1024), and HUT is the HU in lung tissue (40, as given by Lambrou et al (2011)).

When combined with PET scan after inhalation of labelled CO, extravascular lung density can be measured (Rhodes et al., 1981). Peripheral lung density, excluding hilar region, is ∼0.28 g/mL, comprising 63% of blood and 37% extravascular tissue (Brudin et al., 1987). Pulmonary blood may comprise >20% of the volume of the ROI, and the density can increase to 0.6-0.7 g/mL in oedema. Tissue fraction is heterogeneous, especially in lung diseases. Results can be normalized for differences in density (regional inflation) by dividing the parameter by the density of the lung region, providing results per gram tissue. (Chen et al., 2004). If both tissue density and blood volume are measured, results can be calculated per extravascular tissue weight, eliminating also the effect of the high blood volume (Chen et al., 2004).

When Patlak plot is to analyse the pulmonary PET data, the resulting Ki can normalized by dividing it by the y axis intercept (Jones et al., 1997; Coello et al., 2017).

Lung water content (regional lung water volume) can be estimated from [15O]H2O PET study. This could be used in the assessment of pulmonary oedema in the process of cardiac radiowater PET.

Input function

Input function for the lungs should be taken from the pulmonary artery or RV cavity of the heart. In FDG studies of the lungs the ROI drawn on RV cavity can be used to derive the input function (Schroeder et al., 2007). Delay correction may need to be ROI specific, and implemented as an additional parameter in the model fitting (Richard et al., 2002; Wellman et al., 2015).

Pulmonary hypertension (PHTN)

Pulmonary hypertension can be caused by disease of the pulmonary arteries ("primary" PHTN), or diseases in other organs ("secondary" PTHN), especially those of the heart. In pulmonary arterial hypertension (PAH), infiltration of inflammatory cells, proliferation of vascular cells, and deposition of extracellular matrix can be seen. Remodelling of the pulmonary vasculature leads to stiffer vessels, reduced perfusion, and increases the workload for the right side of the heart, causing right ventricular (RV) hypertrophy. Metabolism in lung vasculature and RV shifts into aerobic glycolysis, which can be observed as increased [18F]FDG uptake (Hagan et al., 2011; Archer et al., 2013). [18F]FLT could be used to identify patients with active vascular cell proliferation that would benefit from anti-remodelling therapy (Ashek et al., 2018).

Several neuropeptides are implicated in the development of lung disease (Atanasova & Reznikov, 2018), and specific neuropeptide PET tracers could prove useful in the research of these disorders. Adrenomedullin is a neuropeptide which causes vasodilation, reducing blood pressure, and additionally has anti-inflammatory and anti-proliferative activity. Pulmonary vascular endothelium contains high density of adrenomedullin receptors, and circulating adrenomedullin is mainly cleared in the lungs. Adrenomedullin and its receptor density is reduced in pulmonary arterial hypertension. SPECT imaging using adrenomedullin receptor binding radiopharmaceutical [99m]PulmoBind has shown promise for detecting PHTN and pulmonary embolism (Harel et al., 2018). Another adrenomedullin receptor binding radiopharmaceutical, [18F]AlF-DFH17, may be useful for PET imaging of pulmonary microcirculation (Martinez et al., 2018).

Renin-angiotensin-aldosterone system regulates arterial blood pressure. Angiotensin-converting enzyme (ACE) converts angiotensin I into vasoconstrictor angiotensin II, and metabolises vasodilator bradykinin. ACE is highly expressed in endothelial cells of the lungs, affecting systemic blood pressure, but also vascular smooth cell proliferation locally. ACE activity in the lungs has been assessed using 4-cis-[18F]fluorocaptopril ([18F]FCap) (Hwang et al., 1991; Markham et al., 1995; Schuster et al., 1995; Qing et al., 2000).

Pulmonary adrenergic system has been studied by assessing β-AR density using [11C]CGP12177 (Ueki et al., 1993; Hayes et al., 1996; Qing et al., 1996 and 1997).

Pulmonary function

Pulmonary function tests (PFTs), including spirometry, provide noninvasively information about global lung function, and can be used to assess the severity of pulmonary impairment for example in asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. Static lung imaging is already a standard clinical tool enabling the assessment of regional lung function. Improvements in spatial and temporal resolution of imaging systems will allow development of new methods for quantitation of lung physiology (Robertson & Buxton, 2012).

Ventilation imaging can be performed using SPECT or PET with 99mTc (Technegas®) or 68Ga (Galligas) labelled nanoparticles (Nozaki et al., 1995; Kotzerke et al., 2010a and 2010b; Borges et al., 2011; Blanc-Béguin et al., 2021). For pulmonary perfusion imaging, macroaggregated albumin (MAA) can be labelled with the same isotopes. Pulmonary ventilation and perfusion imaging can provide functional lung volumes that correlate well with PFT parameters (Le Roux et al., 2015 and 2017). PET-Galligas and [68Ga]MAA have also been used to develop and validate 4D-CT methods for the lungs (Callahan et al., 2014; Kipritidis et al., 2014; Eslick et al., 2016). Additionally, alveolar ventilation has been assessed using 81mKr and gamma camera, and with PET using inhaled 19Ne or [13N]N2 (Valind et al., 1987 and 1991; Richard et al., 2005; Wellman et al., 2010).

Regional ventilation-to-perfusion ratio can be assessed with [13N]N2 PET. Constant intravenous infusion of [13N]N2 dissolved in saline leads to steady state, where the delivery of tracer by pulmonary circulation is balanced by net removal mainly by ventilation (Rhodes et al., 1989a and 1989b; Brudin et al., 1992, 1994a, and 1994b). Alternatively, bolus injection and compartmental model allows quantitative assessment of regional ventilation-to-perfusion heterogeneity (Vidal Melo et al., 2003; Musch & Venegas, 2005).

Blood volume in lungs can be measured using [11C]CO or [15O]CO (Sörensen et al., 2003).

Pulmonary perfusion can be measured using PET and [15O]H2O (Mintun et al., 1986), [18F]FDG (Pouzot et al., 2013), or [68Ga]DOTA (Velasco et al., 2017). SPECT and DCE CT imaging has been used to estimate blood flow and volume (Hopkins et al., 2012). The use of Gd-DTPA MRI has also been studied (Neeb et al., 2009). Perfusion in normal lungs is extremely high: calculated from the cardiac output and the weight of lungs, blood flow via pulmonary circulation is ∼5-10 mL/(mL min) at rest, and >30 mL/(mL min) during exercise. [15O]H2O PET can also be used to measure lung water content. Pulmonary perfusion and water content is highly heterogeneous, depending on the lung structure and posture.

Inflammation

Pulmonary inflammation is usually assessed with FDG PET (de Prost et al., 2010; Coello et al., 2017). Neutrophilic inflammation is typical in COPD, and can be detected with FDG PET (Jones et al., 2003; Subramanian et al., 2012).

In addition to FDG, PET radiopharmaceuticals targeting TSPO and integrins can be used for imaging inflammation in the lungs (Jones et al., 2003; Chen et al., 2017, 2021; Bitker et al., 2022).

VAP-1 is expressed in endothelial and inflammatory cells in inflamed lungs (Singh et al., 2003). VAP-1 PET ligand [68Ga]DOTA-Siglec-9 has in animal model shown promise to detect pulmonary inflammation (Retamal et al., 2016).

Assessment of inflammation with radiopharmaceuticals may be affected by increased endothelial permeability. In acute lung injury the pulmonary of transcapillary escape rate of [68Ga]transferrin can be ∼10-fold higher than in normal lung tissue (Mintun et al., 1987).

Lung cancer

Bronchogenic malignancies can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC is more common than SCLC, and has relatively good prognosis is detected in early stages. SCLCs are generally wide-spread. Lung cancer commonly leads to metastases in the liver, bone marrow, and adrenal glands. On the other hand, lungs are one of the most common site of metastases of tumours elsewhere.

FDG PET can be used for the diagnosis, staging, therapy planning, and treatment response evaluation (Minn et al., 1995; Acker & Burrell, 2005; Choi et al., 2013; Im et al., 2015). Lung PET imaging requires scans at more than one bed positions, providing only static images that are usually analyzed semi-quantitatively, for example as SUV images or tumour-to-background ratios. FDG cannot differentiate between malignant and inflammatory lesions (Akhurst, 2018), and for instance radiation therapy causes pneumonitis which is FDG avid. [18F]FLT is a thymidine analogue and a marker of cell proliferation. Intratumoral distribution of [18F]FLT and [18F]FDG is different (Wang et al., 2017). [18F]FLT SUV and TBR are not correlated with perfusion in lung cancer, and can be used for analysis of PET data (Frings et al., 2004a and 2014b; Iqbal et al., 2018). [18F]FLT SUV can be used for monitoring the treatment response in NSCLC (McHugh et al., 2018).

Perfusion images in lung cancer can be calculated from [15O]H2O PET data (van der Veldt et al., 2010). In contrast to the healthy lung tissue, arterial blood can be used as input function for lung tumours (van der Veldt et al., 2010).

Hypoxia in lung cancer has been studied using [62Cu]ATSM (Takahashi et al., 2000), [18F]FAZA (Iqbal et al., 2016), [18F]FMISO (McGowan et al., 2017; Schwartz et al., 2017), and [18F]HX4 (van Elmpt et al., 2016).

Integrin αvβ3 is expressed on mature endothelial and epithelial cells, and on tumour cells requiring continuous angiogenesis. Several αvβ3 targeting PET radiopharmaceuticals have been developed, including [68Ga]-DOTA-E-[c(RGDfK)]2 which could be used to assess the response to angiogenesis inhibitors in lung cancer (Arrieta et al., 2018).

Fibroblast activation protein (FAP) specific PET radioligands, such as [68Ga]FAPI, could be used to assess lung cancer and fibrotic interstitial lung diseases (Röhrich et al., 2022).

The uptake of PSMA radioligand [68Ga]PSMA-11 is increased in primary lung cancer, prostate cancer metastases, and tuberculous lesions (Pyka et al., 2016).


See also:


Literature

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Updated at: 2023-09-05
Created at: 2016-05-14
Written by: Vesa Oikonen